Goodman and Gilman Manual of Pharmacology and Therapeutics
Chemotherapy of Neoplastic Diseases
I. Alkylating Agents and Platinum Coordination Complexes
In 1942, Louis Goodman and Alfred Gilman, the originators of this text, began clinical studies of intravenous nitrogen mustards in patients with lymphoma, launching the modern era of cancer chemotherapy. Six major types of alkylating agents are used in the chemotherapy of neoplastic diseases:
• Nitrogen mustards
• Alkyl sulfonates
• The triazenes
• DNA-methylating drugs, including procarbazine, temozolomide, and dacarbazine
In addition, because of similarities in their mechanisms of action and resistance, platinum complexes are discussed with classical alkylating agents, even though they do not alkylate DNA but instead form covalent metal adducts with DNA.
The chemotherapeutic alkylating agents have in common the property of forming highly reactive carbonium ion intermediates. These reactive intermediates covalently link to sites of high electron density, such as phosphates, amines, sulfhydryl, and hydroxyl groups. Their chemotherapeutic and cytotoxic effects are directly related to the alkylation of reactive amines, oxygens, or phosphates on DNA. The general mechanisms actions of alkylating agents on DNA are illustrated in Figure 61–1 with mechlorethamine (nitrogen mustard). The extreme cytotoxicity of bifunctional alkylators correlates very closely with interstrand cross-linkage of DNA.
Figure 61–1 Mechanism of action of alkylating agents. A. Activation reaction. B. Alkylation of N7 of guanine.
The ultimate cause of cell death related to DNA damage is not known. Specific cellular responses include cell-cycle arrest and attempts to repair DNA. The specific repair enzyme complex utilized will depend on 2 factors: the chemistry of the adduct formed and the repair capacity of the cell involved. The process of recognizing and repairing DNA generally requires an intact nucleotide excision repair (NER) complex, but may differ with each drug and with each tumor. Alternatively, recognition of extensively damaged DNA by p53 can trigger apoptosis. Mutations of p53 lead to alkylating agent resistance.
Structure-Activity Relationships. Although these alkylating agents share the capacity to alkylate biologically important molecules, modification of the basic chloroethylamino structure changes reactivity, lipophilicity, active transport across biological membranes, sites of macromolecular attack, and mechanisms of DNA repair, all of which determine drug activity in vivo. With several of the most valuable agents (e.g., cyclophosphamide, ifosfamide), the active alkylating moieties are generated in vivo through hepatic metabolism (Figure 61–2). Consult Chapter 61 of the 12th edition of the parent text for details on metabolic activation and structure-activity relationships among these compounds.
Figure 61–2 Metabolic activation of cyclophosphamide. Cyclophosphamide is activated (hydroxylated) by CYP2B, with subsequent transport of the activated intermediate to sites of action. The selectivity of cyclophosphamide against certain malignant tissues may result in part from the capacity of normal tissues to degrade the activated intermediates via aldehyde dehydrogenase, glutathione transferase, and other pathways. Ifosfamide is structurally similar to cyclophosphamide: whereas cyclophosphamide has 2 chloroethyl groups on the exocyclic nitrogen atom, 1 of the 2-chloroethyl groups of ifosfamide is on the cyclic phosphoramide nitrogen of the oxazaphosphorine ring. Ifosfamide is activated by hepatic CYP3A4. The activation of ifosfamide proceeds more slowly, with greater production of de-chlorinated metabolites and chloroacetaldehyde. These differences in metabolism likely account for the higher doses of ifosfamide required for equitoxic effects, the greater neurotoxicity of ifosfamide, and perhaps differences in the antitumor spectra of cyclophosphamide and ifosfamide.
The newest approved alkylating agent, bendamustine, has the typical chloroethyl reactive groups attached to a benzimidazole backbone. The unique properties and activity of this drug may derive from this purine-like structure; the agent produces slowly repaired DNA cross-links, lacks cross-resistance with other classical alkylators, and has significant activity in chronic lymphocytic leukemia (CLL) and large-cell lymphomas refractory to standard alkylators. One class of alkylating agents transfers methyl rather than ethyl groups to DNA. The triazene derivative 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, usually called dacarbazine or DTIC, is prototypical of methylating agents. Dacarbazine requires initial activation by hepatic CYPs through an N-demethylation reaction. In the target cell, spontaneous cleavage of the metabolite, methyl-triazeno-imidazole-carboxamide (MTIC), yields an alkylating moiety, a methyl diazonium ion. A related triazene, temozolomide, undergoes spontaneous, nonenzymatic activation to MTIC and has significant activity against gliomas.
The nitrosoureas, which include compounds such as 1,3-bis-(2-chloroethyl)-1-nitrosourea (carmustine [BCNU]), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (lomustine [CCNU]), and its methyl derivative (semustine [methyl-CCNU]), as well as the antibiotic streptozocin (streptozotocin), exert their cytotoxicity through the spontaneous breakdown to an alkylating intermediate, the 2-chloroethyl diazonium ion. As with the nitrogen mustards, interstrand cross-linking appears to be the primary lesion responsible for the cytotoxicity of nitrosoureas. The reactions of the nitrosoureas with macromolecules are shown in Figure 61–3.
Figure 61–3 Generation of alkylating and carbamylating intermediates from carmustine (BCNU). The 2-chloroethyl diazonium ion, a strong electrophile, can alkylate guanine, cytidine, and adenine bases. Displacement of the halogen atom that can then lead to interstrand or intrastrand cross-linking of DNA. The formation of cross-links after the initial alkylation reaction proceeds slowly and can be reversed by the DNA repair enzyme O6-alkyl, methyl guanine methyltransferase (MGMT), which displaces the chloroethyl adduct from its binding to guanine in a suicide reaction. The same enzyme, when expressed in human gliomas, produces resistance to nitrosoureas and to other methylating agents, including DTIC, temozolomide, and procarbazine.
Stable ethyleneimine derivatives have antitumor activity; triethylenemelamine (TEM) and triethylenethiophosphoramide (thiotepa) have been used clinically. In standard doses, thiotepa produces little toxicity other than myelosuppression; it also is used for high-dose chemotherapy regimens, in which it causes both mucosal and CNS toxicity. Altretamine (hexamethylmelamine [HMM]) is chemically similar to TEM. The methylmelamines are N-demethylated by hepatic microsomes with the release of formaldehyde; there is a direct relationship between the degree of the demethylation and their antitumor activity in model systems.
Esters of alkane sulfonic acids alkylate DNA through the release of methyl radicals. Busulfan is of value in high-dose chemotherapy.
GENERAL PHARMACOLOGICAL ACTIONS
Cytotoxic Actions. The capacity of alkylating agents to interfere with DNA integrity and function and to induce cell death in rapidly proliferating tissues provides the basis for their therapeutic and toxic properties. Acute effects manifest primarily against rapidly proliferating tissues; however, certain alkylating agents may have damaging effects on tissues with normally low mitotic indices (e.g., liver, kidney, and mature lymphocytes); effects in these tissues usually are delayed. Lethality of DNA alkylation depends on the recognition of the adduct, the creation of DNA strand breaks by repair enzymes, and an intact apoptotic response. In non-dividing cells, DNA damage activates a checkpoint that depends on the presence of a normal p53 gene. Cells thus blocked in the G1/S interface either repair DNA alkylation or undergo apoptosis. Malignant cells with mutant or absent p53 fail to suspend cell-cycle progression, do not undergo apoptosis, and exhibit resistance to these drugs.
Although DNA is the ultimate target of all alkylating agents, there is a crucial distinction between the bifunctional agents, in which cytotoxic effects predominate, and the monofunctional methylating agents (procarbazine, temozolomide), which have greater capacity for mutagenesis and carcinogenesis. This suggests that the cross-linking of DNA strands represents a much greater threat to cellular survival than do other effects, such as single-base alkylation and the resulting depurination and single-chain scission. Conversely, simple methylation may be bypassed by DNA polymerases, leading to mispairing reactions that permanently modify DNA sequence. These new sequences are transmitted to subsequent generations and may result in mutagenesis or carcinogenesis. Some methylating agents, such as procarbazine, are highly carcinogenic.
Adduct recognition systems and DNA repair systems play important roles in removing adducts, and thereby determine the selectivity of action against particular cell types and the acquisition of resistance to alkylating agents. Alkylation of a single strand of DNA (mono-adducts) is repaired by the nucleotide excision repair pathway; the less frequent cross-links require participation of nonhomologous end joining, an error-prone pathway, or the error-free homologous recombination pathway. After drug infusion in humans, mono-adducts appear rapidly and peak within 2 h of drug exposure, while cross-links peak at 8 h. The t1/2 for repair of adducts varies among normal tissues and tumors; in peripheral blood mononuclear cells, both mono-adducts and cross-links disappear with a t1/2 of 12-16 h.
The repair process depends on the presence and accurate functioning of multiple proteins. Their absence or mutation, as in Fanconi anemia or ataxia telangiectasia, leads to extreme sensitivity to DNA cross-linking agents such as mitomycin, cisplatin, or classical alkylators. Other repair enzymes are specific for removing methyl and ethyl adducts from the O-6 of guanine (MGMT) and for repair of alkylation of the N-3 of adenine and N-7 of guanine (3-methyladenine-DNA glycosylase). High expression of MGMT protects cells from cytotoxic effects of nitrosoureas and methylating agents and confers drug resistance, while methylation and silencing of the gene in brain tumors are associated with clinical response to BCNU and temozolomide. Bendamustine differs from classical chloroethyl alkylators in activating base excision repair, rather than the more complex double-strand break repair or MGMT. It impairs physiological arrest of adduct-containing cells at mitotic checkpoints and leads to mitotic catastrophe rather than apoptosis, and does not require an intact p53 to cause cytotoxicity.
Recognition of DNA adducts is an essential step in promoting attempts at repair and ultimately leading to apoptosis. The Fanconi pathway, consisting of 12 proteins, recognizes adducts and signals the need for repair of a broad array of DNA-damaging drugs and irradiation. Absence or inactivation of components of this pathway leads to increased sensitivity to DNA damage. Conversely, for the methylating drugs, nitrosoureas, cisplatin and carboplatin, and thiopurine analogs, the mismatch repair (MMR) pathway is essential for cytotoxicity, causing strand breaks at sites of adduct formation, creating mispairing of thymine residues, and triggering apoptosis.
Mechanisms of Resistance to Alkylating Agents. Resistance to an alkylating agent develops rapidly when it is used as a single agent. Specific biochemical changes implicated in the development of resistance include:
• Decreased permeation of actively transported drugs (mechlorethamine and melphalan).
• Increased intracellular concentrations of nucleophilic substances, principally thiols such as glutathione, which can conjugate with and detoxify electrophilic intermediates.
• Increased activity of DNA repair pathways, which may differ for the various alkylating agents.
• Increased rates of metabolic degradation of the activated forms of cyclophosphamide and ifosfamide to their inactive keto and carboxy metabolites by aldehyde dehydrogenase (see Figure 61–2), and detoxification of most alkylating intermediates by glutathione transferases.
• Loss of ability to recognize adducts formed by nitrosoureas and methylating agents, as the result of defective mismatch repair (MMR) proteins capability, confers resistance, as does defective checkpoint function, for virtually all alkylating drugs.
• Impaired apoptotic pathways, with overexpression of bcl-2 as an example, confer resistance.
TOXICITIES OF ALKYLATING AGENTS
BONE MARROW. Alkylating agents differ in their patterns of antitumor activity and in the sites and severity of their side effects. Most cause dose-limiting toxicity to bone marrow elements and, to a lesser extent, intestinal mucosa. Most alkylating agents (i.e., melphalan, chlorambucil, cyclophosphamide, and ifosfamide) cause acute myelosuppression, with a nadir of the peripheral blood granulocyte count at 6-10 days and recovery in 14-21 days. Cyclophosphamide has lesser effects on peripheral blood platelet counts than do the other agents. Busulfan suppresses all blood elements, particularly stem cells, and may produce a prolonged and cumulative myelosuppression lasting months or even years. For this reason, it is used as a preparative regimen in allogenic bone marrow transplantation. Carmustine and other chloroethylnitrosoureas cause delayed and prolonged suppression of both platelets and granulocytes, reaching a nadir 4-6 weeks after drug administration and reversing slowly thereafter. Both cellular and humoral immunity are suppressed by alkylating agents, which have been used to treat various autoimmune diseases. Immunosuppression is reversible at usual doses, but opportunistic infections may occur with extended treatment.
MUCOSA. Alkylating agents are highly toxic to dividing mucosal cells and to hair follicles, leading to oral mucosal ulceration, intestinal denudation, and alopecia. Mucosal effects are particularly damaging in high-dose chemotherapy protocols associated with bone marrow reconstitution, as they predispose to bacterial sepsis arising from the GI tract. In these protocols, cyclophosphamide, melphalan, and thiotepa have the advantage of causing less mucosal damage than the other agents. In high-dose protocols, however, other toxicities become limiting (Table 61–1).
Dose-Limiting Extramedullary Toxicities of Single Alkylating Agents
NERVOUS SYSTEM. Nausea and vomiting commonly follow agent administration of nitrogen mustard or BCNU. Ifosfamide is the most neurotoxic agent of this class and may produce altered mental status, coma, generalized seizures, and cerebellar ataxia. These side effects result from the release of chloroacetaldehyde from the phosphate-linked chloroethyl side chain of ifosfamide. High-dose busulfan can cause seizures; in addition, it accelerates the clearance of phenytoin, an antiseizure medication.
OTHER ORGANS. All alkylating agents, including temozolomide, have caused pulmonary fibrosis, usually several months after treatment. In high-dose regimens, particularly those employing busulfan or BCNU, vascular endothelial damage may precipitate veno-occlusive disease (VOD) of the liver, an often fatal side effect that is successfully reversed by the investigational drug defibrotide. The nitrosoureas and ifosfamide, after multiple cycles of therapy, may lead to renal failure. Cyclophosphamide and ifosfamide release a nephrotoxic and urotoxic metabolite, acrolein, which causes a severe hemorrhagic cystitis in high-dose regimens. This adverse effect can be prevented by coadministration of 2-mercaptoethanesulfonate (mesna [MESNEX]), which conjugates acrolein in urine. Ifosfamide in high doses for transplant causes a chronic, and often irreversible, renal toxicity. Nephrotoxicity correlates with the total dose of drug received and increases in frequency in children <5 years of age. The syndrome may be due to chloroacetaldehyde and/or acrolein excreted in the urine.
The more unstable alkylating agents (e.g., mechlorethamine and the nitrosoureas) have strong vesicant properties, damage veins with repeated use and, if extravasated, produce ulceration. All alkylating agents have toxic effects on the male and female reproductive systems, causing an often permanent amenorrhea, particularly in perimenopausal women, and an irreversible azoospermia in men.
Leukemogenesis. Alkylating agents are highly leukemogenic. Acute nonlymphocytic leukemia, often associated with partial or total deletions of chromosome 5 or 7, peaks in incidence ~4 years after therapy and may affect up to 5% of patients treated on regimens containing alkylating drugs. Leukemia often is preceded by a period of neutropenia or anemia and by bone marrow morphology consistent with myelodysplasia. Melphalan, the nitrosoureas, and the methylating agent procarbazine have the greatest propensity to cause leukemia, while it is less common after cyclophosphamide.
Mechlorethamine HCl (MUSTARGEN) was the first clinically used nitrogen mustard and is the most reactive of the drugs in this class. It is used topically for treatment of cutaneous T-cell lymphoma (CTCL) as a solution that is rapidly mixed and applied to affected areas. It has been largely replaced by cyclophosphamide, melphalan, and other, more stable alkylating agents.
Severe local reactions of exposed tissues necessitate rapid intravenous injection of mechlorethamine for most uses. Mechlorethamine, rapidly and within minutes, undergoes chemical degradation (affected markedly by pH) as it combines with either water or cellular nucleophiles. The major acute toxic manifestations of mechlorethamine are nausea and vomiting, lacrimation, and myelosuppression. Leukopenia and thrombocytopenia limit the amount of drug that can be given in a single course.
ADME. Cyclophosphamide is well absorbed orally and is activated to the 4-hydroxy intermediate (see Figure 61–2). Its rate of metabolic activation exhibits significant interpatient variability and increases with successive doses in high-dose regimens but appears to be saturable at infusion rates of >4 g/90 min and concentrations of the parent compound >150 μM. 4-Hydroxycyclophosphamide may be oxidized further by aldehyde oxidase, either in liver or in tumor tissue, to inactive metabolites. The hydroxyl metabolite of ifosfamide similarly is inactivated by aldehyde dehydrogenase. 4-Hydroxycyclophosphamide and its tautomer, aldophosphamide, travel in the circulation to tumor cells where aldophosphamide cleaves spontaneously, generating stoichiometric amounts of phosphoramide mustard and acrolein. Phosphoramide mustard is responsible for antitumor effects, while acrolein causes hemorrhagic cystitis often seen during therapy with cyclophosphamide. Patients should receive vigorous intravenous hydration during high-dose treatment. Brisk hematuria in a patient receiving daily oral therapy should lead to immediate drug discontinuation. Refractory bladder hemorrhage can become life-threatening and may require cystectomy for control of bleeding. Inappropriate secretion of antidiuretic hormone has been observed, usually at doses >50 mg/kg (see Chapter 25). It is important to be aware of the possibility of water intoxication, because these patients usually are vigorously hydrated.
Pretreatment with CYP inducers such as phenobarbital enhances the rate of activation of the azoxyphosphorenes but does not alter total exposure to active metabolites over time and does not affect toxicity or efficacy. Cyclophosphamide can be used in full doses in patients with renal dysfunction, because it is eliminated by hepatic metabolism. Patients with significant hepatic dysfunction (bilirubin <3 mg/dL) should receive reduced doses. Maximal CP is achieved 1 hour after oral administration; the t1/2 of parent drug in plasma is ~7 h.
Therapeutic Uses. Cyclophosphamide (LYOPHILIZED CYTOXAN) is administered orally or intravenously. Recommended doses vary widely, and standard protocols for determining the schedule and dose of cyclophosphamide in combination with other chemotherapeutic agents should be consulted. As a single agent, a daily oral dose of 100 mg/m2 for 14 days has been recommended for patients with lymphomas and CLL. Higher doses of 500 mg/m2 intravenously every 2-4 weeks are used in combination with other drugs in the treatment of breast cancer and lymphomas. The neutrophil nadir of 500-1000 cells/mm3 generally serves as a lower limit for dosage adjustments in prolonged therapy. In regimens associated with bone marrow or peripheral stem cell rescue, cyclophosphamide may be given in total doses of 5-7 g/m2 over a 3-5-day period. GI ulceration, cystitis (counteracted by mesna and diuresis), and, less commonly, pulmonary, renal, hepatic, and cardiac toxicities (hemorrhagic myocardial necrosis) may occur after high-dose therapy with total doses >200 mg/kg.
The clinical spectrum of activity for cyclophosphamide is very broad. It is an essential component of many effective drug combinations for non-Hodgkin lymphomas, other lymphoid malignancies, breast and ovarian cancers, and solid tumors in children. Complete remissions and presumed cures have been reported when cyclophosphamide was given as a single agent for Burkitt lymphoma. It frequently is used in combination with doxorubicin and a taxane as adjuvant therapy after surgery for breast cancer. Because of its potent immunosuppressive properties, cyclophosphamide has been used to treat autoimmune disorders, including Wegener granulomatosis, rheumatoid arthritis, and the nephrotic syndrome. Caution is advised when the drug is considered for non-neoplastic conditions, not only because of its acute toxic effects but also because of its potential for inducing sterility, teratogenic effects, and leukemia.
Ifosfamide (IFEX, others) is an analog of cyclophosphamide. Severe urinary tract and CNS toxicity initially limited the use of ifosfamide, but adequate hydration and coadministration of mesna have reduced its bladder toxicity.
Therapeutic Uses. Ifosfamide is approved for treatment of relapsed germ cell testicular cancer and is frequently used for first-time treatment of pediatric and adult sarcomas. It is a common component ofhigh-dose chemotherapy regimens with bone marrow or stem cell rescue; in these regimens, in total doses of 12-14 g/m2, it may cause severe neurological toxicity, including hallucinations, coma, and death, with symptoms appearing 12 h to 7 days after beginning the ifosfamide infusion. This toxicity may result from a metabolite, chloroacetaldehyde. Ifosfamide also causes nausea, vomiting, anorexia, leukopenia, nephrotoxicity, and VOD of the liver. In nonmyeloablative regimens, ifosfamide is infused intravenously over at least 30 min at a dose of ≤1.2 g/m2/day for 5 days. Intravenous mesna is given as bolus injections in a dose equal to 20% of the ifosfamide dose concomitantly and an additional 20% again 4 and 8 h later, for a total mesna dose of 60% of the ifosfamide dose. Alternatively, mesna may be given concomitantly in a single dose equal to the ifosfamide dose. Patients also should receive at least 2 L of oral or intravenous fluid daily. Treatment cycles are repeated every 3-4 weeks.
Pharmacokinetics. Ifosfamide has a plasma elimination t1/2 ~1.5 h after doses of 3.8-5 g/m2 and a somewhat shorter t1/2 at lower doses; its pharmacokinetics are highly variable due to variable rates of hepatic metabolism (see legend to Figure 61–2).
Toxicity. Ifosfamide has virtually the same toxicity profile as cyclophosphamide, although it causes greater platelet suppression, neurotoxicity, nephrotoxicity, and in the absence of mesna, urothelial damage.
This alkylating agent primarily is used to treat multiple myeloma and, less commonly, in high-dose chemotherapy with marrow transplantation. The general pharmacological and cytotoxic actions of melphalan are similar to those of other bifunctional alkylators. The drug is not a vesicant.
ADME. Oral melphalan is absorbed in an inconsistent manner and, for most indications, is given as an intravenous infusion. The drug has a plasma t1/2 ~45-90 min; 10-15% of an administered dose is excreted unchanged in the urine. Patients with decreased renal function may develop unexpectedly severe myelosuppression.
Therapeutic Uses. Melphalan (ALKERAN) for multiple myeloma is given in doses of 4-10 mg orally for 4-7 days every 28 days, with dexamethasone or thalidomide. Treatment is repeated at 4-week intervals based on response and tolerance. Dosage adjustments should be based on blood cell counts. Melphalan also may be used in myeloablative regimens followed by bone marrow or peripheral blood stem cell reconstitution, at a dose of 180-200 mg/m2. The toxicity of melphalan is mostly hematological and is similar to that of other alkylating agents. Nausea and vomiting are less frequent. The drug causes less alopecia and, rarely, renal or hepatic dysfunction.
The cytotoxic effects of chlorambucil on the bone marrow, lymphoid organs, and epithelial tissues are similar to those observed with other nitrogen mustards. As an orally administered agent, chlorambucil is well tolerated in small daily doses and provides flexible titration of blood counts. Nausea and vomiting may result from single oral doses of ≥20 mg.
ADME. Oral absorption of chlorambucil is adequate and reliable. The drug has a t1/2 in plasma of ~1.5 h and is hydrolyzed to inactive products.
Therapeutic Uses. Chlorambucil is almost exclusively used in treating CLL, for which it has largely been replaced by fludarabine and cyclophosphamide. In treating CLL, the initial daily dose of chlorambucil (LEUKERAN) is 0.1-0.2 mg/kg, given once daily and continued for 3-6 weeks. With a fall in the peripheral total leukocyte count or clinical improvement, the dosage is titrated to maintain neutrophils and platelets at acceptable levels. Maintenance therapy (usually 2 mg daily) often is required to maintain clinical response. Chlorambucil treatment may continue for months or years, achieving its effects gradually and often without significant toxicity to a compromised bone marrow. Marked hypoplasia of the bone marrow may be induced with excessive doses, but the myelosuppressive effects are moderate, gradual, and rapidly reversible. GI discomfort, azoospermia, amenorrhea, pulmonary fibrosis, seizures, dermatitis, and hepatotoxicity rarely may be encountered. A marked increase in the incidence of acute myelocytic leukemia (AML) and other tumors was noted in the treatment of polycythemia vera and in patients with breast cancer receiving chlorambucil as adjuvant chemotherapy.
This drug is approved for treatment of CLL and non-Hodgkin lymphoma. Bendamustine is given as a 30-min intravenous infusion in dosages of 100 mg/m2/day on days 1 and 2 of a 28-day cycle. Lower doses may be indicated in heavily pretreated patients. Bendamustine is rapidly degraded through sulfhydryl interaction and adduct formation with macromolecules; <5% of the parent drug is excreted in the urine intact. N-demethylation and oxidation produces metabolites that have antitumor activity, but less than that of the parent molecule. The parent drug has a plasma t1/2 ~30 min. The clinical toxicity pattern of bendamustine is typical of alkylators, with a rapidly reversible myelosuppression and mucositis, both generally tolerable.
MISCELLANEOUS ALKYLATING DRUGS
Although nitrogen mustards containing chloroethyl groups constitute the most widely used class of alkylating agents, alternative alkylators with greater chemical stability and well-defined activity in specific types of cancer have value in clinical practice.
ETHYLENEIMINES AND METHYLMELAMINES
Altretamine (hexamethylmelamine [HEXALEN]) is structurally similar to TEM (tretamine). Its precise mechanism of cytotoxicity is unknown. It is a palliative treatment for persistent or recurrent ovarian cancer following cisplatin-based combination therapy. The usual dosage of altretamine as a single agent in ovarian cancer is 260 mg/m2/day in 4 divided doses, for 14 or 21 consecutive days out of a 28-day cycle, for up to 12 cycles.
ADME. Altretamine is well absorbed from the GI tract; its elimination t1/2 is 4-10 h. The drug undergoes rapid demethylation in the liver; the principal metabolites are pentamethylmelamine and tetramethyl melamine.
Clinical Toxicities. The main toxicities of altretamine are myelosuppression and neurotoxicity. Altretamine causes both peripheral and central neurotoxicity (ataxia, depression, confusion, drowsiness, hallucinations, dizziness, and vertigo). Neurological symptoms abate upon discontinuation of therapy. Peripheral blood counts and a neurological examination should be performed prior to the initiation of each course of therapy. Therapy should be interrupted for at least 14 days and subsequently restarted at a lower dosage of 200 mg/m2/day if the white cell count falls to <2000 cells/mm3 or the platelet count falls to <75,000 cells/mm3 or if neurotoxic or intolerable GI symptoms occur. If neurological symptoms fail to stabilize on the reduced-dose schedule, altretamine should be discontinued. Nausea and vomiting also are common side effects and may be dose limiting. Renal dysfunction may necessitate discontinuing the drug. Other rare adverse effects include rashes, alopecia, and hepatic toxicity. Severe, life-threatening orthostatic hypotension may develop in patients who receive MAO-inhibitors, amitriptyline, imipramine, or phenelzine concurrently with altretamine.
Thiotepa (THIOPLEX, others) consists of 3 ethyleneimine groups stabilized by attachment to the nucleophilic thiophosphoryl base. Its current use is primarily for high-dose chemotherapy regimens. Both thiotepa and its desulfurated primary metabolite, triethylenephosphoramide (TEPA), to which it is rapidly converted by hepatic CYPs, form DNA cross-links.
ADME. TEPA becomes the predominant form of the drug present in plasma within hours of thiotepa administration. The parent compound has a plasma t1/2 of 1.2-2 h, TEPA has a longer t1/2, 3-24 h. Thiotepa pharmacokinetics essentially are the same in children as in adults at conventional doses (<80 mg/m2), and drug and metabolite t1/2 are unchanged in children receiving high-dose therapy of 300 mg/m2/day for 3 days. Less than 10% of the administered drug appears in urine as the parent drug or the primary metabolite.
Clinical Toxicities. Toxicities include myelosuppression and, to a lesser extent, mucositis. Myelosuppression tends to develop somewhat later than with cyclophosphamide, with leukopenic nadirs at 2 weeks and platelet nadirs at 3 weeks. In high-doses, thiotepa may cause neurotoxic symptoms, including coma and seizures.
Busulfan (MYLERAN, BUSULFEX) exerts few pharmacological actions other than myelosuppression at conventional doses and, prior to the advent of imatinib mesylate (GLEEVEC), was a standard agent for patients in the chronic phase of myelocytic leukemia and caused a severe and prolonged pancytopenia in some patients. Busulfan now is primarily used in high-dose regimens, in which pulmonary fibrosis, GI mucosal damage, and hepatic veno-occlusive disease (VOD) are important toxicities.
ADME. Busulfan is well absorbed after oral administration in dosages of 2-6 mg/day and has a plasma t1/2 of 2-3 h. The drug is conjugated to GSH by GSTA1A and further metabolized by CYP-dependent pathways; its major urinary metabolite is methane sulfonic acid. In high doses, children <18 years of age clear the drug 2-4 times faster than adults and tolerate higher doses. Busulfan clearance varies considerably among patients. VOD is associated with high area under the curve (AUC) (AUC > 1500 1M × min) peak drug levels and slow clearance, leading to recommendations for dose adjustment based on drug level monitoring. A target steady-state concentration of 600-900 ng/mL in plasma in adults or AUC <1000 1M × min in children achieves an appropriate balance between toxicity and therapeutic benefit.
Therapeutic Uses. In treating chronic myelogenous leukemia (CML), the initial oral dose of busulfan varies with the total leukocyte count and the severity of the disease; daily doses of 2-8 mg for adults (~60 μg/kg or 1.8 mg/m2 for children) are used to initiate therapy and are adjusted appropriately to subsequent hematological and clinical responses, with the aim of reducing the total leukocyte count to ≤10,000 cells/mm3. A decrease in the leukocyte count usually is not seen during the first 10-15 days of treatment, and the leukocyte count may actually increase during this period. Because the leukocyte count may fall for >1 month after discontinuing the drug, it is recommended that busulfan be withdrawn when the total leukocyte count has declined to ~15,000 cells/mm3. A normal leukocyte count usually is achieved within 12-20 weeks. During remission, daily treatment resumes when the total leukocyte count reaches ~50,000 cells/mm3. Daily maintenance doses are 1-3 mg.
In high-dose therapy, doses of 1 mg/kg are given every 6 h for 4 days, with adjustment based on pharmacokinetics. Anticonvulsants must be used concomitantly to protect against acute CNS toxicities, including tonic-clonic seizures that may occur several hours after each dose. Although phenytoin is a frequent choice, phenytoin induces the GSTs that metabolize busulfan, reducing its AUC by ~20%. In patients requiring concomitant anti-seizure medication, non-enzyme-inducing benzodiazepines such as lorazepam and clonazepam are recommended as an alternative to phenytoin. If phenytoin is used concurrently, plasma busulfan levels should be monitored and the busulfan dose adjusted accordingly.
Clinical Toxicity. The toxic effects of busulfan are related to its myelosuppressive properties; prolonged thrombocytopenia may occur. Occasionally, patients experience nausea, vomiting, and diarrhea. Long-term use leads to impotence, sterility, amenorrhea, and fetal malformation. Rarely, patients develop asthenia and hypotension. High-dose busulfan causes VOD of the liver in ≤10% of patients, as well as seizures, hemorrhagic cystitis, permanent alopecia, and cataracts. The coincidence of VOD and hepatotoxicity is increased by its coadministration with drugs that inhibit CYPs, including imidazoles and metronidazole, possibly through inhibition of the clearance of busulfan and/or its toxic metabolites.
The nitrosoureas have an important role in the treatment of brain tumors and find occasional use in treating lymphomas and in high-dose regimens with bone marrow reconstitution. They function as bifunctional alkylating agents but differ from conventional nitrogen mustards in both pharmacological and toxicological properties.
Carmustine (BCNU) and lomustine (CCNU) are highly lipophilic and thus readily cross the blood-brain barrier, an important property in the treatment of brain tumors. Unfortunately, with the exception of streptozocin, nitrosoureas cause profound and delayed myelosuppression with recovery 4-6 weeks after a single dose. Long-term treatment with the nitrosoureas, especially semustine (methyl-CCNU), has resulted in renal failure. As with other alkylating agents, the nitrosoureas are highly carcinogenic and mutagenic. They generate both alkylating and carbamylating moieties (see Figure 61–3).
Carmustine’s major action is its alkylation of DNA at the O6-guanine position, an adduct repaired by MGMT. Methylation of the MGMT promoter inhibits its expression in ~30% of primary gliomas and is associated with sensitivity to nitrosoureas. In high doses with bone marrow rescue, carmustine produces hepatic VOD, pulmonary fibrosis, renal failure, and secondary leukemia.
ADME. Carmustine is unstable in aqueous solution and in body fluids. After intravenous infusion, it disappears from the plasma with a highly variable t1/2 of ≥15-90 min. Approximately 30-80% of the drug appears in the urine within 24 h as degradation products. The alkylating metabolites enter rapidly into the cerebrospinal fluid (CSF), and their concentrations in the CSF reach 15-30% of the concurrent plasma values.
Therapeutic Uses. Carmustine (BICNU) is administered intravenously at doses of 150-200 mg/m2, given by infusion over 1-2 h and repeated every 6 weeks. Because of its ability to cross the blood-brain barrier, carmustine has been used in the treatment of malignant gliomas. An implantable carmustine wafer (GLIADEL) is available for use as an adjunct to surgery and radiation in newly diagnosed high-grade malignant glioma patients and as an adjunct to surgery for recurrent glioblastoma multiforme.
Streptozocin (or streptozotocin) has a methylnitrosourea (MNU) moiety attached to the 2-carbon of glucose. It has a high affinity for cells of the islets of Langerhans and causes diabetes in experimental animals.
ADME. Streptozocin is rapidly degraded following intravenous administration. The t1/2 of the drug is ~15 min. Only 10-20% of a dose is recovered intact in the urine.
Therapeutic Uses. Streptozocin (ZANOSAR) is used in the treatment of human pancreatic islet cell carcinoma and malignant carcinoid tumors. It is administered intravenously, 500 mg/m2 once daily for 5 days; this course is repeated every 6 weeks. Alternatively, 1000 mg/m2 can be given weekly for 2 weeks, and the weekly dose then can be increased to a maximum of 1500 mg/m2 as tolerated. Nausea is frequent. Mild, reversible renal or hepatic toxicity occurs in approximately two-thirds of cases; in <10% of patients, renal toxicity may be cumulative with each dose and may lead to irreversible renal failure. Streptozocin should not be given with other nephrotoxic drugs. Hematological toxicities (anemia, leukopenia, thrombocytopenia) occur in 20% of patients.
Dacarbazine functions as a methylating agent after metabolic activation to the monomethyl triazeno metabolite, MTIC. It kills cells in all phases of the cell cycle. Resistance has been ascribed to the removal of methyl groups from the O6– guanine bases in DNA by MGMT.
ADME. Dacarbazine is administered intravenously. After an initial rapid phase (t1/2 of ~20 min), dacarbazine is cleared from plasma with a terminal t1/2 of ~5 h. The t1/2 is prolonged in the presence of hepatic or renal disease. Almost 50% of the compound is excreted intact in the urine by tubular secretion.
Therapeutic Uses. The primary clinical indication for dacarbazine (DTIC-DOME) is in the chemotherapy of Hodgkin disease. In combination with other drugs for Hodgkin disease, dacarbazine is given in dosages of 150 mg/m2/day for 5 days, repeated every 4 weeks; it can be used alone as a single dose of 375 mg/m2, repeated every 15 days. It is modestly effective against malignant melanoma and adult sarcomas. Dacarbazine (DTIC-DOME) for malignant melanoma is given in dosages of 2-4.5 mg/kg/day for a 10-day period, repeated every 28 days; alternatively, 250 mg/m2 can be given daily for 5 days and repeated every 3 weeks. Extravasation of the drug may cause tissue damage and severe pain.
Toxicity. DTIC induces nausea and vomiting in >90% of patients; vomiting usually develops 1-3 h after treatment and may last up to 12 h. Myelosuppression, with both leukopenia and thrombocytopenia, is mild and readily reversible within 1-2 weeks. A flu-like syndrome may occur. Hepatotoxicity, alopecia, facial flushing, neurotoxicity, and dermatological reactions are less common adverse effects.
Temozolomide (TEMODAR) is the standard agent in combination with radiation therapy for patients with malignant glioma and for astrocytoma. Temozolomide, like dacarbazine, forms the methylating metabolite MTIC and kills cells in all phases of the cell cycle.
ADME. Temozolomide is administered orally or intravenously in dosages of ~200 mg/day; it has a bioavailability approaching 100%. Plasma levels of the parent drug decline with a t1/2 of 1-2 h. The primary active metabolite MTIC reaches a maximum plasma concentration (150 ng/mL) 90 min after a dose and declines with a t1/2 of 2 h. Little intact drug is recovered in the urine, the primary urinary metabolite being the inactive imidazole carboxamide.
Toxicity. The toxicities of temozolomide mirror those of DTIC. Hematological monitoring is necessary to guide dosing adjustments.
Procarbazine is employed for second-line therapy in malignant brain tumors.
Cytotoxic Action. The antineoplastic activity of procarbazine results from its conversion by CYP-mediated hepatic oxidative metabolism to highly reactive alkylating species that methylate DNA. Activated procarbazine can produce chromosomal damage, including chromatid breaks and translocations, consistent with its mutagenic and carcinogenic actions. Resistance to procarbazine develops rapidly when it is used as a single agent; one mechanism of resistance results from increased expression of MGMT, which repairs methylation of guanine.
Pharmacokinetics. The pharmacokinetic behavior of procarbazine has not yet been thoroughly defined. The drug is extensively metabolized by CYP isoenzymes to azo, methylazoxy, and benzylazoxy intermediates, which are found in the plasma and yield the alkylating metabolites in tumor cells. In brain cancer patients, the concurrent use of anti-seizure drugs that induce hepatic CYPs does not significantly alter the pharmacokinetics of the parent drug.
Therapeutic Uses. The recommended dosage of procarbazine (MATULANE) for adults is 100 mg/m2/day for 10-14 days in combination regimens such as MOPP (nitrogen mustard, Oncovin, procarbazine, and prednisone) for Hodgkin disease. The drug rarely is used in current practice.
Toxicity. The most common toxic effects include leukopenia and thrombocytopenia, which begin during the second week of therapy and reverse within 2 weeks off treatment. GI symptoms such as mild nausea and vomiting occur in most patients; diarrhea and rash are noted in 5-10% of cases. Behavioral disturbances also have been reported. Because procarbazine augments sedative effects, the concomitant use of CNS depressants should be avoided. The drug is a weak MAO inhibitor; it blocks the metabolism of catecholamines, sympathomimetics, and dietary tyramine and may provoke hypertension in patients concurrently exposed to these. Procarbazine has disulfiram-like actions, and therefore the ingestion of alcohol should be avoided. The drug is highly carcinogenic, mutagenic, and teratogenic and is associated with a 5-10% risk of acute leukemia in patients treated with MOPP. The highest risk is for patients who also receive radiation therapy. Procarbazine is a potent immunosuppressive agent. It causes infertility, particularly in males.
PLATINUM COORDINATION COMPLEXES
Platinum coordination complexes have broad antineoplastic activity and have become the foundation for treatment of ovarian, head and neck, bladder, esophagus, lung, and colon cancers. Although cisplatin and other platinum complexes do not form carbonium ion intermediates like other alkylating agents or formally alkylate DNA, they covalently bind to nucleophilic sites on DNA and share many pharmacological attributes with alkylators.
MECHANISM OF ACTION. Cisplatin, carboplatin, and oxaliplatin enter cells by an active Cu2+ transporter, CTR1, and in doing so rapidly degrade the transporter. The compounds are actively extruded from cells by ATP7A and ATP7B copper transporters and by multidrug resistance protein 1 (MRP1); variable expression of these transporters may contribute to clinical resistance. Inside the cell, the chloride, cyclohexane, or oxalate ligands of the analogs are displaced by water molecules, yielding a positively charged molecule that reacts with nucleophilic sites on DNA and proteins.
Aquation of cisplatin is favored at the low concentrations of Cl– inside the cell and in the urine. High concentrations of Cl– stabilize the drug, explaining the effectiveness of Cl– diuresis in preventing nephrotoxicity. The activated platinum complexes can react with electron-rich regions, such as sulfhydryls, and with various sites on DNA, forming both intrastrand and interstrand cross-links. The DNA-platinum adducts inhibit replication and transcription, lead to single- and double-stranded breaks and miscoding, and if recognized by p53 and other checkpoint proteins, cause induction of apoptosis. Adduct formation is an important predictor of clinical response. The analogs differ in the conformation of their adducts and the effects of adduct on DNA structure and function. Oxaliplatin and carboplatin are slower to form adducts. The oxaliplatin adducts are bulkier and less readily repaired, create a different pattern of distortion of the DNA helix, and differ from cisplatin adducts in the pattern of hydrogen bonding to adjacent segments of DNA.
Unlike the other platinum analogs, oxaliplatin exhibits a cytotoxicity that does not depend on an active MMR system, which may explain its greater activity in colorectal cancer. It also seems less dependent on the presence of high mobility group (HMG) proteins that are required by the other platinum derivatives. Testicular cancers have a high concentration of HMG proteins and are quite sensitive to cisplatin. Basal-type breast cancers, such as those with BRCA1 and BRCA2 mutations, lack Her 2 amplification and hormone-receptor expression and appear to be uniquely susceptible to cisplatin through their upregulation of apoptotic pathways governed by p63 and p73. The cell cycle specificity of cisplatin differs among cell types; the effects of cross-linking are most pronounced during the S phase. The platinum analogs are mutagenic, teratogenic, and carcinogenic. Cisplatin- or carboplatin-based chemotherapy for ovarian cancer is associated with a 4-fold increased risk of developing secondary leukemia.
Resistance to Platinum Analogs. Resistance to the platinum analogs likely is multifactorial; the compounds differ in their degree of cross-resistance. Carboplatin shares cross-resistance with cisplatin in most experimental tumors, while oxaliplatin does not. A number of factors influence sensitivity to platinum analogs in experimental cells, including intracellular drug accumulation and intracellular levels of glutathione and other sulfhydryls such as metallothionein that bind to and inactivate the drug and rates of repair of DNA adducts. Repair of platinum-DNA adducts requires participation of the NER pathway. Inhibition or loss of NER increases sensitivity to cisplatin in ovarian cancer patients, while overexpression of NER components is associated with poor response to cisplatin or oxaliplatin-based therapy in lung, colon, and gastric cancer.
Resistance to cisplatin, but not oxaliplatin, appears to be partly mediated through loss of function in the MMR proteins. In the absence of effective repair of DNA-platinum adducts, sensitive cells cannot replicate or transcribe affected portions of the DNA strand. Some DNA polymerases can bypass adducts, possibly contributing to resistance. Overexpression of copper efflux transporters, ATP7A and ATP7B, correlates with poor survival after cisplatin-based therapy for ovarian cancer.
ADME. After intravenous administration, cisplatin has an initial plasma elimination t1/2 of 25-50 min; concentrations of total (bound and unbound) drug fall thereafter, with a t1/2 of ≥24 h. More than 90% of the platinum in the blood is covalently bound to plasma proteins. High concentrations of cisplatin are found in the kidney, liver, intestine, and testes; cisplatin penetrates poorly into the CNS. Only a small portion of the drug is excreted by the kidney during the first 6 h; by 24 h, up to 25% is excreted, and by 5 days, up to 43% of the administered dose is recovered in the urine, mostly covalently bound to protein and peptides. Biliary or intestinal excretion of cisplatin is minimal.
Therapeutic Uses. Cisplatin (PLATINOL) is given only intravenously. The usual dosage is 20 mg/m2/day for 5 days, 20-30 mg weekly for 3-4 weeks, or 100 mg/m2 given once every 4 weeks. To prevent renal toxicity, it is important to establish a chloride diuresis by the infusion of 1-2 L of normal saline prior to treatment. The appropriate amount of cisplatin then is diluted in a solution containing dextrose, saline, and mannitol and administered intravenously over 4-6 h. Because aluminum inactivates cisplatin, the drug should not come in contact with needles or other infusion equipment that contain aluminum during its preparation or administration.
Cisplatin, in combination with bleomycin, etoposide, ifosfamide, or vinblastine, cures 90% of patients with testicular cancer. Used with paclitaxel, cisplatin or carboplatin induces complete response in the majority of patients with carcinoma of the ovary. Cisplatin produces responses in cancers of the bladder, head and neck, cervix, and endometrium; all forms of carcinoma of the lung; anal and rectal carcinomas; and neoplasms of childhood. The drug also sensitizes cells to radiation therapy and enhances control of locally advanced lung, esophageal, and head and neck tumors when given with irradiation.
TOXICITY. Cisplatin-induced nephrotoxicity has been largely abrogated by adequate pretreatment hydration and chloride diuresis. Amifostine (ETHYOL), a thiophosphate cytoprotective agent, reduces renal toxicity associated with repeated administration of cisplatin. Ototoxicity caused by cisplatin is unaffected by diuresis and is manifested by tinnitus and high-frequency hearing loss. Marked nausea and vomiting occur in almost all patients and usually can be controlled with 5HT3 antagonists, NK1-receptor antagonists, and high-dose corticosteroids (see Table 46–6).
At higher doses or after multiple cycles of treatment, cisplatin causes a progressive peripheral motor and sensory neuropathy that may worsen after discontinuation of the drug and may be aggravated by subsequent or simultaneous treatment with taxanes or other neurotoxic drugs. Cisplatin causes mild to moderate myelosuppression, with transient leukopenia and thrombocytopenia. Anemia may become prominent after multiple cycles of treatment. Electrolyte disturbances, including hypomagnesemia, hypocalcemia, hypokalemia, and hypophosphatemia, are common. Hypocalcemia and hypomagnesemia secondary to tubular damage and renal electrolyte wasting may produce tetany if untreated. Routine measurement of Mg2+ concentrations in plasma is recommended. Hyperuricemia, hemolytic anemia, and cardiac abnormalities are rare side effects. Anaphylactic-like reactions, characterized by facial edema, bronchoconstriction, tachycardia, and hypotension, may occur within minutes after administration and should be treated by intravenous injection of epinephrine and with corticosteroids or anti-histamines. Cisplatin has been associated with the development of AML, usually ≥4 years after treatment.
The mechanisms of action and resistance and the spectrum of clinical activity of carboplatin (PARAPLATIN; CBDCA, JIM-8) are similar to cisplatin. However, the 2 drugs differ significantly in their chemical, pharmacokinetic, and toxicological properties.
ADME. Because carboplatin is much less reactive than cisplatin, the majority of drug in plasma remains in its parent form, unbound to proteins. Most drug is eliminated via renal excretion, with a t1/2 ~2 h. A small fraction of platinum binds irreversibly to plasma proteins and disappears slowly, with a t1/2 ≥5 days.
Therapeutic Uses. Carboplatin and cisplatin are equally effective in the treatment of suboptimally debulked ovarian cancer, non–small cell lung cancer, and extensive-stage small cell lung cancer; however, carboplatin may be less effective than cisplatin in germ cell, head and neck, and esophageal cancers. Carboplatin is an effective alternative for responsive tumors in patients unable to tolerate cisplatin because of impaired renal function, refractory nausea, significant hearing impairment, or neuropathy, but doses must be adjusted for renal function. In addition, it may be used in high-dose therapy with bone marrow or peripheral stem cell rescue. Carboplatin is administered as an intravenous infusion over at least 15 min and is given once every 21-28 days; the dose of carboplatin should be adjusted in proportion to the reduction in creatinine clearance (CrCl) for patients with a CrCl <60 mL/min.
Toxicity. Carboplatin is relatively well tolerated clinically, causing less nausea, neurotoxicity, ototoxicity, and nephrotoxicity than cisplatin. The dose-limiting toxicity of carboplatin is myelosuppression, primarily thrombocytopenia. It may cause a hypersensitivity reaction; in patients with a mild reaction, premedication, graded doses of drug, and more prolonged infusion lead to desensitization.
ADME. Oxaliplatin has a short t1/2 in plasma, probably as a result of its rapid uptake by tissues and its reactivity; the initial t1/2 ~17 min. No dose adjustment is required for hepatic dysfunction or for patients with a CrCl ≥20 mL/min.
Therapeutic Uses. Oxaliplatin exhibits a range of antitumor activity (colorectal and gastric cancer) that differs from other platinum agents. Oxaliplatin’s effectiveness in colorectal cancer is perhaps due to its MMR- and HMG-independent effects. It also suppresses expression of thymidylate synthase (TS), the target enzyme of 5-fluorouracil (5-FU) action, which may promote synergy of these 2 drugs. In combination with 5-FU, it is approved for treatment of patients with colorectal cancer.
Toxicity. The dose-limiting toxicities of oxaliplatin are peripheral neuropathies. An acute form, often triggered by exposure to cold liquids, manifests as paresthesias and/or dysesthesias in the upper and lower extremities, mouth, and throat. A second type relates to cumulative dose and has features similar to cisplatin neuropathy; 75% of patients receiving a cumulative dose of 1560 mg/m2 experience some progressive sensory neurotoxicity, with dysesthesias, ataxia, and numbness of the extremities. Hematological toxicity is mild to moderate, except for rare immune-mediated cytopenias; nausea is well controlled with 5HT3-receptor antagonists. Oxaliplatin causes leukemia and pulmonary fibrosis months to years after administration. Oxaliplatin may cause an acute allergic response with urticaria, hypotension, and bronchoconstriction.
FOLIC ACID ANALOGS
Folic acid is an essential dietary factor that is converted by enzymatic reduction to a series of tetrahydrofolate (FH4) cofactors that provide methyl groups for the synthesis of precursors of DNA (thymidylate and purines) and RNA (purines). Interference with FH4 metabolism reduces the cellular capacity for one-carbon transfer and the necessary methylation reactions in the synthesis of purine ribonucleotides and thymidine monophosphate (TMP), thereby inhibiting DNA replication.
Antifolate chemotherapy produced the first striking, although temporary, remissions in leukemia and the first cure of a solid tumor, choriocarcinoma. Recognition that methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR), also directly inhibits the folate-dependent enzymes of de novo purine and thymidylate synthesis led to development of antifolate analogs that specifically target these other folate-dependent enzymes (Figure 61–4). New congeners have greater capacity for transport into tumor cells (pralatrexate) and exert their primary inhibitory effect on TS (raltitrexed, TOMUDEX), early steps in purine biosynthesis (lometrexol), or both (the multitargeted antifolate, pemetrexed, ALIMTA).
Mechanism of Action. The primary target of MTX is the enzyme DHFR (see Figure 61–4). To function as a cofactor in 1-carbon transfer reactions, folate must be reduced by DHFR to FH4. Inhibitors such as MTX, with a high affinity for DHFR (Ki 0.01-0.2 nM), cause partial depletion of the FH4 cofactors (5-10 methylene tetrahydrofolic acid and N-10 formyl tetrahydrofolic acid) required for the synthesis of thymidylate and purines. In addition, MTX, like cellular folates, undergoes conversion to a series of polyglutamates (MTX-PGs) in both normal and tumor cells. These MTX-PGs constitute an intracellular storage form of folates and folate analogs and dramatically increase inhibitory potency of the analog for additional sites, including TS and 2 early enzymes in the purine biosynthetic pathway. The dihydrofolic acid polyglutamates that accumulate in cells behind the blocked DHFR reaction also act as inhibitors of TS and other enzymes (see Figure 61–4).
Figure 61–4 Actions of methotrexate and its polyglutamates. AICAR, aminoimidazole carboxamide; dUMP, deoxyuridine monophosphate; FH2Glun/FH4Glun, dihydro-/tetrahydro-folate polyglutamates; GAR, glycinamide ribonucleotide; IMP, inosine monophosphate; PRPP, 5-phosphoribosyl-1-pyrophosphate; TMP, thymidine monophosphate.
Selective Toxicity; Rescue. As with most antimetabolites, MTX is only partially selective for tumor cells and kills rapidly dividing normal cells, such as those of the intestinal epithelium and bone marrow. Folate antagonists kill cells during the S phase of the cell cycle and are most effective when cells are proliferating rapidly. The toxic effects of MTX may be terminated by administering leucovorin, a fully reduced folate coenzyme that repletes the intracellular pool of FH4 cofactors.
Cellular Entry and Retention. Because folic acid and many of its analogs are polar, they cross the blood-brain barrier poorly and require specific transport mechanisms to enter mammalian cells. Three inward folate transport systems are found on mammalian cells: (1) a folate receptor, which has high affinity for folic acid but much reduced ability to transport MTX and other analogs; (2) the reduced folate transporter, the major transit protein for MTX, raltitrexed, pemetrexed, and most analogs; and (3) a transporter that is active at low pH. The reduced folate transporter is highly expressed in the hyperdiploid subtype of acute lymphoblastic leukemia (ALL), which has extreme sensitivity to MTX. Once in the cell, additional glutamyl residues are added to the molecule by the enzyme folylpolyglutamate synthetase. Because these higher polyglutamates are strongly charged and cross cellular membranes poorly, polyglutamation serves as a mechanism of entrapment and may account for the prolonged retention of MTX in chorionic epithelium (where it is a potent abortifacient); in tumors derived from this tissue, such as choriocarcinoma cells; and in normal tissues subject to cumulative drug toxicity, such as liver. Polyglutamyl folates and analogs have substantially greater affinity than the monoglutamate form for folate-dependent enzymes that are required for purine and thymidylate synthesis and have at least equal affinity for DHFR.
Newer Congeners. New folate antagonists that are better substrates for the reduced folate carrier have been identified. In efforts to bypass the obligatory membrane transport system and to facilitate penetration of the blood-brain barrier, lipid-soluble folate antagonists also have been synthesized. Trimetrexate (NEUTREXIN), a lipid-soluble analog that lacks a terminal glutamate, has modest antitumor activity, primarily in combination with leucovorin rescue. However, it is beneficial in the treatment of Pneumocystis jiroveci (Pneumocystis carinii) pneumonia where leucovorin provides differential rescue of the host but not the parasite. The most important new folate analog, MTA or pemetrexed (ALIMTA), is a pyrrole–pyrimidine structure. It is avidly transported into cells via the reduced folate carrier and is converted to polyglutamates that inhibit TS and glycine amide ribonucleotide transformylase, as well as DHFR. It has activity against ovarian cancer, mesothelioma, and non–small cell adenocarcinomas of the lung. Pemetrexed and its polyglutamates have a somewhat different spectrum of biochemical actions. Like MTX, pemetrexed inhibits DHFR, but as a polyglutamate, it even more potently inhibits glycinamide ribonucleotide formyltransferase (GART) and TS. Unlike MTX, it produces little change in the pool of reduced folates, indicating that the distal sites of inhibition (TS and GART) predominate. Its pattern of deoxynucleotide depletion also differs; it causes a greater fall in thymidine triphosphate (TTP) than in other triphosphates. Like MTX, it induces p53 and cell-cycle arrest, but this effect does not depend on induction of p21. A newer congener, pralatrexate, is more effectively taken up and polyglutamated than MTX and is approved for treatment of cutaneous T-cell lymphoma.
MECHANISMS OF RESISTANCE TO ANTIFOLATES. Resistance to MTX can involve alterations in each known step in MTX action, including:
• Impaired transport of MTX into cells
• Production of altered forms of DHFR that have decreased affinity for the inhibitor
• Increased concentrations of intracellular DHFR through gene amplification or altered gene regulation
• Decreased ability to synthesize MTX polyglutamates
• Increased expression of a drug efflux transporter of the MRP class (see Chapter 5)
DHFR levels in leukemic cells increase within 24 h after treatment of patients with MTX, probably as a result of induction of DHFR synthesis. Unbound DHFR protein may bind to its own message and reduce its own translation, while the DHFR-MTX complex is ineffective in blocking the DHFR translation. With longer periods of drug exposure, tumor cell populations that contain markedly increased levels of DHFR emerge. These cells contain multiple gene copies of DHFR either in mitotically unstable double-minute chromosomes (extrachromosomal elements) or in stably integrated, homogeneously staining chromosomal regions or amplicons. Similar gene amplification target proteins have been implicated in the resistance to many antitumor agents, including 5-FU and pentostatin (2′-deoxycoformycin).
High doses of MTX may permit entry of the drug into transport-defective cells and may permit the intracellular accumulation of MTX in concentrations that inactivate high levels of DHFR. The understanding of resistance to pemetrexed is incomplete. In various cell lines, resistance to this agent seems to arise from loss of influx transport, TS amplification, changes in purine biosynthetic pathways, or loss of polyglutamation.
ADME. MTX is readily absorbed from the GI tract at doses of M25 mg/m2; larger doses are absorbed incompletely and are routinely administered intravenously. After intravenous administration, the drug disappears from plasma in a triphasic fashion. The rapid distribution phase is followed by a second phase, which reflects renal clearance (t1/2 of 2-3 h). A third phase has a t1/2 of ~8-10 h. This terminal phase of disappearance, if unduly prolonged by renal failure, may be responsible for major toxic effects of the drug on the marrow, GI epithelium, and skin. Distribution of MTX into body spaces, such as the pleural or peritoneal cavity, occurs slowly. However, if such spaces are expanded (e.g., by ascites or pleural effusion), they may act as a site of storage and slow release of the drug, resulting in prolonged elevation of plasma concentrations and more severe bone marrow toxicity.
Approximately 50% of MTX binds to plasma proteins and may be displaced from plasma albumin by myriad agents (e.g., sulfonamides, salicylates, tetracycline, chloramphenicol, and phenytoin); caution should be used if these drugs are given concomitantly. Up to 90% of a given dose is excreted unchanged in the urine, mostly within the first 8-12 h. Metabolism of MTX usually is minimal. After high doses, however, metabolites are readily detectable; these include 7-hydroxy-MTX, which is potentially nephrotoxic. Renal excretion of MTX occurs through a combination of glomerular filtration and active tubular secretion. Therefore, the concurrent use of drugs that reduce renal blood flow (e.g., NSAIDs), that are nephrotoxic (e.g., cisplatin), or that are weak organic acids (e.g., aspirin, piperacillin) can delay drug excretion and lead to severe myelosuppression. In patients with renal insufficiency, the dose should be adjusted in proportion to decreases in renal function, and high-dose regimens should be avoided. Concentrations of MTX in CSF are only 3% of those in the systemic circulation at steady state; hence, neoplastic cells in the CNS probably are not killed by standard dosage regimens. When high doses of MTX are given, cytotoxic concentrations of MTX reach the CNS. MTX is retained in the form of polyglutamates for long periods (e.g., weeks in the kidneys, several months in the liver).
Pharmacogenetics may influence the response to antifolates and their toxicity. The C677T substitution in methylenetetrahydrofolate reductase reduces the activity of the enzyme that generates methylenetetrahydrofolate, the cofactor for TS, and thereby increases MTX toxicity. The presence of this polymorphism in leukemic cells confers increased sensitivity to MTX and might also modulate the toxicity and therapeutic effect of pemetrexed, a predominant TS inhibitor. Likewise, polymorphisms in the promoter region of TS affect its expression, and by altering the intracellular levels of TS, modulate the response and toxicity of both antifolates and fluoropyrimidines.
Therapeutic Uses. MTX is a critical drug in the management of childhood ALL. High-dose MTX is of great value in remission induction and consolidation and in the maintenance of remissions in this highly curable disease. A 6- to 24-h infusion of relatively large doses of MTX may be employed every 2-4 weeks (≥1-7.5 g/m2) but only when leucovorin rescue follows within 24 h of the MTX infusion. For maintenance therapy, it is administered weekly, 20 mg/m2 orally. Outcome of treatment in children correlates inversely with the rate of drug clearance. During MTX infusion, high steady-state levels are associated with a lower leukemia relapse rate. MTX is of limited value in adults with AML, except for treatment and prevention of leukemic meningitis. The intrathecal administration of MTX has been employed for treatment or prophylaxis of meningeal leukemia or lymphoma and for treatment of meningeal carcinomatosis. This route of administration achieves high concentrations of MTX in the CSF and also is effective in patients whose systemic disease has become resistant to MTX. The recommended intrathecal dose in all patients >3 years of age is 12 mg. The dose is repeated every 4 days until malignant cells no longer are evident in the CSF. Leucovorin may be administered to counteract the potential toxicity of MTX that escapes into the systemic circulation, although this generally is not necessary. Because MTX administered into the lumbar space distributes poorly over the cerebral convexities, the drug may be given via an intraventricular Ommaya reservoir in the treatment of active intrathecal disease. MTX is of established value in choriocarcinoma and related trophoblastic tumors of women; cure is achieved in ~75% of advanced cases treated sequentially with MTX and dactinomycin and in >90% when early diagnosis is made. For choriocarcinoma, 1 mg/kg of MTX is administered intramuscularly every other day for 4 doses, alternating with leucovorin (0.1 mg/kg every other day). Courses are repeated at 3-week intervals, toxicity permitting, and urinary β-human chorionic gonadotropin titers are used as a guide for persistence of disease.
Beneficial effects also are observed in the combination therapy of Burkitt and other non-Hodgkin lymphomas. MTX is a component of regimens for carcinomas of the breast, head and neck, ovary, and bladder. High-dose MTX with leucovorin rescue (HDM-L) is a standard agent for adjuvant therapy of osteosarcoma and produces a high complete response rate in CNS lymphomas. The administration of HDM-L has the potential for renal toxicity, probably related to the precipitation of the drug, a weak acid, in the acidic tubular fluid. Thus, vigorous hydration and alkalinization of urine pH are required prior to drug administration. If MTX values measured 48 h after drug administration are 1 μM or higher, higher doses (100 mg/m2) of leucovorin must be given until the plasma concentration of MTX falls to <50 nM. With appropriate hydration and urine alkalinization, and in patients with normal renal function, the incidence of nephrotoxicity following HDM-L is <2%. In patients who become oliguric, intermittent hemodialysis is ineffective in reducing MTX levels. Continuous-flow hemodialysis can eliminate MTX at ~50% of the clearance rate in patients with intact renal function. Alternatively, a MTX-cleaving enzyme, carboxypeptidase G2, can be obtained from the Cancer Therapy Evaluation Program at the National Cancer Institute. MTX concentrations in plasma fall by >99% within 5-15 min following enzyme administration, with insignificant rebound. Systemically administered carboxypeptidase G2 has little effect on MTX levels in the CSF.
MTX (amethopterin; RHEUMATREX, TREXALL, others) is used in the treatment of severe, disabling psoriasis (see Chapter 65) in doses of 2.5 mg orally for 5 days, followed by a rest period of at least 2 days, or 10-25 mg intravenously weekly. It also is used at low dosage to induce remission in refractory rheumatoid arthritis. MTX inhibits cell-mediated immune reactions and is employed to suppress graft-versus-host disease in allogenic bone marrow and organ transplantation and for the treatment of dermatomyositis, Wegener granulomatosis, and Crohn disease (see Chapters 35 and 47). MTX is also used as an abortifacient, generally in combination with a prostaglandin (see Chapter 66).
CLINICAL TOXICITIES. The primary toxicities of antifolates are on the bone marrow and the intestinal epithelium. Patients may be at risk for spontaneous hemorrhage or life-threatening infection, and may require prophylactic transfusion of platelets and broad-spectrum antibiotics if febrile. Side effects usually reverse completely within 2 weeks, but prolonged myelosuppression may occur in patients with compromised renal function who have delayed drug excretion. The dosage of MTX (and likely pemetrexed) must be reduced in proportion to any reduction in CrCL. Additional toxicities of MTX include alopecia, dermatitis, an allergic interstitial pneumonitis, nephrotoxicity (after high-dose therapy), defective oogenesis or spermatogenesis, abortion, and teratogenesis. Low-dose MTX may lead to cirrhosis after long-term continuous treatment, as in patients with psoriasis. Intrathecal administration of MTX often causes meningismus and an inflammatory response in the CSF. Seizures, coma, and death may occur rarely. Leucovorin does not reverse neurotoxicity.
Pemetrexed toxicity mirrors that of MTX, with the additional feature of a prominent erythematous and pruritic rash in 40% of patients. Dexamethasone, 4 mg twice daily on days ~1, 0, and +1, markedly diminishes this toxicity. Unpredictably severe myelosuppression with pemetrexed, seen especially in patients with preexisting homocystinemia, largely is eliminated by concurrent administration of low dosages of folic acid, 350-1000 mg/day, beginning 1-2 weeks prior to pemetrexed and continuing while the drug is administered. Patients should receive intramuscular vitamin B12 (1 mg) with the first dose of pemetrexed to correct possible B12 deficiency. These small doses of folate and B12 do not compromise the therapeutic effect.
The pyrimidine antimetabolites encompass a diverse group of drugs that inhibit RNA and DNA function. The fluoropyrimidines and certain purine analogs (6-mercaptopurine and 6-thioguanine) inhibit the synthesis of essential precursors of DNA. Others, such as the cytidine and adenosine nucleoside analogs, become incorporated into DNA and block its further elongation and function. Other inhibitory effects of these analogs may contribute to their cytotoxicity and their capacity to induce differentiation.
Cellular Actions of Pyrimidine Antimetabolites. Four bases (Figure 61–5) form DNA: 2 pyrimidines (thymine and cytosine) and 2 purines (guanine and adenine). RNA differs in that it incorporates uracil instead of thymine as one of its bases. Strategies for inhibiting DNA synthesis are based on the ability to create analogs of these precursors that readily enter tumor cells and become activated by intracellularly. As an example, the pyrimidine analog, 5-FU, is converted to a deoxynucleotide, fluorodeoxyuridine monophosphate (FdUMP), which in turn blocks the enzyme, TS, required for the physiological conversion of dUMP to dTMP, a component of DNA. Other analogs incorporate into DNA itself and thereby block its function.
Cells can make the purine and pyrimidine bases de novo and convert them to their active triphosphates (dNTPs), providing substrates for DNA polymerase. Alternatively, cells can salvage free bases or their deoxynucleosides from the bloodstream. Thus, cells can take up uracil, guanine, and their analogs and convert them to (deoxy) nucleotides by the addition of deoxyribose and phosphate groups. Antitumor analogs of these bases (5-FU, 6-thioguanine) can be formulated as simple substituted bases. Other bases, including cytosine, thymine, and adenine, and their analogs can only be used as deoxynucleosides, which are readily transported into cells and activated to deoxynucleotides by intracellular kinase. Thus, cytarabine (cytosine arabinoside; Ara-C), gemcitabine, 5-azacytidine, and adenosine analogs (cladribine) (Figures 61–5 and 61–6) are nucleosides readily taken up by cells, converted to nucleotides, and incorporated into DNA.
Figure 61–5 Structural modification of base and deoxyribonucleoside analogs. Yellow ellipses indicate sites modified to create antimetabolites. Specific substitutions are noted in red for each drug. Modifications occur in the base ring systems, in their amino or hydroxyl side groups, and in the deoxyribose sugar found in deoxyribonucleosides. See structures in Figure 61–6.
Figure 61–6 Pyrimidine analogs.
Fludarabine phosphate, a nucleotide, is dephosphorylated rapidly in plasma, releasing the nucleoside that is readily taken up by cells. Analogs may differ from the physiological bases in a variety of ways: by altering in the purine or pyrimidine ring; by altering the sugar attached to the base, as in the arabinoside, Ara-C; or by altering both the base and sugar, as in fludarabine phosphate (see Figure 61–5). These alterations produce inhibitory effects on vital enzymatic pathways and prevent DNA synthesis.
FLUOROURACIL, CAPECITABINE, AND FLOXURIDINE (FLUORODEOXYURIDINE)
Fluorouracil is available as 5-FU, as the derivative fluorodeoxyuridine (FUdR, not often used in clinical practice), and as a prodrug, capecitabine, which is ultimately converted to 5-FU.
Mechanisms of Action. 5-FU requires enzymatic conversion (ribosylation and phosphorylation) to the nucleotide form to exert its cytotoxic activity. As the triphosphate FUTP, the drug is incorporated into RNA. Alternative reactions can produce the deoxy derivative FdUMP; FdUMP inhibits TS and blocks the synthesis of TTP, a necessary constituent of DNA (Figure 61–7). The folate cofactor, 5,10-methylenetetrahydrofolate, and FdUMP form a covalently bound ternary complex with TS. The physiological complex of TS-folate-dUMP progresses to the synthesis of thymidylate by transfer of the methylene group and 2 hydrogen atoms from folate to dUMP, but this reaction is blocked in the inhibited complex of TS-FdUMP-folate by the stability of the fluorine carbon bond on FdUMP; sustained inhibition of the enzyme results.
Figure 61–7 Actions of 5-fluoro-2′-deoxyuridine-5′-phosphate (5-FdUMP) and 5-FU nucleotides. 5-FU, 5-fluorouracil; dUMP FdUMP, deoxyuridine mono-phosphate/fluoro dUMP; FH2Glun/FH4Glun, dihydro-/tetrahydro-folate polyglutamates; TMP/TTP, thymidine monophosphate/triphosphate.
5-FU is incorporated into both RNA and DNA. In 5-FU-treated cells, both FdUTP and dUTP (that accumulates behind the blocked TS reaction) incorporate into DNA in place of the depleted physiological TTP. Presumably, such incorporation into DNA calls into action the excision-repair process, which can lead to DNA strand breakage because DNA repair requires TTP, which is lacking as a result of TS inhibition. 5-FU incorporation into RNA also causes toxicity as the result of major effects on both the processing and functions of RNA.
Mechanisms of Resistance. Resistance to the cytotoxic effects of 5-FU or FUdR has been ascribed to loss or decreased activity of the enzymes necessary for activation of 5-FU, amplification of TS, mutation of TS to a form that is not inhibited by FdUMP, and high levels of the degradative enzymes dihydrouracil dehydrogenase and thymidine phosphorylase. TS levels are finely controlled by an autoregulatory feedback mechanism wherein the unbound enzyme interacts with and inhibits the translational efficiency of its own mRNA, which provides for the rapid TS modulation needed for cellular division. When TS is bound to FdUMP, inhibition of translation is relieved, and levels of free TS rise, restoring thymidylate synthesis. Thus, TS autoregulation may be an important mechanism by which malignant cells become insensitive to the effects of 5-FU.
Some malignant cells appear to have insufficient concentrations of 5,10-methylenetetrahydrofolate, and thus cannot form maximal levels of the inhibited ternary complex with TS. Addition of exogenous folate in the form of leucovorin increases formation of the complex and enhances responses to 5-FU. A number of other agents have been combined with 5-FU in attempts to enhance the cytotoxic activity through biochemical modulation. MTX, by inhibiting purine synthesis and increasing cellular pools of 5-phosphoribosyl-1-pyrophosphate (PRPP), enhances the activation of 5-FU and increases antitumor activity of 5-FU when given prior to but not following 5-FU. The combination of cisplatin and 5-FU has yielded impressive responses in tumors of the upper aerodigestive tract, but the molecular basis of their interaction is unclear. Oxaliplatin, which downregulates TS expression, is commonly used with 5-FU and leucovorin for treating metastatic colorectal cancer. A most important interaction is the enhancement of irradiation by fluoropyrimidines, the basis for which is unclear. 5-FU with simultaneous irradiation cures anal cancer and enhances local tumor control in head, neck, cervical, rectal, gastroesophageal, and pancreatic cancer.
ADME. 5-FU is administered parenterally because absorption after oral ingestion of the drug is unpredictable and incomplete. 5-FU is inactivated by reduction of the pyrimidine ring in a reaction carried out by dihydropyrimidine dehydrogenase (DPD), which is found in liver, intestinal mucosa, tumor cells, and other tissues. Inherited deficiency of this enzyme leads to greatly increased sensitivity to the drug. DPD deficiency can be detected either by enzymatic or molecular assays using peripheral white blood cells or by determining the plasma ratio of 5-FU to its metabolite, 5-fluoro-5,6-dihydrouracil.
Plasma clearance is rapid (t1/2 ~10-20 min). Only 5-10% of a single intravenous dose of 5-FU is excreted intact in the urine. The dose does not have to be modified in patients with hepatic dysfunction, presumably because of sufficient degradation of the drug at extrahepatic sites. 5-FU enters the CSF in minimal amounts.
5-FLUOROURACIL. 5-FU produces partial responses in 10-20% of patients with metastatic colon carcinomas, upper GI tract carcinomas, and breast carcinomas but rarely is used as a single agent. 5-FU in combination with leucovorin and oxaliplatin or irinotecan in the adjuvant setting is associated with a survival advantage for patients with colorectal cancers. For average-risk patients in good nutritional status with adequate hematopoietic function, the weekly dosage regimen employs 500-600 mg/m2 with leucovorin once each week for 6 of 8 weeks. Other regimens use daily doses of 500 mg/m2 for 5 days, repeated in monthly cycles. When used with leucovorin, doses of daily 5-FU for 5 days must be reduced to 375-425 mg/m2 because of mucositis and diarrhea. 5-FU increasingly is used as a biweekly infusion, a schedule that has less overall toxicity as well as superior response rates and progression-free survival for patients with metastatic colon cancer.
FLOXURIDINE (FUdR). FUdR (fluorodeoxyuridine [FUDR]) is converted directly to FdUMP by thymidine kinase. The drug is administered primarily by continuous infusion into the hepatic artery for treatment of metastatic carcinoma of the colon or following resection of hepatic metastases; the response rate to such infusion is 40-50%, double that observed with intravenous administration. Intrahepatic arterial infusion for 14-21 days causes minimal systemic toxicity; however, there is a significant risk of biliary sclerosis if this route is used for multiple cycles of therapy. Treatment should be discontinued at the earliest manifestation of toxicity (usually stomatitis or diarrhea) because the maximal effects of bone marrow suppression and gut toxicity will not be evident until days 7-14.
CAPECITABINE (XELODA). Capecitabine, an orally administered prodrug of 5-FU, is approved for the treatment of (1) metastatic breast cancer in patients who have not responded to a regimen of paclitaxel and an anthracycline antibiotic; (2) metastatic breast cancer when used in combination with docetaxel in patients who have had a prior anthracycline-containing regimen; and (3) metastatic colorectal cancer. The recommended dosage is 2500 mg/m2/day, given in 2 divided doses with food, for 2 weeks, followed by a rest period of 1 week. Capecitabine is well absorbed orally. It is rapidly de-esterified and deaminated, yielding high plasma concentrations of an inactive prodrug 5′-deoxyfluorodeoxyuridine (5′-dFdU), which disappears with a t1/2 of 1 h. The conversion of 5′-dFdU to 5-FU by thymidine phosphorylase occurs in liver tissues, peripheral tissues, and tumors. 5-FU levels are <10% of those of 5′-dFdU, reaching a maximum of 0.3 mg/L or 1 μM at 2 h. Liver dysfunction delays the conversion of the parent compound to 5′-dFdU and 5-FU, but there is no consistent effect on toxicity.
Combination Therapy. Higher response rates are seen when 5-FU or capecitabine is used in combination with other agents (e.g., with cisplatin in head and neck cancer, with oxaliplatin or irinotecan in colon cancer). The combination of 5-FU and oxaliplatin or irinotecan has become the standard first-line treatment for patients with metastatic colorectal cancer. The use of 5-FU in combination regimens has improved survival in the adjuvant treatment for breast cancer and, with oxaliplatin and leucovorin, for colorectal cancer. 5-FU also is a potent radiation sensitizer. Beneficial effects also have been reported when combined with irradiation as primary treatment for locally advanced cancers of the esophagus, stomach, pancreas, cervix, anus, and head and neck. 5-FU produces very favorable results for the topical treatment of premalignant keratoses of the skin and multiple superficial basal cell carcinomas.
Clinical Toxicities. The clinical manifestations of toxicity caused by 5-FU and floxuridine are similar. The earliest untoward symptoms during a course of therapy are anorexia and nausea, followed by stomatitis and diarrhea, reliable warning signs that a sufficient dose has been administered. Mucosal ulcerations occur throughout the GI tract and may lead to fulminant diarrhea, shock, and death, particularly in patients who are DPD deficient. The major toxic effects of bolus-dose regimens result from the myelosuppressive action of 5-FU. The nadir of leukopenia usually occurs 9-14 days after the first injection of drug. Thrombocytopenia and anemia also may occur, as may loss of hair (occasionally progressing to total alopecia), nail changes, dermatitis, and increased pigmentation and atrophy of the skin may. Hand-foot syndrome, a particularly prominent adverse effect of capecitabine, consists of erythema, desquamation, pain, and sensitivity to touch of the palms and soles. Acute chest pain with evidence of ischemia in the electrocardiogram may result from coronary artery vasospasms during or shortly after 5-FU infusion. In general, myelosuppression, mucositis, and diarrhea occur less often with infusional than with bolus regimens, while hand-foot syndrome occurs more often with infusional than with bolus regimens. The significant risk of toxicity with fluoropyrimidines emphasizes the need for very skillful supervision by physicians familiar with the action and possible hazards.
Capecitabine causes a similar spectrum of toxicities as 5-FU (diarrhea, myelosuppression), but the hand-foot syndrome occurs more frequently and may require dose reduction or cessation of therapy.
CYTARABINE (CYTOSINE ARABINOSIDE; Ara-C)
Cytarabine (1-β-D-arabinofuranosylcytosine; Ara-C [CYTOSAR-U, TARABINE PFS, others]) is the most important antimetabolite used in the therapy of AML; it is the single most effective agent for induction of remission in this disease.
MECHANISM OF ACTION. Ara-C is an analog of 2′-deoxycytidine; the 2′-hydroxyl in a position trans to the 3′-hydroxyl of the sugar (see Figures 61–5 and 61–6) hinders rotation of the pyrimidine base around the nucleoside bond and interferes with base pairing. The drug enters cells via nucleoside transporters; hENT1 appears to be the primary mediator of Ara-C influx. In the cell, Ara-C is converted to its active form, the 5′-monophosphate ribonucleotide, by deoxycytidine kinase (CdK), an enzyme that shows polymorphic expression among patients (see below). Ara-CMP then reacts with deoxynucleotide kinases to form diphosphate and triphosphates (Ara-CDP and Ara-CTP). Ara-CTP competes with deoxycytidine 5′-triphosphate (dCTP) for incorporation into DNA by DNA polymerases. The incorporated Ara-CMP residue is a potent inhibitor of DNA polymerase, both in replication and repair synthesis, and blocks the further elongation of the nascent DNA molecule. If DNA breaks are not repaired, apoptosis ensues. Ara-C cytotoxicity correlates with the total Ara-C incorporated into DNA; incorporation of ~5 molecules of Ara-C per 104 bases of DNA decreases cellular clonogenicity by ~50%.
In infants and adults with ALL and t(4;11) mixed-lineage leukemia (MLL) translocation, high-dose Ara-C is particularly effective; in these patients, the nucleoside transporter, hENT1, is highly expressed, and its expression correlates with sensitivity to Ara-C. At extracellular drug concentrations >10 1M (levels achievable with high-dose Ara-C), the nucleoside transporter no longer limits drug accumulation, and intracellular metabolism to a triphosphate becomes rate limiting. Particular subtypes of AML derive benefit from high-dose Ara-C treatment; these include t(8;21), inv(16), t(9;16), and del(16). Approximately 20% of AML patients have leukemic cells with a k-RAS mutation, and these patients seem to derive greater benefit from high dose Ara-C regimens than do patients with wild type k-RAS.
MECHANISMS OF RESISTANCE. Response to Ara-C is strongly influenced by the relative activities of anabolic and catabolic enzymes that determine the proportion of drug converted to Ara-CTP. The rate-limiting activating enzyme, CdK, produces Ara-CMP. It is opposed by the degradative enzyme, cytidine deaminase, which converts Ara-C to a nontoxic metabolite, ara-uridine (Ara-U). Cytidine deaminase activity is high in many normal tissues, including intestinal mucosa, liver, and neutrophils, but lower in AML cells and other human tumors. A second degradative enzyme, dCMP deaminase, converts Ara-CMP to the inactive metabolite, Ara-UMP. Increased synthesis and retention of Ara-CTP in leukemic cells lead to a longer duration of complete remission in patients with AML. The capacity of cells to transport Ara-C also may affect response. Clinical studies have implicated a loss of CdK as the primary mechanism of resistance to Ara-C in AML.
ADME. Due to the presence of high concentrations of cytidine deaminase in the GI mucosa and liver, only ~20% of the drug reaches the circulation after oral Ara-C administration; thus, the drug must be given intravenously. Peak concentrations of 2-50 μM are measurable in plasma after intravenous injection of 30-300 mg/m2 but fall rapidly (t1/2 ≈ 10 min). Less than 10% of the injected dose is excreted unchanged in the urine within 12-24 h; most appears as the inactive deaminated product, Ara-U. Higher concentrations of Ara-C are found in CSF after continuous infusion than after rapid intravenous injection, but are ≤10% of concentrations in plasma. After intrathecal administration of the drug at a dose of 50 mg/m2, deamination proceeds slowly, with a t1/2 of 3-4 h, and peak concentrations of 1-2 μM are achieved. CSF concentrations remain above the threshold for cytotoxicity (0.4 μM) for ≥24 h. A depot liposomal formulation of Ara-C (DEPOCYT) provides sustained release into the CSF. After a standard 50-mg dose, liposomal Ara-C remains above cytotoxic levels for an average of 12 days, thus avoiding the need for frequent lumbar punctures.
Therapeutic Uses. Continuous inhibition of DNA synthesis for a duration equivalent to at least 1 cell cycle or 24 h is necessary to expose most tumor cells during the S, or DNA-synthetic, phase of the cycle. The optimal interval between bolus doses of Ara-C is ~8-12 h, a schedule that maintains intracellular concentrations of Ara-CTP at inhibitory levels during a multi-day cycle of treatment. Typical schedules for administration of Ara-C employ bolus doses every 12 h or continuous drug infusion for 5-7 days. Two dosage schedules are recommended: (1) rapid intravenous infusion of 100 mg/m2 every 12 h for 5-7 days or (2) continuous intravenous infusion of 100-200 mg/m2/day for 5-7 days. In general, children tolerate higher doses than adults. Intrathecal doses of 30 mg/m2 every 4 days have been used to treat meningeal or lymphomatous leukemia. The intrathecal administration of liposomal cytarabine (DEPOCYT), 50 mg for adults, 35 mg for children, every 2 weeks seems equally effective as the every-4-days regimen with the standard drug. Ara-C is indicated for induction and maintenance of remission in AML and is useful in the treatment of other leukemias, such as ALL, CML in the blast phase, acute promyelocytic leukemia, and high-grade lymphomas. Because drug concentration in plasma rapidly falls below the level needed to saturate transport and intercellular activation, clinicians have employed high-dose regimens (2-3 g/m2 every 12 h for 6-8 doses) to achieve 20-50 times higher serum levels, with improved results in remission induction and consolidation for AML. Injection of the liposomal formulation is indicated for the intrathecal treatment of lymphomatous meningitis.
CLINICAL TOXICITIES. Cytarabine is a potent myelosuppressive agent capable of producing acute, severe leukopenia, thrombocytopenia, and anemia with striking megaloblastic changes. Other toxic manifestations include GI disturbances, stomatitis, conjunctivitis, reversible hepatic enzyme elevations, noncardiogenic pulmonary edema, and dermatitis. The onset of dyspnea, fever, and pulmonary infiltrates on chest computed tomography scans may follow 1-2 weeks after high-dose Ara-C and may be fatal in 10-20% of patients, especially in patients being treated for relapsed leukemia. No specific therapy, other than Ara-C discontinuation, is indicated. Intrathecal Ara-C, either the free drug or the liposomal preparation, may cause arachnoiditis, seizures, delirium, myelopathy, or coma, especially if given concomitantly with systemic high-dose MTX or systemic Ara-C. Cerebellar toxicity, manifesting as ataxia and slurred speech, and cerebral toxicity (seizures, dementia, and coma) may follow intrathecal administration or high-dose systemic administration, especially in patients >40 years of age and/or patients with poor renal function.
5-Azacytidine (see Figure 61–6) and decitabine (2′-deoxy-5-azacytidine) have antileukemic activity and induce differentiation by inhibiting DNA cytosine methyltransferase activity. Both drugs are approved for treatment of myelodysplasia, for which they induce normalization of bone marrow in 15-20% of patients and reduce transfusion requirement in one-third of patients. 5-Azacytidine improves survival.
Mechanism of Action. The aza-nucleosides enter cells by the human equilibrative transporter. The drugs incorporate into DNA, where they become covalently bound to the methyltransferase, depleting intracellular enzyme and leading to global demethylation of DNA, tumor cell differentiation, and apoptosis. Decitabine also induces double-strand DNA breaks, perhaps as a consequence of the effort to repair the protein-DNA adduct.
Pharmacokinetics. After subcutaneous administration of the standard dose of 75 mg/m2, 5-azacytidine undergoes rapid deamination by cytidine deaminase (plasma t1/2 20-40 min). Due to the formation of intracellular nucleotides, which become incorporated into DNA, the effects of the aza-nucleosides persist for many hours.
Therapeutic Use. The usual regimen for 5-azacytidine in myelodysplastic syndrome (MDS) is 75 mg/m2/day for 7 days every 28 days, while decitabine is given in a dose of 20 mg intravenously every day for 5 days every 4 weeks. Best responses may become apparent only after 2-5 courses of treatment.
Toxicity. The major toxicities of the aza-nucleosides include myelosuppression and mild GI symptoms. 5-Azacytidine produces rather severe nausea and vomiting when given intravenously in large doses (150-200 mg/m2/day for 5 days).
Gemcitabine (2′,2′-difluorodeoxycytidine; dFdC) (see Figure 61–6), a difluoro analog of deoxycytidine, is used for patients with metastatic pancreatic; non-squamous, non–small cell lung; ovarian; and bladder cancer.
Mechanism of Action. Gemcitabine enters cells via 3 distinct nucleoside transporters: hENT (the major route), hCNT, and a nucleobase transporter found in malignant mesothelioma cells. Intracellularly, CdK phosphorylates gemcitabine to the monophosphate (dFdCMP), which is converted to di- and triphosphates (dFdCDP and dFdCTP). Although gemcitabine’s anabolism and effects on DNA in general mimic those of cytarabine, there are distinct differences in kinetics of inhibition, additional enzymatic sites of action, different effects of incorporation into DNA, and a distinct spectrum of clinical activity. Unlike that of cytarabine, the cytotoxicity of gemcitabine is not confined to the S phase of the cell cycle. The cytotoxic activity may reflect several actions on DNA synthesis. dFdCTP competes with dCTP as a weak inhibitor of DNA polymerase. dFdCDP is a stoichiometric inhibitor of ribonucleotide reductase (RNR), resulting in depletion of deoxyribonucleotide pools necessary for DNA synthesis. Incorporation of dFdCTP into DNA causes DNA strand termination and appears resistant to repair. The capacity of cells to incorporate dFdCTP into DNA is critical for gemcitabine-induced apoptosis. Gemcitabine is inactivated by cytidine deaminase, which is found both in tumor cells and throughout the body.
ADME. Gemcitabine is administered as an intravenous infusion. The pharmacokinetics of the parent compound are largely determined by deamination in liver, plasma, and other organs, and the predominant urinary elimination product is dFdU. In patients with significant renal dysfunction, dFdU and its triphosphate accumulate to high and potentially toxic levels. Gemcitabine has a short plasmat1/2 (~15 min); women and elderly patients clear the drug more slowly.
Therapeutic Uses. The standard dosing schedule for gemcitabine (GEMZAR) is a 30-min intravenous infusion of 1-1.25 g/m2 on days 1, 8, and 15 of each 21- to 28-day cycle, depending on the indication. Conversion of gemcitabine to dFdCMP by CdK is saturated at infusion rates of ~10 mg/m2/min. To increase dFdCTP formation, the duration of infusion at this maximum concentration has been extended to 100-150 min at a fixed rate of 10 mg/min. The 150-min infusion produces a higher level of dFdCTP within peripheral blood mononuclear cells and increases the degree of myelosuppression but does not improve antitumor activity. The inhibition of DNA repair by gemcitabine may increase cytotoxicity of other agents, particularly platinum compounds, and with radiation therapy.
Clinical Toxicities. The principal toxicity is myelosuppression. Longer-duration infusions lead to greater myelosuppression and hepatic toxicity. Nonhematological toxicities include a flu-like syndrome, asthenia, and rarely a posterior leukoencephalopathy syndrome. Mild, reversible elevation in liver transaminases may occur in ≥40% of patients. Interstitial pneumonitis, at times progressing to acute respiratory distress syndrome (ARDS), may occur within the first 2 cycles of treatment and usually responds to corticosteroids. Rarely, patients treated for many months may develop a slowly progressive hemolytic uremic syndrome, necessitating drug discontinuation. Gemcitabine is a very potent radiosensitizer and should not be used with radiotherapy.
The pioneering studies of Hitchings and Elion identified analogs of naturally occurring purine bases with antileukemic and immunosuppressant properties. Figure 61–8 shows structural formulas of several of these, with adenosine for comparison.
Figure 61–8 Adenosine and various purine analogs.
Other purine analogs that have valuable roles in leukemia and lymphoid malignancies include cladribine (standard therapy for hairy cell leukemia), fludarabine phosphate (standard treatment for CLL), nelarabine (pediatric ALL), and clofarabine (T-cell leukemia/lymphoma). The apparent selectivity of these agents may relate to their effective uptake, activation, and apoptotic effects in lymphoid tissue.
6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG) are approved agents for human leukemias and function as analogs of the natural purines, hypoxanthine and guanine. The substitution of sulfur for oxygen on C6 of the purine ring creates compounds that are readily transported into cells, including activated malignant cells. Nucleotides formed from 6-MP and 6-TG inhibit de novo purine synthesis and also become incorporated into nucleic acids.
Mechanism of Action. Hypoxanthine guanine phosphoribosyl transferase (HGPRT) converts 6-TG and 6-MP to the ribonucleotides 6-thioguanosine-5′-monophosphate (6-thioGMP) and 6-thioinosine-5′-monophosphate (T-IMP), respectively. Because T-IMP is a poor substrate for guanylyl kinase (the enzyme that converts GMP to GDP), T-IMP accumulates intracellularly. T-IMP inhibits the new formation of ribosyl-5-phosphate, as well as conversion of IMP to adenine and guanine nucleotides. The most important point of attack seems to be the reaction of glutamine and PRPP to form ribosyl-5-phosphate, the first committed step in the de novo pathway. 6-Thioguanine nucleotide is incorporated into DNA, where it induces strand breaks and base mispairing.
Mechanisms of Resistance. The most common mechanism of 6-MP resistance observed in vitro is deficiency or complete lack of the activating enzyme, HGPRT, or increased alkaline phosphatase activity. Other mechanisms for resistance include (1) decreased drug uptake, or increased efflux due to active transporters; (2) alteration in allosteric inhibition of ribosylamine 5-phosphate synthase; and (3) impaired recognition of DNA breaks and mismatches due to loss of a component (MSH6) of MMR.
Pharmacokinetics and Toxicity. Absorption of oral mercaptopurine is incomplete (10-50%); the drug is subject to first-pass metabolism by xanthine oxidase in the liver. Food or oral antibiotics decrease absorption. Oral bioavailability is increased when mercaptopurine is combined with high-dose MTX. After an intravenous dose, the t1/2 of the drug is ~50 min in adults, due to rapid metabolic degradation by xanthine oxidase and by thiopurine methyltransferase (TPMT). Restricted brain distribution of mercaptopurine results from an efficient efflux transport system in the blood-brain barrier. In addition to the HGPRT-catalyzed anabolism of mercaptopurine, there are 2 other pathways for its metabolism. The first involves methylation of the sulfhydryl group and subsequent oxidation of the methylated derivatives. Activity of the enzyme TPMT reflects the inheritance of polymorphic alleles; up to 15% of the Caucasian population has decreased enzyme activity. Low levels of erythrocyte TPMT activity are associated with increased drug toxicity in individual patients and a lower risk of relapse. In patients with autoimmune disease treated with mercaptopurine, those with polymorphic alleles may experience bone marrow aplasia and life-threatening toxicity. Testing for these polymorphisms prior to treatment is recommended in this patient population.
A relatively large percentage of the administered sulfur appears in the urine as inorganic sulfate. The second major pathway for 6-MP metabolism involves its oxidation by xanthine oxidase to 6-thiourate, an inactive metabolite. Oral doses of 6-MP should be reduced by 75% in patients receiving the xanthine oxidase inhibitor, allopurinol; no dose adjustment is required for intravenous dosing.
Therapeutic Uses. In the maintenance therapy of ALL, the initial daily oral dose of 6-MP (PURINETHOL) is 50-100 mg/m2 and is thereafter adjusted according to white blood cell and platelet count. The combination of MTX and 6-MP appears to be synergistic. By inhibiting the earliest steps in purine synthesis, MTX elevates the intracellular concentration of PRPP, a cofactor required for 6-MP activation.
CLINICAL TOXICITIES. The principal toxicity of 6-MP is bone marrow depression; thrombocytopenia, granulocytopenia, or anemia may not become apparent for several weeks. When depression of normal bone marrow elements occurs, dose reduction usually results in prompt recovery, although myelosuppression may be severe and prolonged in patients with a polymorphism affecting TPMT. Anorexia, nausea, or vomiting is seen in ~25% of adults, but stomatitis and diarrhea are rare; manifestations of GI effects are less frequent in children than in adults. Jaundice and hepatic enzyme elevations occur in up to one-third of adult patients treated with 6-MP and usually resolve upon discontinuation of therapy. 6-MP and its derivative, azathioprine, predispose to opportunistic infection (e.g., reactivation of hepatitis B, fungal infection, and Pneumocystis pneumonia), and an increased incidence of squamous cell malignancies of the skin. 6-MP is teratogenic during the first trimester of pregnancy, and AML has been reported after prolonged 6-MP therapy for Crohn disease.
Fludarabine phosphate is a fluorinated, deamination-resistant, phosphorylated analog of the antiviral agent vidarabine (9-β-D-arabinofuranosyl-adenine). It is active in CLL and low-grade lymphomas and is also effective as a potent immunosuppressant.
Mechanisms of Action and Resistance. The drug is dephosphorylated extracellularly to the nucleoside fludarabine, which enters the cell and is rephosphorylated by CdK to the active triphosphate. This antimetabolite inhibits DNA polymerase, DNA primase, DNA ligase, and RNR, and becomes incorporated into DNA and RNA. The nucleotide is an effective chain terminator when incorporated into DNA. Incorporation of fludarabine into RNA inhibits RNA function, RNA processing, and mRNA translation.
In experimental tumors, resistance to fludarabine is associated with decreased activity of CdK (the enzyme that phosphorylates the drug), increased drug efflux, and increased RNR activity. Its mechanism of immunosuppression and paradoxical stimulation of autoimmunity stems from the particular susceptibility of lymphoid cells to purine analogs and the specific effects on the CD4+ subset of T cells, as well as its inhibition of regulatory T-cell responses.
ADME. Fludarabine phosphate is administered both intravenously and orally and is rapidly converted to fludarabine in the plasma. The median time to reach maximal concentrations of drug in plasma after oral administration is 1.5 h, and oral bioavailability averages 55-60%. The t1/2 of fludarabine in plasma is ~10 h. The compound is eliminated primarily by renal excretion.
THERAPEUTIC USES. Fludarabine phosphate (FLUDARA, OFORTA) is approved for intravenous and oral use and is equally active by both routes. The recommended dose is 25 mg/m2 daily for 5 days by intravenous infusion, or 40 mg/m2 daily for 5 days by mouth. The drug is administered intravenously over 30-120 min. Dosage should be reduced in patients with renal impairment in proportion to the reduction in CrCl. Treatment may be repeated every 4 weeks, and gradual improvement in CLL usually occurs within 2-3 cycles. Fludarabine phosphate is highly active alone or with rituximab and cyclophosphamide for the treatment of patients with CLL; overall response rates in previously untreated patients approximate 80% and the duration of response averages 22 months. The synergy of fludarabine with alkylators may stem from the observation that it blocks the repair of double-strand DNA breaks and interstrand cross-links induced by alkylating agents. It also is effective in follicular B-cell lymphomas refractory to standard therapy. It is increasingly used as a potent immunosuppressive agent in nonmyeloablative allogeneic bone marrow transplantation.
CLINICAL TOXICITIES. Oral and intravenous therapy cause myelosuppression in ~50% of patients, nausea and vomiting in a minor fraction, and, uncommonly, chills and fever, malaise, anorexia, peripheral neuropathy, and weakness. Lymphopenia and thrombocytopenia and cumulative side effects are expected. Depletion of CD4+ T cells with therapy predisposes to opportunistic infections. Tumor lysis syndrome, a rare complication, occurs primarily in previously untreated patients with CLL. Altered mental status, seizures, optic neuritis, and coma have been observed at higher doses and in older patients. Autoimmune events may occur after fludarabine treatment. CLL patients may develop an acute hemolytic anemia or pure red cell aplasia during or following fludarabine treatment. Prolonged cytopenias, probably mediated by autoimmunity, also complicate fludarabine treatment. Myelodysplasia and acute leukemias may arise as late complications. Pneumonitis is an occasional side effect and responds to corticosteroids. In patients with compromised renal function, the initial doses should be reduced in proportion to the reduction in CrCl.
Cladribine (2-chlorodeoxyadenosine [2-CdA]) is an adenosine deaminase-resistant purine analog that has potent and probably curative activity in hairy cell leukemia, CLL, and low-grade lymphomas.
Mechanisms of Action and Resistance. Cladribine enters cells via active nucleoside transport. After phosphorylation by CdK and conversion to cladribine triphosphate, it is incorporated into DNA. It produces DNA strand breaks and depletion of NAD and ATP, leading to apoptosis. It is a potent inhibitor of RNR. The drug does not require cell division to be cytotoxic. Resistance is associated with loss of the activating enzyme, CdK; increased expression of RNR; or increased active efflux by ABCG2 or other members of the ABC cassette family of transporters.
ADME. Cladribine is moderately well absorbed orally (55%) but is routinely administered intravenously. It is excreted by the kidneys, with a terminal t1/2 in plasma of 6.7 h. Cladribine crosses the blood-brain barrier and reaches CSF concentrations of ~25% of those seen in plasma. Doses should be adjusted for renal dysfunction.
Therapeutic Uses. Cladribine (LEUSTATIN, others) is administered as a single course of 0.09 mg/kg/day for 7 days by continuous intravenous infusion. It is the drug of choice in hairy cell leukemia. Eighty percent of patients achieve a complete response after a single course of therapy. The drug also is active in CLL; low-grade lymphomas; Langerhans cell histiocytosis; CTCLs, including mycosis fungoides and the Sézary syndrome; and Waldenström macroglobulinemia.
Clinical Toxicities. The major dose-limiting toxicity of cladribine is myelosuppression. Cumulative thrombocytopenia may occur with repeated courses. Opportunistic infections are common and correlate with decreased CD4+ cell counts. Other toxic effects include nausea, infections, high fever, headache, fatigue, skin rashes, and tumor lysis syndrome.
This analog incorporates the 2-chloro, glycosylase-resistant substituent of cladribine and a 2′-fluoro-arabinosyl substitution, which adds stability and enhances uptake and phosphorylation. The resulting compound is approved for pediatric ALL after failure of 2 prior therapies. Clofarabine produces complete remissions in 20-30% of these patients. It has activity as well in pediatric and adult AML and in myelodysplasia. The uptake and metabolic activation of clofarabine in tumor cells follow the same path as cladribine and the other purine nucleosides, although clofarabine is more readily phosphorylated by dCK. Clofarabine triphosphate has a long intracellular t1/2 (24 h). It incorporates into DNA, where it terminates DNA synthesis and leads to apoptosis; clofarabine also inhibits RNR.
Clinical Pharmacology. In children, it is administered in doses of 52 mg/m2 given as a 2-h infusion daily for 5 days. The primary elimination t1/2 in plasma is 6.5 h. Most of the drug is excreted unchanged in the urine. Doses should be adjusted according to reductions in CrCl. The primary toxicities are myelosuppression; a clinical syndrome of hypotension, tachyphemia, pulmonary edema, organ dysfunction, and fever, all suggestive of capillary leak syndrome and cytokine release that necessitate immediate discontinuation of the drug; elevated hepatic enzymes and increased bilirubin; nausea, vomiting, and diarrhea; and hypokalemia and hypophosphatemia.
Nelarabine is the only guanine nucleoside in clinical use. It has selective activity against acute T-cell leukemia (20% complete responses) and the closely related T-cell lymphoblastic lymphoma and is approved for use in relapsed/refractory patients. Its basic mechanism of action closely resembles that of the other purine nucleosides, in that it is incorporated into DNA and terminates DNA synthesis.
ADME. Following infusion, the parent methoxy compound is rapidly activated in blood and tissues by adenosine deaminase–mediated cleavage of the methyl group, yielding the phosphorylase resistant Ara-G, which has a plasma t1/2 of 3 h. The active metabolite is transported into tumor cells, where it is activated by CdK to Ara-G triphosphate (Ara-GTP) that incorporates into DNA and terminates DNA synthesis. The drug and its metabolite, Ara-G, are primarily eliminated by metabolism to guanine, and a smaller fraction is eliminated by renal excretion of Ara-G. The dose should be used with close clinical monitoring in patients with severe renal impairment (CrCL <50 mg/mL). Adults are given a dose of 1500 mg/m2 intravenously as a 2-h infusion on days 1, 3, and 5 of a 21-day cycle, and children are given a lower dose of 650 mg/m2/day intravenously for 5 days and repeated every 21 days.
Clinical Toxicity. Side effects include myelosuppression and liver function test abnormalities, as well as frequent, serious neurological sequelae, such as seizures, delirium, somnolence, peripheral neuropathy, or Guillain-Barré syndrome. Neurological side effects may not be reversible.
Pentostatin (2′-deoxycoformycin; see Figure 61–8), a transition-state analog of the intermediate in the adenosine deaminase (ADA) reaction, potently inhibits ADA. Its effects mimic the phenotype of genetic ADA deficiency (severe immunodeficiency affecting both T- and B-cell functions).
Mechanism of Action. Inhibition of ADA by pentostatin leads to accumulation of intracellular adenosine and deoxyadenosine nucleotides, which can block DNA synthesis by inhibiting RNR. Deoxyadenosine also inactivates S-adenosyl homocysteine hydrolase. The resulting accumulation of S-adenosyl homocysteine is particularly toxic to lymphocytes. Pentostatin also can inhibit RNA synthesis, and its triphosphate derivative is incorporated into DNA, resulting in strand breakage. Although the precise mechanism of cytotoxicity is not known, it is probable that the imbalance in purine nucleotide pools accounts for its antineoplastic effect in hairy cell leukemia and T-cell lymphomas.
ADME. Pentostatin is administered intravenously and has a mean terminal t1/2 of 5.7 h. The recommended dose is 4 mg/m2 administered intravenously, every other week. After hydration with 500-1000 mL of 5% dextrose in half-normal (0.45%) saline, the drug is administered by rapid intravenous injection or by infusion over a period of ≤30 min, followed by an additional 500 mL of fluids. The drug is eliminated almost entirely by renal excretion. Proportional reduction of dosage is recommended in patients with renal impairment as measured by reduced CrCl.
Clinical Use. Pentostatin is effective in producing complete remissions (58%) and partial responses (28%) in hairy cell leukemia. It largely has been superseded by cladribine. Toxic manifestations include myelosuppression, GI symptoms, skin rashes, and abnormal liver function studies. Depletion of normal T cells occurs, and neutropenic fever and opportunistic infections may result. Immunosuppression may persist for several years after discontinuation. At high doses (10 mg/m2), major renal and neurological complications are encountered. Pentostatin in combination with fludarabine phosphate may result in severe or even fatal pulmonary toxicity.
III. Natural Products
Purified alkaloids from the periwinkle plant, including vinblastine and vincristine, were among the earliest clinical agents for treatment of leukemias, lymphomas, and testicular cancer. A closely related derivative, vinorelbine, has important activity against lung and breast cancer.
Mechanism of Action. The vinca alkaloids are cell-cycle–specific agents and, in common with other drugs, such as colchicine, podophyllotoxin, the taxanes, and the epothilones, block cells in mitosis. The biological activities of the vincas can be explained by their ability to bind specifically to β tubulin and to block its polymerization with α tubulin into microtubules. The mitotic spindle cannot form, duplicated chromosomes cannot align along the division plate, and cell division arrests in metaphase. Cells blocked in mitosis undergo changes characteristic of apoptosis. Microtubules are found in high concentration in the brain and contribute to other cellular functions such as movement, phagocytosis, and axonal transport. Side effects of the vinca alkaloids, such as their neurotoxicity, may relate to disruption of these functions.
Resistance. Despite their structural similarity, the individual vinca alkaloids have unique patterns of clinical efficacy (see below). However, in most experimental systems, they share cross-resistance. Their antitumor effects are blocked by multidrug resistance mediated by the mdr gene/P-glycoprotein, which confers resistance to a broad range of agents (the vinca alkaloids, epipodophyllotoxins, anthracyclines, and taxanes). Chromosomal abnormalities consistent with gene amplification and markedly increased levels of P-glycoprotein (a membrane efflux transporter) have been observed in resistant cells in culture. Other membrane transporters, such as the MRP and the closely related breast cancer resistance protein, may contribute to resistance. Other forms of resistance to vinca alkaloids stem from mutations in β tubulin or in the relative expression of isoforms of β tubulin that prevent the inhibitors from effectively binding to their target.
Cytotoxic Actions. The very limited myelosuppressive action of vincristine makes it a valuable component of several combination therapy regimens for leukemia and lymphoma, while the lack of severe neurotoxicity of vinblastine is a decided advantage in lymphomas and in combination with cisplatin against testicular cancer. Vinorelbine, which causes a mild neurotoxicity as well as myelosuppression, has an intermediate toxicity profile.
Metabolism and Excretion. The liver cytochromes extensively metabolize all 3 agents, and the metabolites are excreted in the bile. Only a small fraction of a dose (<15%) is found in the urine unchanged. In patients with hepatic dysfunction (bilirubin >3 mg/dL), a 50-75% reduction in dose of any of the vinca alkaloids is advisable. The elimination t1/2 is 20 h for vincristine, 23 h for vinblastine, and 24 h for vinorelbine.
Therapeutic Uses. Vinblastine sulfate (VELBAN) is given intravenously; special precautions must be taken against subcutaneous extravasation, which may cause painful irritation and ulceration. The drug should not be injected into an extremity with impaired circulation. After a single dose of 0.3 mg/kg of body weight, myelosuppression reaches its maximum in 7-10 days. If a moderate level of leukopenia (~3000 cells/mm3) is not attained, the weekly dose may be increased gradually by increments of 0.05 mg/kg of body weight. For testicular cancer, vinblastine is used in doses of 0.3 mg/kg every 3 weeks. Doses should be reduced by 50% for patients with plasma bilirubin >1.5 mg/dL. Vinblastine is used with bleomycin and cisplatin in the curative therapy of metastatic testicular tumors, although it has been supplanted by etoposide or ifosfamide. It is a component of the standard curative regimen for Hodgkin disease (doxorubicin [ADRIAMYCIN], bleomycin, vinblastine, and dacarbazine [ABVD]). It also is active in Kaposi sarcoma, neuroblastoma, Langerhans cell histiocytosis, bladder cancer, carcinoma of the breast, and choriocarcinoma.
Clinical Toxicities. Maximal leukopenia occurs within 7-10 days, after which recovery ensues within 7 days. Other toxic effects of vinblastine include mild neurological manifestations. GI disturbances including nausea, vomiting, anorexia, and diarrhea may be encountered. The syndrome of inappropriate secretion of antidiuretic hormone has been reported. Loss of hair, stomatitis, and dermatitis occur infrequently. Extravasation during injection may lead to cellulitis and phlebitis.
Therapeutic Uses. Vincristine is a standard component of regimens for treating pediatric leukemias, lymphomas, and solid tumors, such as Wilms, tumor, neuroblastoma, and rhabdomyosarcoma. In large-cell non-Hodgkin lymphomas, vincristine remains an important agent, particularly when used in the CHOP regimen with cyclophosphamide, doxorubicin, and prednisone. Vincristine sulfate (VINCASARPFS) used with glucocorticoids is the treatment of choice to induce remissions in childhood leukemia and in combination with alkylating agents and anthracycline for pediatric sarcomas. The common intravenous dosage for vincristine is 2 mg/m2 of body surface area at weekly or longer intervals. Vincristine is tolerated better by children than by adults, who may experience severe, progressive neurological toxicity and require a lower dose of 1.4 mg/m2. Administration of the drug more frequently than every 7 days or at higher doses increases the toxic manifestations without proportional improvement in the response rate. Precautions also should be used to avoid extravasation during intravenous administration. Doses should be reduced for patients with elevated plasma bilirubin.
Clinical Toxicities. The clinical toxicity of vincristine is mostly neurological. Severe neurological manifestations may be reversed by suspending therapy or reducing the dosage, upon first evidence of motor dysfunction. Severe constipation, sometimes resulting in colicky abdominal pain and obstruction, may be prevented by a prophylactic program of laxatives and hydrophilic (bulk-forming) agents, and usually is a problem only with doses >2 mg/m2. Reversible alopecia occurs in ~20% of patients. Modest leukopenia may occur. Thrombocytopenia, anemia, and the syndrome of inappropriate secretion of ADH are less common. Inadvertent injection of vincristine into the CSF causes a devastating and often fatal irreversible coma and seizures.
Vinorelbine has activity against non–small cell lung cancer and breast cancer. Vinorelbine (NAVELBINE, others) is administered in normal saline as an intravenous infusion over 6-10 min. When used alone, it is given at doses of 30 mg/m2 either weekly or for 2 out of every 3 weeks. When used with cisplatin for the treatment of non–small cell lung cancer, it is given at doses of 25 mg/m2 either weekly or for 3 out of every 4 weeks. A lower dose (20-25 mg/m2) may be required for patients who have received prior chemotherapy and for hematological toxicity. Its primary toxicity is granulocytopenia, with only modest thrombocytopenia and less neurotoxicity than other vinca alkaloids. Vinorelbine may cause allergic reactions and mild, reversible changes in liver enzymes. Doses should be reduced in patients with elevated plasma bilirubin.
Paclitaxel (TAXOL, others) was first isolated from the bark of the Western yew tree. Paclitaxel and its congener, the semisynthetic docetaxel (TAXOTERE), exhibit unique pharmacological properties as inhibitors of mitosis, differing from the vinca alkaloids and colchicine derivatives in that they bind to a different β-tubulin site and promote rather than inhibit microtubule formation. The taxanes have a central role in the therapy of ovarian, breast, lung, GI, genitourinary, and head and neck cancers.
Paclitaxel has very limited water solubility and is administered in a vehicle of 50% ethanol and 50% polyethoxylated castor oil (CREMOPHOR EL); this vehicle likely is responsible for a high rate of hypersensitivity reactions. Patients receiving this formulation are protected by pretreatment with an H1 receptor antagonist such as diphenhydramine, an H2 receptor antagonist such as cimetidine (seeChapter 32), and a glucocorticoid such as dexamethasone (see Chapter 42).
An albumin-bound nanoparticle solution for infusion (nab-paclitaxel, ABRAXANE) is soluble in aqueous solutions and can be administered safely without prophylactic antihistamines or steroids. This form of paclitaxel has increased cellular uptake via an albumin-specific mechanism. Docetaxel, somewhat more soluble than paclitaxel, is administered in polysorbate 80 and is associated with a lower incidence of hypersensitivity reactions than paclitaxel dissolved in CREMOPHOR. However, pretreatment with dexamethasone for 3 days starting 1 day prior to therapy is required to prevent progressive fluid retention and minimize the severity of hypersensitivity reactions.
Mechanism of Action; Drug Interactions; Resistance. Paclitaxel binds specifically to the β-tubulin subunit of microtubules and antagonizes their disassembly, with the result that bundles of microtubules and aberrant structures derived from microtubules appear in the mitotic phase of the cell cycle. Arrest in mitosis follows. Cell death occurs by apoptosis and depends on both drug concentration and duration of drug exposure. Drugs that block cell-cycle progression prior to mitosis antagonize the toxic effects of taxanes.
Drug interactions have been noted; the sequence of cisplatin preceding paclitaxel decreases paclitaxel clearance and produces greater toxicity than the opposite schedule. Paclitaxel decreases doxorubicin clearance and enhances cardiotoxicity, while docetaxel has no apparent effect on anthracycline pharmacokinetics.
The basis of clinical drug resistance is not known. Resistance to taxanes is associated in some cultured tumor cells with increased expression of the mdr-1 gene and its product, P-glycoprotein; other resistant cells have β-tubulin mutations and may display heightened sensitivity to vinca alkaloids. Other resistant cell lines display an increase in survivin, an anti-apoptotic factor, i Aurora kinase, that promotes completion of mitosis. The taxanes preferentially bind to the βII-tubulin subunit of microtubules; therefore, cells may become resistant by upregulating the βIII-isoform of tubulin.
ADME. Paclitaxel is administered as a 3-h infusion of 135-175 mg/m2 every 3 weeks or as a weekly 1-h infusion of 80-100 mg/m2. Prolonged infusions (96 h) also are active. Hepatic CYPs (primarily CYP2C8, secondarily CYP3A4) extensively metabolize the drug. The primary metabolite is 6-OH paclitaxel, which is inactive; multiple additional hydroxylation products are found in plasma; <10% of a dose is excreted in the urine intact. Dose reductions in patients with abnormal hepatic function have been suggested, and 50-75% doses of taxanes should be used in the presence of hepatic metastases >2 cm in size or in patients with abnormal serum bilirubin. Drugs that induce CYP2C8 or CYP3A4, such as phenytoin and phenobarbital, or those that inhibit these CYPs, such as antifungal imidazoles, significantly alter drug clearance and toxicity.
Paclitaxel clearance is nonlinear and decreases with increasing dose or dose rate; the plasma t1/2 ~10-14 h and clearance is 15-18 L/hr/m2. The critical plasma concentration for inhibiting bone marrow elements depends on duration of exposure but likely is 50-100 nM. Paclitaxel clearance is markedly delayed by cyclosporine A and other drugs that inhibit P-glycoprotein.
Nab-paclitaxel achieves a higher serum concentration of paclitaxel compared to CREMOPHOR-solubilized paclitaxel, but the increased clearance of nab-paclitaxel results in a similar drug exposure. Nab-paclitaxel is most often administered intravenously over 30 min at 260 mg/m2 every 3 weeks. Like the other taxanes, nab-paclitaxel should not be given to patients with an absolute neutrophil count <1500 cells/mm3.
Docetaxel pharmacokinetics are similar to those of paclitaxel, with an elimination t1/2 of ~12 h. Clearance is primarily through CYP3A4- and CYP3A5-mediated hydroxylation, leading to inactive metabolites. In contrast to paclitaxel, the pharmacokinetics of docetaxel are linear for doses ≤115 mg/m2.
Therapeutic Uses. The taxanes have become central components of regimens for treating metastatic ovarian, breast, lung, GI, genitourinary, and head and neck cancers. These drugs are administered once weekly or once every 3 weeks. The appropriate use of the steroid-sparing nab-paclitaxel still is being evaluated in clinical trials.
Clinical Toxicities. Paclitaxel exerts its primary toxic effects on the bone marrow. Neutropenia usually occurs 8-11 days after a dose and reverses rapidly by days 15-21. Used with filgrastim (granulocyte-colony stimulating factor [G-CSF]), doses as high as 250 mg/m2 over 24 h are well tolerated, and peripheral neuropathy becomes dose limiting. Many patients experience myalgias after receiving paclitaxel. In high-dose schedules, or with prolonged use, a stocking-glove sensory neuropathy can be disabling, particularly in patients with underlying diabetic neuropathy or concurrent cisplatin therapy. Mucositis is prominent in 72- or 96-h infusions and in the weekly schedule. Hypersensitivity reactions can occur in patients receiving paclitaxel infusions of short duration (1-6 h) but are largely averted by pretreatment with dexamethasone, diphenhydramine, and histamine H2 receptor antagonists, as noted above. Premedication is not necessary with 96-h infusions. Many patients experience asymptomatic bradycardia; occasional episodes of silent ventricular tachycardia also occur and resolve spontaneously during 3- or 24-h infusions. Nab-paclitaxel produces increased rates of peripheral neuropathy compared to CREMOPHOR-delivered paclitaxel but rarely causes hypersensitivity reactions.
Docetaxel causes greater degrees of neutropenia than paclitaxel but less peripheral neuropathy and asthenia and less frequent hypersensitivity. Fluid retention is a progressive problem with multiple cycles of docetaxel therapy, leading to peripheral edema, pleural and peritoneal fluid, and pulmonary edema in extreme cases. Oral dexamethasone, 8 mg/day, begun 1 day prior to drug infusion and continuing for 3 days, greatly ameliorates fluid retention. In rare cases, docetaxel may cause a progressive interstitial pneumonitis and respiratory failure if the drug is not discontinued.
Estramustine (EMCYT, estramustine phosphate) combines estradiol and normustine (nornitrogen mustard) through a carbamate link. Although the intent of the combination was to enhance the uptake of the alkylating agent into estradiol-sensitive prostate cancer cells, estramustine does not function in vivo as an alkylating agent; rather, it binds to β tubulin and microtubule-associated proteins, causing microtubule disassembly and antimitotic actions.
Therapeutic Use. Estramustine is used solely for the treatment of metastatic or locally advanced hormone refractory prostate cancer at an initial dosage of 14 mg/kg/day in 3 or 4 divided doses.
ADME. Following oral administration, at least 75% of a dose of estramustine phosphate is absorbed from the GI tract and rapidly dephosphorylated. The drug undergoes extensive first-pass metabolism by hepatic CYPs to an active 17-keto derivative, estromustine, and to multiple inactive products; the active drug forms accumulate in the prostate. Some hydrolysis of the carbamate linkage occurs in the liver, releasing estradiol, estrone, and the normustine group. Estramustine and estromustine have a plasma t1/2 of 10 and 14 h, respectively, and are excreted as inactive metabolites, mainly in the feces.
Clinical Toxicities; Drug Interactions. In addition to myelosuppression, estramustine also possesses estrogenic side effects (gynecomastia, impotence, elevated risk of thrombosis, and fluid retention), hypercalcemia, acute attacks of porphyria, impaired glucose tolerance, and hypersensitivity reactions, including angioedema. Estramustine inhibits the clearance of taxanes.
The epothilones are 16-membered polyketides discovered as cytotoxic metabolites from a strain of Sorangium cellulosum, a myxobacterium originally isolated from soil on the bank of the Zambezi River in southern Africa. These compounds overcome some of the problems of other microtubule disrupting and stabilizing agents, such as difficulties in formulation, drug delivery, and susceptibility to multidrug resistance. Ixabepilone (IXEMPRA) is approved for breast cancer treatment.
Others in development include the epothilone B analogs patupilone (EPO906) and 21-aminoepothilone B (BMS-310705), the epothilone D analog KOS-1584 (R1645), and the synthetic sagopilone.
Mechanism of Action; Resistance. They bind to β tubulin and trigger microtubule nucleation at multiple sites away from the centriole. This chaotic microtubule stabilization triggers cell-cycle arrest at the G2-M interface and apoptosis. Epothilones bind to a site distinct from that of taxanes. In colon cancer cell lines, p53 and Bax trigger apoptosis in ixabepilone-treated cells. In vitro studies suggest that ixabepilone is less susceptible to P-glycoprotein-mediated multidrug resistance than are taxanes. Other mechanisms implicated in epothilone resistance include mutation of the β-tubulin binding site and upregulation of isoforms of β tubulin.
ADME. Ixabepilone is administered intravenously. Because of its minimal aqueous solubility, it is delivered in the solubilizing agent, polyoxyethylated castor oil/ethanol (CREMOPHOR EL). CREMOPHOR has been implicated as the cause of infusion reactions; such reactions are infrequent when administration is preceded by premedication with H1 and H2 antagonists. The drug is cleared by hepatic CYPs and has a plasma t1/2 of 52 h.
Therapeutic Uses. In patients with metastatic breast cancer resistant to or pretreated with anthracyclines and resistant to taxanes, ixabepilone plus capecitabine provides an improved progression-free survival of 1.6 months compared to capecitabine alone. Ixabepilone also is indicated as monotherapy for metastatic breast cancer in patients who have previously progressed through treatment with anthracyclines, taxanes, and capecitabine. The recommended dose of ixabepilone as monotherapy or in combination with capecitabine is 40 mg/m2 administered over 3 h every 3 weeks. Because of additive myelosuppression, the phase III trial used an attenuated dose of capecitabine (2000 mg/m2) administered with ixabepilone. Patients should be premedicated with both an H1 and H2 antagonist before receiving ixabepilone to minimize hypersensitivity reactions.
The combination of ixabepilone and capecitabine is contraindicated in patients with a baseline neutrophil count <1500 cells/mm3, a platelet count <100,000 cells/mm3, serum transaminases >2.5 × ULN or bilirubin above normal. In patients receiving ixabepilone monotherapy with mild to moderate hepatic dysfunction (bilirubin <1.5 × ULN or 1.5-3 × ULN, respectively), starting doses of 32 and 20 mg/m2are recommended due to delayed drug clearance.
Toxicities. Epothilones have toxicities similar to those of the taxanes: neutropenia, peripheral sensory neuropathy, fatigue, diarrhea, and asthenia.
The camptothecins are potent, cytotoxic antineoplastic agents that target the nuclear enzyme topoisomerase I. The lead compound in this class, camptothecin, was isolated from the tree Camptotheca acuminata. Irinotecan and topotecan, currently the only camptothecin analogs approved for clinical use, have activity in colorectal, ovarian, and small cell lung cancer.
Chemistry. All camptothecins have a fused 5-ring backbone that includes a labile lactone ring (see Figures 6–5 and 6–6 for examples). The hydroxyl group and S-conformation of the chiral center at C20 in the lactone ring are required for biological activity. Appropriate substitutions on the A and B rings of the quinoline subunit enhance water solubility and increase potency for inhibiting topoisomerase I. Topotecan is a semisynthetic molecule with a basic dimethylamino group that increases its water solubility. Irinotecan (CPT-11) differs from topotecan in that it is a prodrug. The carbamate bond between the camptothecin moiety and the dibasic bis-piperidine side chain at position C10 (which makes the molecule water soluble) is cleaved by a carboxylesterase to form the active metabolite, SN-38 (see Figure 6–5).
Mechanism of Action. The DNA topoisomerases are nuclear enzymes that reduce torsional stress in supercoiled DNA, allowing selected regions of DNA to become sufficiently untangled to permit replication, repair, and transcription. Two classes of topoisomerase (I and II) mediate DNA strand breakage and resealing. Camptothecin analogs inhibit the function of topoisomerase I; myriad other chemical entities (e.g., anthracyclines, epipodophyllotoxins, acridines) inhibit topoisomerase II. The camptothecins bind to and stabilize the normally transient DNA-topoisomerase I cleavable complex. Although the initial cleavage action of topoisomerase I is not affected, the re-ligation step is inhibited, leading to the accumulation of single-stranded breaks in DNA. These lesions are reversible and not by themselves toxic to the cell. However, the collision of a DNA replication fork with this cleaved strand of DNA causes an irreversible double-strand DNA break, ultimately leading to cell death. The precise sequence of events that leads from drug-induced DNA damage to cell death has not been fully elucidated; one does observe internucleosomal DNA fragmentation, a characteristic of programmed cell death.
Camptothecins are S phase–specific drugs, because ongoing DNA synthesis is necessary for cytotoxicity. This has important clinical implications. S phase–specific cytotoxic agents generally require prolonged exposures of tumor cells to drug concentrations above a minimum threshold for optimal therapeutic efficacy. In fact, low-dose, protracted administration of camptothecin analogs have less toxicity, and equal or greater antitumor activity, than shorter, more intense courses.
Mechanisms of Resistance. Decreased intracellular drug accumulation may underlie resistance in cell lines. Topotecan, but not SN-38 or irinotecan, is a substrate for P-glycoprotein; however, compared with other substrates, such as etoposide or doxorubicin, topotecan is a relatively poor substrate. Other reports have associated topotecan and irinotecan resistance with the MRP class of transporters. Cell lines that lack carboxylesterase activity demonstrate resistance to irinotecan, but the liver and red blood cells may have sufficient carboxylesterase activity to convert irinotecan to SN-38. Camptothecin resistance also may result from decreased expression or mutation of topoisomerase I. A transient downregulation of topoisomerase I has been demonstrated following prolonged exposure to camptothecins in vitro and in vivo. Mutations leading to reduced topoisomerase I enzyme catalytic activity or DNA-binding affinity have been associated with experimental camptothecin resistance. Finally, exposure of cells to topoisomerase I–targeted agents upregulates topoisomerase II, an alternative enzyme for DNA strand passage.
ADME. Topotecan is approved for intravenous administration. An oral dosage form in development has a bioavailability of 30-40% in cancer patients. Topotecan exhibits linear pharmacokinetics, and it is rapidly eliminated from systemic circulation with a t1/2 ~3.5-4.1 h. Only 20-35% of the total drug in plasma is found to be in the active lactone form. Within 24 h, 30-40% of the administered dose appears in the urine. Doses should be reduced in proportion to reductions in CrCl. Hepatic metabolism appears to be a relatively minor route of drug elimination. Plasma protein binding of topotecan is low (7-35%), which may explain its relatively greater CNS penetration.
Therapeutic Uses. Topotecan (HYCAMTIN) is indicated for previously treated patients with ovarian and small cell lung cancer. Significant hematological toxicity limits its use in combination with other active agents in these diseases (e.g., cisplatin). The recommended dosing regimen of topotecan for ovarian cancer and small cell lung cancer is a 30-min infusion of 1.5 mg/m2/day for 5 consecutive days every 3 weeks. For cervical cancer in conjunction with cisplatin, the dose of topotecan is 0.75 mg/m2 on days 1, 2, and 3, repeated every 21 days. The dose of topotecan should be reduced to 0.75 mg/m2/day in patients with moderate renal dysfunction (CrCl of 20-40 mL/min); topotecan should not be administered to patients with severe renal impairment (CrCl <20 mL/min). Hepatic dysfunction does not alter topotecan clearance and toxicity. A baseline neutrophil count <1500 cells/mm3 and a platelet count >100,000 is necessary prior to topotecan administration.
Clinical Toxicities. The dose-limiting toxicity with all dosing schedules is neutropenia, with or without thrombocytopenia. The incidence of severe neutropenia at 1.5 mg/m2 daily for 5 days every 3 weeks may be as high as 81%, with a 26% incidence of febrile neutropenia. In patients with hematological malignancies, GI side effects such as mucositis and diarrhea become dose limiting. Other less common and generally mild topotecan-related toxicities include nausea and vomiting, elevated liver transaminases, fever, fatigue, and rash.
ADME. The conversion of irinotecan to SN-38 is mediated predominantly by carboxylesterases in the liver (see Figure 6–5). Although SN-38 can be measured in plasma shortly after beginning an intravenous infusion of irinotecan, the AUC of SN-38 is only ~4% of the AUC of irinotecan, suggesting that only a relatively small fraction of the dose is ultimately converted to the active form of the drug. Irinotecan exhibits linear pharmacokinetics. In comparison to topotecan, a relatively large fraction of both irinotecan and SN-38 are present in plasma as the biologically active intact lactone form. The t1/2of SN-38 is 11.5 h, 3 times that of topotecan. CSF penetration of SN-38 in humans has not been characterized.
In contrast to topotecan, hepatic metabolism of irinotecan and SN-38 represents an important route of elimination for both. Oxidative metabolites have been identified in plasma, all of which result from CYP3A-mediated reactions directed at the bis-piperidine side chain. These metabolites are not significantly converted to SN-38. The total body clearance of irinotecan was found to be 2 times greater in brain cancer patients taking anti-seizure drugs that induce hepatic CYPs.
UGT1A1 glucuronidates the hydroxyl group at position C10 (resulting from cleavage of the bispiperidine promoiety), producing the inactive metabolite SN-38G (see Figure 6–6). Biliary excretion appears to be the primary elimination route of irinotecan, SN-38, and metabolites, although urinary excretion also contributes (14-37%). The extent of SN-38 glucuronidation inversely correlates with the risk of severe diarrhea after irinotecan therapy. UGT1A1 polymorphisms associated with familial hyperbilirubinemia syndromes may have a major impact on the clinical use of irinotecan. A positive correlation has been found between baseline serum unconjugated bilirubin concentration and both severity of neutropenia and the AUC of irinotecan and SN-38 in patients treated with irinotecan. Severe irinotecan toxicity has been observed in cancer patients with Gilbert syndrome, presumably due to decreased glucuronidation of SN-38. The presence of bacterial glucuronidase in the intestinal lumen potentially can contribute to irinotecan’s GI toxicity by releasing unconjugated SN-38 from the inactive glucuronide metabolite.
Therapeutic Uses. Approved single-agent dosage schedules of irinotecan (CAMPTOSAR, others) in the U.S. include 125 mg/m2 as a 90-min infusion administered weekly (on days 1, 8, 15, and 22) for 4 out of 6 weeks, and 350 mg/m2 given every 3 weeks. In patients with advanced colorectal cancer, irinotecan is used as first-line therapy in combination with fluoropyrimidines or as a single agent or in combination with cetuximab following failure of a 5-FU/oxaliplatin regimen.
Clinical Toxicities. The dose-limiting toxicity with all dosing schedules is delayed diarrhea (35%), with or without neutropenia. An intensive regimen of loperamide (4 mg of loperamide starting at the onset of any loose stool beginning more than a few hours after receiving therapy, followed by 2 mg every 2 h; see Chapter 47) reduces this incidence by more than half. However, once severe diarrhea occurs, standard doses of antidiarrheal agents tend to be ineffective. Diarrhea generally resolves within a week and, unless associated with fever and neutropenia, rarely is fatal.
The second most common irinotecan-associated toxicity is myelosuppression. Severe neutropenia occurs in 14-47% of the patients treated with the every-3-weeks schedule and is less frequently encountered among patients treated with the weekly schedule. Febrile neutropenia is observed in 3% of patients and may be fatal, particularly when associated with concomitant diarrhea. A cholinergic syndrome resulting from the inhibition of acetylcholinesterase activity by irinotecan may occur within the first 24 h after irinotecan administration. Symptoms include acute diarrhea, diaphoresis, hypersalivation, abdominal cramps, visual accommodation disturbances, lacrimation, rhinorrhea, and less often, asymptomatic bradycardia. These effects are short lasting and respond within minutes to atropine. Other common toxicities include nausea and vomiting, fatigue, vasodilation or skin flushing, mucositis, elevation in liver transaminases, and alopecia. There have been case reports of dyspnea and interstitial pneumonitis associated with irinotecan therapy.
DACTINOMYCIN (ACTINOMYCIN D)
Actinomycin D has beneficial effects in the treatment of solid tumors in children and choriocarcinoma in adult women.
Actinomycins are chromopeptides. Most contain the same chromophore, the planar phenoxazone actinosin, which is responsible for their yellow-red color. The differences among naturally occurring actinomycins are confined to variations in the structure of the amino acids of the peptide side chains.
Mechanism of Action. The capacity of actinomycins to bind to double-helical DNA is responsible for their biological activity and cytotoxicity. The planar phenoxazone ring intercalates between adjacent guanine–cytosine base pairs of DNA, while the polypeptide chains extend along the minor groove of the helix, resulting in a dactinomycin-DNA complex with stability sufficient to block the transcription of DNA by RNA polymerase. The DNA-dependent RNA polymerases are much more sensitive to the effects of dactinomycin than are the DNA polymerases. In addition, dactinomycin causes single-strand breaks in DNA, possibly through a free-radical intermediate or as a result of the action of topoisomerase II. Dactinomycin inhibits rapidly proliferating cells of normal and neoplastic origin, and is among the most potent antitumor agents known.
ADME. Dactinomycin is administered by intravenous injection. Metabolism of the drug is minimal. The drug is excreted in both bile and urine and disappears from plasma with a terminal t1/2 of 36 h. Dactinomycin does not cross the blood-brain barrier.
Therapeutic Uses. The usual daily dose of dactinomycin (actinomycin D; COSMEGEN) is 10-15 μg/kg; given intravenously for 5 days. If no manifestations of toxicity are encountered, additional courses may be given at intervals of 2-4 weeks. In other regimens, 3-6 μg/kg/day, for a total of 125 μg/kg, and weekly maintenance doses of 7.5 μg/kg have been used. The main clinical use of dactinomycin is in the treatment of rhabdomyosarcoma and Wilms, tumor in children, where it is curative in combination with primary surgery, radiotherapy, and other drugs, particularly vincristine and cyclophosphamide. Ewing, Kaposi, and soft-tissue sarcomas also respond. Dactinomycin and MTX form a curative therapy for choriocarcinoma.
Clinical Toxicities. Toxic manifestations include anorexia, nausea, and vomiting, usually beginning a few hours after administration. Hematopoietic suppression with pancytopenia may occur in the first week after completion of therapy. Proctitis, diarrhea, glossitis, cheilitis, and ulcerations of the oral mucosa are common; dermatological manifestations include alopecia, as well as erythema, desquamation, and increased inflammation and pigmentation in areas previously or concomitantly subjected to X-ray radiation. Severe injury may occur as a result of local drug extravasation; the drug is extremely corrosive to soft tissues.
ANTHRACYCLINES AND ANTHRACENEDIONES
Anthracyclines are derived from the fungus Streptomyces peucetius var. caesius. Idarubicin and epirubicin are analogs of the naturally produced anthracyclines doxorubicin anddaunorubicin, differing only slightly in chemical structure, but having somewhat distinct patterns of clinical activity. Daunorubicin and idarubicin primarily have been used in the acute leukemias, whereas doxorubicin and epirubicin display broader activity against human solid tumors. These agents, which possess potential for generating free radicals, cause an unusual and often irreversible cardiomyopathy, the occurrence of which is related to the total dose of the drug. The structurally similar agent mitoxantrone has less cardiotoxicity and is useful against prostate cancer and AML, and in high-dose chemotherapy.
Mechanisms of Action and Resistance. Anthracyclines and anthracenediones can intercalate with DNA, directly affecting transcription and replication. More important is their capacity to form a heterotrimeric complex with topoisomerase II and DNA. Topoisomerase II produces double-strand breaks at the 3′-phosphate backbone, allowing strand passage and uncoiling of super-coiled DNA. Following strand passage, topoisomerase II re-ligates the DNA strands; this enzymatic function is essential for DNA replication and repair. Formation of the ternary complex with anthracyclines or with etoposide inhibits the re-ligation of the broken DNA strands, leading to apoptosis. Defects in DNA double-strand break repair sensitize cells to damage by these drugs, while overexpression of transcription-linked DNA repair may contribute to resistance.
The quinone moieties of anthracyclines can form radical intermediates that react with O2 to produce superoxide anion radicals, which can generate H2O2 and •OH that attack DNA and oxidize DNA bases, leading to apoptosis. The production of free radicals is significantly stimulated by the interaction of doxorubicin with iron. Enzymatic defenses such as superoxide dismutase and catalase protect cells against the toxicity of the anthracyclines, and these defenses can be augmented by exogenous antioxidants such as alpha tocopherol or by an iron chelator, dexrazoxane (ZINECARD, others), which protects against cardiac toxicity. Multidrug resistance is observed in tumor cell populations exposed to anthracyclines. Anthracyclines also are exported from tumor cells by members of the MRP transporter family and by ABCG2 (the breast cancer resistance protein). Other biochemical changes in resistant cells include increased glutathione peroxidase activity, decreased activity or mutation of topoisomerase II, and enhanced ability to repair DNA strand breaks.
ADME. Daunorubicin, doxorubicin, epirubicin, and idarubicin usually are administered intravenously and are cleared by a complex pattern of hepatic metabolism and biliary excretion. Each anthracycline is converted to an active alcohol intermediate that plays a variable role in the therapeutic activity. The plasma disappearance curves for doxorubicin and daunorubicin are multiphasic, with a terminal t1/2 of 30 h. Idarubicin has a t1/2 of 15 h, and its active metabolite, idarubicinol, has a t1/2 of 40 h. The drugs rapidly enter the heart, kidneys, lungs, liver, and spleen; they do not cross the blood-brain barrier. Clearance is delayed in the presence of hepatic dysfunction; at least a 50% initial reduction in dose should be considered in patients with elevated serum bilirubin levels.
IDARUBICIN AND DAUNORUBICIN
Therapeutic Use. The recommended dosage for idarubicin (IDAMYCIN PFS) is 12 mg/m2/day for 3 days by intravenous injection in combination with cytarabine. Slow injection over 10-15 min is recommended to avoid extravasation. Idarubicin has less cardiotoxicity than the other anthracyclines.
Daunorubicin (daunomycin, rubidomycin; CERUBIDINE, others) is available for intravenous use. The recommended dosage is 25-45 mg/m2/day for 3 days. The agent is administered with care to prevent extravasation. Total doses of >1000 mg/m2 are associated with a high risk of cardiotoxicity. Daunorubicin may impart a red color to the urine. Daunorubicin and idarubicin also are used in the treatment of AML in combination with Ara-C.
Clinical Toxicities. Toxic effects of daunorubicin and idarubicin include bone marrow depression, stomatitis, alopecia, GI disturbances, rash, and cardiac toxicity. Cardiac toxicity is characterized by tachycardia, arrhythmias, dyspnea, hypotension, pericardial effusion, and congestive heart failure poorly responsive to digitalis.
Therapeutic Uses. The recommended dose is 60-75 mg/m2, administered as a single rapid intravenous infusion that is repeated after 21 days. A doxorubicin liposomal product (DOXIL) is available for treatment of AIDS-related Kaposi sarcoma and is given intravenously in a dose of 20 mg/m2 over 60 min and repeated every 3 weeks. The liposomal formulation also is approved for ovarian cancer at a dose of 50 mg/m2 every 4 weeks and as a treatment for multiple myeloma (in conjunction with bortezomib), where it is given as a 30-mg/m2 dose on day 4 of each 21-day cycle. Patients should be advised that the drug may impart a red color to the urine. Doxorubicin is effective in malignant lymphomas. In combination with cyclophosphamide, vinca alkaloids, and other agents, it is an important ingredient for the successful treatment of lymphomas. It is a valuable component of various regimens of chemotherapy for adjuvant and metastatic carcinoma of the breast. The drug also is beneficial in pediatric and adult sarcomas, including osteogenic, Ewing, and soft-tissue sarcomas.
Clinical Toxicities. Toxicities of doxorubicin are similar to those of daunorubicin. Myelosuppression is a major dose-limiting complication, with maximal leukopenia usually occurring during the second week of therapy and recovering by the fourth week; thrombocytopenia and anemia follow a similar pattern but usually are less pronounced. Stomatitis, mucositis, diarrhea, and alopecia are common but reversible. Erythematous streaking near the site of infusion (“ADRIAMYCIN flare”) is a benign local allergic reaction and should not be confused with extravasation. Facial flushing, conjunctivitis, and lacrimation may occur rarely. The drug may produce severe local toxicity in irradiated tissues (e.g., the skin, heart, lung, esophagus, and GI mucosa) even when the 2 therapies are not administered concomitantly.
Cardiomyopathy is the most important long-term toxicity and may take 2 forms:
• An acute form, characterized by abnormal electrocardiographic changes, including ST- and T-wave alterations and arrhythmias. This is brief and rarely a serious problem. An acute reversible reduction in ejection fraction is observed in some patients in the 24 h after a single dose, and plasma troponin T may increase in a minority of patients in the first few days following drug administration. Acute myocardial damage, the “pericarditis–myocarditis syndrome,” may begin in the days following drug infusion and is characterized by severe disturbances in impulse conduction and frank congestive heart failure, often associated with pericardial effusion.
• Chronic, cumulative dose-related toxicity (usually total doses of ≥550 mg/m2) progressing to congestive heart failure. The mortality rate in patients with congestive failure approaches 50%. The risk increases markedly, with estimates as high as 20% at total doses of 550 mg/m2 (a total dose limit of 300 mg/m2 is advised for pediatric cases). These total dosages should be exceeded only under exceptional circumstances or with the concomitant use of dexrazoxane, a cardioprotective iron-chelating agent. Cardiac irradiation, administration of high doses of cyclophosphamide or another anthracycline, or concomitant trastuzumab increases the risk of cardiotoxicity. Late-onset cardiac toxicity, with congestive heart failure years after treatment, may occur in both pediatric and adult populations. In children treated with anthracyclines, there is a 3- to 10-fold elevated risk of arrhythmias, congestive heart failure, and sudden death in adult life. Concomitant administration of dexrazoxane may reduce troponin T elevations and avert later cardiotoxicity.
This anthracycline is indicated as a component of adjunctive therapy for treatment of breast cancer. It is administered in doses of 100-120 mg/m2 intravenously every 3-4 weeks. Total doses >900 mg/m2sharply increase the risk of cardiotoxicity. Its toxicity profile is the same as that of doxorubicin.
Valrubicin is a semi-synthetic analog of doxorubicin, used exclusively for intravesicular treatment of bladder cancer. Once a week for 6 weeks, 800 mg are instilled into the bladder. Less than 10% of instilled drug is absorbed systemically. Side effects relate to bladder irritation.
Mitoxantrone is approved for use in AML, prostate cancer, and late-stage, secondary progressive multiple sclerosis. Mitoxantrone has limited ability to produce quinone-type free radicals and causes less cardiac toxicity than does doxorubicin. It produces acute myelosuppression, cardiac toxicity (less than doxorubicin), and mucositis as its major toxicities; the drug causes less nausea, vomiting, and alopecia than does doxorubicin. Mitoxantrone (NOVANTRONE, others) is administered by intravenous infusion. To induce remission in acute nonlymphocytic leukemia in adults, the drug is given in a daily dose of 12 mg/m2 for 3 days with cytarabine. It also is used in advanced hormone-resistant prostate cancer in a dose of 12-14 mg/m2 every 21 days.
ETOPOSIDE AND TENIPOSIDE
Two synthetic derivatives of podophyllotoxins have significant therapeutic activity in pediatric leukemia, small cell carcinomas of the lung, testicular tumors, Hodgkin disease, and large cell lymphomas. These derivatives are etoposide (VP-16-213) and teniposide (VM-26). Although podophyllotoxin binds to tubulin, etoposide and teniposide have no effect on microtubular structure or function at usual concentrations.
Mechanisms of Action and Resistance. Etoposide and teniposide form ternary complexes with topoisomerase II and DNA and prevent resealing of the break that normally follows topoisomerase binding to DNA. The enzyme remains bound to the free end of the broken DNA strand, leading to an accumulation of DNA breaks and cell death. Cells in the S and G2 phases of the cell cycle are most sensitive to etoposide and teniposide. Resistant cells demonstrate (1) amplification of the mdr-1 gene that encodes the P-glycoprotein drug efflux transporter, (2) mutation or decreased expression of topoisomerase II, or (3) mutations of the p53 tumor suppressor gene, a required component of the apoptotic pathway.
ADME. Oral administration of etoposide results in variable absorption that averages ~50%. After intravenous injection, there is a biphasic pattern of clearance with a terminal t1/2 of 6-8 h in patients with normal renal function. Approximately 40% of an administered dose is excreted intact in the urine. In patients with compromised renal function, dosage should be reduced in proportion to the reduction in CrCl. In patients with advanced liver disease, increased toxicity may result from a low serum albumin (decreased drug binding) and elevated bilirubin (which displaces etoposide from albumin); guidelines for dose reduction in this circumstance have not been defined. Drug concentrations in the CSF average 1-10% of those in plasma.
Therapeutic Uses. The intravenous dose of etoposide (VEPESID, others) for testicular cancer in combination therapy (with bleomycin and cisplatin) is 50-100 mg/m2 for 5 days, or 100 mg/m2 on alternate days for 3 doses. For small cell carcinoma of the lung, the dosage in combination therapy (with cisplatin and ifosfamide) is 35 mg/m2/day intravenously for 4 days or 50 mg/m2/day intravenously for 5 days. The oral dose for small cell lung cancer is twice the IV dose. Cycles of therapy usually are repeated every 3-4 weeks. When given intravenously, the drug should be administered slowly over a 30- to 60-min period to avoid hypotension and bronchospasm, which likely result from the additives used to dissolve etoposide.
Etoposide is also active against non-Hodgkin lymphomas, acute nonlymphocytic leukemia, and Kaposi sarcoma associated with AIDS. Etoposide has a favorable toxicity profile for dose escalation in that its primary acute toxicity is myelosuppression. In combination with ifosfamide and carboplatin, it frequently is used for high-dose chemotherapy in total doses of 1500-2000 mg/m2.
Clinical Toxicities. The dose-limiting toxicity of etoposide is leukopenia (nadir at 10-14 days, recovery by 3 weeks). Thrombocytopenia occurs less often and usually is not severe. Nausea, vomiting, stomatitis, and diarrhea complicate treatment in ~15% of patients. Alopecia is common but reversible. Hepatic toxicity is particularly evident after high-dose treatment. For both etoposide and teniposide, toxicity increases in patients with decreased serum albumin, an effect related to decreased protein binding of the drug. A disturbing complication of etoposide therapy is the development of an unusual form of acute nonlymphocytic leukemia with a translocation in chromosome 11q23. At this locus is a gene (the MLL gene) that regulates the proliferation of pluripotent stem cells. The leukemic cells have the cytological appearance of acute monocytic or monomyelocytic leukemia. Another distinguishing feature of etoposide-related leukemia is the short time interval between the end of treatment and the onset of leukemia (1-3 years), compared to the 4- to 5-year interval for secondary leukemias related to alkylating agents, and the absence of a myelodysplastic period preceding leukemia. Patients receiving weekly or twice-weekly doses of etoposide, with cumulative doses >2000 mg/m2, seem to be at higher risk of leukemia.
Teniposide (VUMON) is administered intravenously. It has a multiphasic pattern of clearance from plasma: after distribution, a t1/2 of 4 h and another t1/2 of 10-40 h are observed. Approximately 45% of the drug is excreted in the urine; in contrast to etoposide, as much as 80% is recovered as metabolites. Anticonvulsants such as phenytoin increase the hepatic metabolism of teniposide and reduce systemic exposure. Dosage need not be reduced for patients with impaired renal function. Less than 1% of the drug crosses the blood-brain barrier. Teniposide is available for treatment of refractory ALL in children and is synergistic with cytarabine. Teniposide is administered by intravenous infusion in dosages that range from 50 mg/m2/day for 5 days to 165 mg/m2/day twice weekly. The drug has limited utility and is given primarily for acute leukemia in children and monocytic leukemia in infants, as well as glioblastoma, neuroblastoma, and brain metastases from small cell carcinomas of the lung. Myelosuppression, nausea, and vomiting are its primary toxic effects.
DRUGS OF DIVERSE MECHANISM OF ACTION
The bleomycins, a unusual group of DNA-cleaving antibiotics, are fermentation products of Streptomyces verticillus. The drug currently employed clinically is a mixture of the 2 copper-chelating peptides, bleomycins A2 and B2, that differ only in their terminal amino acid. Because their toxicities do not overlap with those of other cytotoxic drugs, and because of their unique mechanism of action, bleomycin maintains an important role in treating Hodgkin disease and testicular cancer.
Mechanisms of Action and Resistance. Bleomycin’s cytotoxicity results from its capacity to cause oxidative damage to the deoxyribose of thymidylate and other nucleotides, leading to single- and double-stranded breaks in DNA. Bleomycin causes accumulation of cells in the G2 phase of the cell cycle, and many of these cells display chromosomal aberrations, including chromatid breaks, gaps, fragments, and translocations. Bleomycin cleaves DNA by generating free radicals. In the presence of O2 and a reducing agent, the metal–drug complex becomes activated and functions as a ferrous oxidase, transferring electrons from Fe2+ to molecular oxygen to produce oxygen radicals. Metallobleomycin complexes can be activated by reaction with the flavin enzyme, NADPH-CYP450 reductase. Bleomycin binds to DNA, and the activated complex generates free radicals that are responsible for abstraction of a proton at the 3′ position of the deoxyribose backbone of the DNA chain, opening the deoxyribose ring and generating a strand break in DNA. An excess of breaks generates apoptosis.
Bleomycin is degraded by a specific hydrolase found in various normal tissues, including liver. Hydrolase activity is low in skin and lung, perhaps contributing to the serious toxicity. Some bleomycin-resistant cells contain high levels of hydrolase activity. In other cell lines, resistance has been attributed to decreased uptake, repair of strand breaks, or drug inactivation by thiols or thiol-rich proteins.
ADME. Bleomycin is administered intravenously, intramuscularly, or subcutaneously, or instilled into the bladder for local treatment of bladder cancer. Having a high molecular mass, bleomycin crosses the blood-brain barrier poorly. The elimination t1/2 is ~3 h. About two-thirds of the drug is excreted intact in the urine. Concentrations in plasma are greatly elevated in patients with renal impairment and doses of bleomycin should be reduced in the presence of a CrCl <60 mL/min.
Therapeutic Uses. The recommended dose of bleomycin (BLENOXANE, others) is 10-20 units/m2 given weekly or twice weekly by the intravenous, intramuscular, or subcutaneous route. A test dose of ≤2 units is recommended for lymphoma patients. Myriad regimens are employed clinically, with bleomycin doses expressed in units. Total courses exceeding 250 mg should be given with caution, and usually only in high-risk testicular cancer treatment, because of a marked increase in the risk of pulmonary toxicity. Bleomycin also may be instilled into the pleural cavity in doses of 5-60 mg to ablate the pleural space in patients with malignant effusions. Bleomycin is highly effective against germ cell tumors of the testis and ovary. In testicular cancer, it is curative when used with cisplatin and vinblastine or cisplatin and etoposide. It is a component of the standard curative ABVD regimen (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) for Hodgkin lymphoma.
Clinical Toxicities. Because bleomycin causes little myelosuppression, it has significant advantages in combination with other cytotoxic drugs. However, it does cause a constellation of cutaneous toxicities, including hyperpigmentation, hyperkeratosis, erythema, and even ulceration, and rarely, Raynaud phenomenon. Skin lesions may recur when patients are treated with other antineoplastic drugs. Rarely, bleomycin causes a flagellate dermatitis consisting of bands of pruritic erythema on the arms, back, scalp, and hands; this rash responds readily to topical corticosteroids.
The most serious adverse reaction to bleomycin is pulmonary toxicity, which begins with a dry cough, fine rales, and diffuse basilar infiltrates on X-ray and may progress to life-threatening pulmonary fibrosis. Approximately 5-10% of patients receiving bleomycin develop clinically apparent pulmonary toxicity, and ~1% die of this complication. Most who recover experience a significant improvement in pulmonary function, but fibrosis may be irreversible. Pulmonary function tests are not of predictive value for detecting early onset of this complication. The risk of pulmonary toxicity is related to total dose, with a significant increase in risk in total doses >250 mg and in patients >40 years of age, in those with a CrCl of <80 mL/min, and in those with underlying pulmonary disease; single doses of ≥30 mg/m2also are associated with an increased risk of pulmonary toxicity. Administration of high O2 concentrations during anesthesia or respiratory therapy may aggravate or precipitate pulmonary toxicity in patients previously treated with the drug. There is no known specific therapy for bleomycin lung injury except for symptomatic management and standard pulmonary care. Steroids are of variable benefit, with greatest effectiveness in the earliest inflammatory stages of the lesion.
Other toxic reactions to bleomycin include hyperthermia, headache, nausea and vomiting, and a peculiar acute fulminant reaction observed in patients with lymphomas. This reaction is characterized by profound hyperthermia, hypotension, and sustained cardiorespiratory collapse; it does not appear to be a classical anaphylactic reaction and may be related to release of an endogenous pyrogen. This reaction has occurred in ~1% of patients with lymphomas or testicular cancer.
Mitomycin has limited clinical utility, having been replaced by less toxic and more effective drugs, with the exception of anal cancers, for which it is curative.
Mechanisms of Action and Resistance. After intracellular enzymatic or spontaneous chemical alteration, mitomycin becomes a bifunctional or trifunctional alkylating agent. The drug inhibits DNA synthesis and cross-links DNA at the N6 position of adenine and at the O6 and N7 positions of guanine. Attempts to repair DNA lead to strand breaks. Mitomycin is a potent radiosensitizer, teratogen, and carcinogen in rodents. Resistance has been ascribed to deficient activation, intracellular inactivation of the reduced Q form, and P-glycoprotein-mediated drug efflux.
ADME. Mitomycin is administered intravenously. It has a t1/2 of 25-90 min. The drug distributes widely throughout the body but is not detected in the CNS. Inactivation occurs by hepatic metabolism or chemical conjugation with sulfhydryls. Less than 10% of the active drug is excreted in the urine or the bile.
Therapeutic Uses. Mitomycin (mitomycin-C; MUTAMYCIN, others) is administered at a dose of 6-20 mg/m2, given as a single bolus every 6-8 weeks. Dosage is modified based on hematological recovery. Mitomycin also may be used by direct instillation into the bladder to treat superficial carcinomas. Mitomycin is used in combination with 5-FU and cisplatin for anal cancer. Mitomycin is used off label (as an extemporaneously compounded eye drop) as an adjunct to surgery to inhibit wound healing and reduce scarring.
Clinical Toxicities. The major toxic effect is myelosuppression, characterized by marked leukopenia and thrombocytopenia; after higher doses, maximal suppression may be delayed and cumulative, with recovery only after 6-8 weeks of pancytopenia. Nausea, vomiting, diarrhea, stomatitis, rash, fever, and malaise also are observed. Patients who have received >50 mg/m2 total dose may acutely develop hemolysis, neurological abnormalities, interstitial pneumonia, and glomerular damage resulting in renal failure. The incidence of renal failure increases to 28% in patients who receive total doses of ≥70 mg/m2. There is no effective treatment for the disorder. It must be recognized early, and mitomycin must be discontinued immediately. Mitomycin causes interstitial pulmonary fibrosis; total doses >30 mg/m2 have infrequently led to congestive heart failure. Mitomycin may potentiate the cardiotoxicity of doxorubicin.
Mitotane (o,p′-DDD), a compound chemically similar to the insecticides DDT and DDD, is used in the treatment of neoplasms derived from the adrenal cortex.
The mechanism of action of mitotane has not been elucidated, but its relatively selective destruction of adrenocortical cells, normal or neoplastic, is well established. Administration of the drug causes a rapid reduction in the levels of adrenocorticosteroids and their metabolites in blood and urine, a response that is useful in both guiding dosage and following the course of hyperadrenocorticism (Cushing syndrome) resulting from an adrenal tumor or adrenal hyperplasia. It does not damage other organs.
ADME. Approximately 40% of mitotane is absorbed after oral administration. Plasma concentrations of mitotane are still measurable for 6-9 weeks following discontinuation of therapy. Although the drug is found in all tissues, fat is the primary site of storage. A water-soluble metabolite of mitotane found in the urine constitutes 25% of an oral or parenteral dose. About 60% of an oral dose is excreted unchanged in the stool.
Therapeutic Uses. Mitotane (LYSODREN) is administered in initial daily oral doses of 2-6 g, usually in 3 or 4 divided portions, and increasing to 9-10 g/day if tolerated. The maximal tolerated dose may vary from 2-16 g/day. Treatment should continue for at least 3 months; if beneficial effects are observed, therapy should be maintained indefinitely. Spironolactone should not be administered concomitantly, because it interferes with the adrenal suppression produced by mitotane. Treatment with mitotane is indicated for the palliation of inoperable adrenocortical carcinoma, producing symptomatic benefit in 30-50% of such patients.
Clinical Toxicity. Although the administration of mitotane produces anorexia and nausea in most patients, somnolence and lethargy in ~34%, and dermatitis in 15-20%, these effects do not contraindicate the use of the drug at lower doses. Because this drug damages the adrenal cortex, administration of replacement doses of adrenocorticosteroids is necessary.
Trabectedin (YONDELIS) is the only drug used clinically that is derived from a sea animal, the marine tunicate, Ecteinascidin turbinate.
Trabectedin binds to the minor groove of DNA, allowing the alkylation of the N2 position of guanine and bending the helix toward the major groove. The bulky DNA adduct is recognized by the transcription-coupled nucleotide excision repair complex, and these proteins initiate attempts to repair the damaged strand, converting the adduct to a double-stranded break. Trabectedin has particular cytotoxic effects on cells that lack components of the Fanconi anemia complex or those that lack the ability to repair double-strand DNA breaks through homologous recombination. Unlike cisplatin and other DNA adduct–forming drugs, its activity requires the presence of intact components of NER, including XPG, which may be important for initiation of single breaks and attempts at adduct removal.
ADME. Trabectedin is administered as a 24-h infusion of 1.3 mg/m2 every 3 weeks. It is administered with dexamethasone, 4 mg twice daily, starting 24 h before drug infusion to diminish hepatic toxicity. The drug is slowly cleared by CYP3A4, with a plasma t1/2 24-40 h.
Therapeutic Uses. Trabectedin is designated as an orphan drug in the U.S. for ovarian cancer, sarcoma, and pancreatic cancer. It is approved outside the U.S. for second-line treatment of soft-tissue sarcomas and for ovarian cancer in combination with a doxorubicin formulation (DOXIL). It produces a very high >50%) disease control rate in myxoid liposarcomas.
Clinical Toxicity. Without dexamethasone pretreatment, trabectedin causes significant hepatic enzyme elevations and fatigue in at least one-third of patients. With the steroid, the increases in transaminase are less pronounced and rapidly reversible. Other toxicities include mild myelosuppression and, rarely, rhabdomyolysis.
Malignant lymphoid cells depend on exogenous sources of L-asparagine. Thus, L-asparaginase (L-ASP) has become a standard agent for treating ALL.
Mechanism of Action. Most normal tissues synthesize L-asparagine in amounts sufficient for protein synthesis, but lymphocytic leukemias lack adequate amounts of asparagine synthase and derive the required amino acid from plasma. L-ASP, by catalyzing the hydrolysis of circulating asparagine to aspartic acid and ammonia, deprives these malignant cells of asparagine, leading to cell death. L-ASP is used in combination with other agents, including MTX, doxorubicin, vincristine, and prednisone for the treatment of ALL and for high-grade lymphomas. Resistance arises through induction of asparagine synthetase in tumor cells.
ADME and Therapeutic Use. L-ASP (ELSPAR) is given intramuscularly or intravenously. After intravenous administration, E. coli–derived L-ASP has a clearance rate from plasma of 0.035 mL/min/kg, a volume of distribution that approximates the volume of plasma in humans, and a t1/2 of 1 day. The enzyme is given in doses of 6000-10,000 IU every third day for 3-4 weeks. Pegaspargase (PEG-L-ASPARAGINASE; ONCASPAR) a preparation in which the enzyme is conjugated to 5000-Da units of monomethoxy polyethylene glycol, has much slower clearance from plasma (t1/2 of 6-7 days), and it is administered in doses of 2500 IU/m2 intramuscularly no more frequently than every 14 days, producing rapid and complete depletion of plasma and tumor cell asparagine for 21 days in most patients. Pegaspargase has much reduced immunogenicity (<20% of patients develop antibodies) and has been approved for first-line ALL therapy.
Intermittent dosage regimens and longer durations of treatment increase the risk of inducing hypersensitivity. In hypersensitive patients, neutralizing antibodies inactivate L-ASP. Not all patients with neutralizing antibodies experience clinical hypersensitivity, although enzyme may be inactivated and therapy may be ineffective. In previously untreated ALL, pegaspargase produces more rapid clearance of lymphoblasts from bone marrow than does the E. coli preparation and circumvents the rapid antibody-mediated clearance seen with E. coli enzyme in relapsed patients. Asparaginase preparations only partially deplete CSF asparagine.
Clinical Toxicity. L-ASP toxicities result from its antigenicity as a foreign protein and its inhibition of protein synthesis. Hypersensitivity reactions, including urticaria and full-blown anaphylaxis, occur in 5-20% of patients and may be fatal. In these patients, pegaspargase is a safe and effective alternative. So-called “silent” enzyme inactivation by antibodies occurs in a higher percentage of patients than overt hypersensitivity and may be associated with a negative clinical outcome, especially in high-risk ALL patients.
Other toxicities result from inhibition of protein synthesis in normal tissues (e.g., hyperglycemia due to insulin deficiency, clotting abnormalities due to deficient clotting factors, hypertriglyceridemia due to effects on lipoprotein production, hypoalbuminemia). Pancreatitis also has been observed. The clotting problems may take the form of spontaneous thrombosis, or less frequently, hemorrhagic episodes. Brain magnetic resonance imaging studies should be considered in patients treated with L-ASP who present with seizures, headache, or altered mental status. Intracranial hemorrhage in the first week of L-ASP treatment is an infrequent but devastating complication. L-ASP also suppresses immune function. L-ASP terminates the antitumor activity of MTX when given shortly after the antimetabolite. By lowering serum albumin concentrations, L-ASP may decrease protein binding and accelerate plasma clearance of other drugs.
Hydroxyurea (HU) has unique and diverse biological effects as an antileukemic drug, radiation sensitizer, and an inducer of fetal hemoglobin in patients with sickle cell disease. It is orally administered, and its toxicity is modest and limited to myelosuppression.
Mechanisms of Action and Resistance. HU inhibits the enzyme ribonucleoside diphosphate reductase, which catalyzes the reductive conversion of ribonucleotides to deoxyribonucleotides, a rate-limiting step in the biosynthesis of DNA. HU binds the iron molecules that are essential for activation of a tyrosyl radical in the catalytic subunit of RNR. The drug is specific for the S phase of the cell cycle, during which RNR concentrations are maximal. It causes cells to arrest at or near the G1–S interface through both p53-dependent and -independent mechanisms. Because cells are highly sensitive to irradiation at the G1–S boundary, HU and irradiation cause synergistic antitumor effects. Through depletion of deoxynucleotides, HU potentiates the antiproliferative effects of DNA-damaging agents such as cisplatin, alkylating agents, or topoisomerase II inhibitors and facilitates the incorporation of antimetabolites such as Ara-C, gemcitabine, and fludarabine into DNA. It also promotes degradation of the p21 cell-cycle checkpoint and thereby enhances the effects of HDAC (histone deacetylase) inhibitors in vitro.
HU is the primary drug for improving control of sickle cell (HbS) disease in adults and for inducing fetal hemoglobin (HbF) in thalassemia HbC and HbC/S patients. It reduces vaso-occlusive events, painful cries, hospitalizations, and the need for blood transfusions in patients with sickle cell disease. The mechanism of stimulated HbF production is uncertain. HU stimulates NO production, causing nitrosylation of small-molecular-weight GTPases, a process that stimulates γ-globin production in erythroid precursors. Another property of HU that may be therapeutically relevant is its capacity to reduce L-selectin expression and thereby to reduce adhesion of red cells and neutrophils to vascular endothelium. Also, by suppressing the production of neutrophils, it decreases their contribution to vascular occlusion. Tumor cells become resistant to HU through increased synthesis of the catalytic subunit of RNR, thereby restoring enzyme activity.
ADME. The oral bioavailability of HU is 80-100%; comparable plasma concentrations are seen after oral or intravenous dosing. HU disappears from plasma with a t1/2 of 3.5-4.5 h. The drug readily crosses the blood-brain barrier; significant quantities appear in human breast milk. From 40-80% of the drug is recovered in the urine within 12 h after administration. It is advisable to modify initial doses for patients with renal dysfunction.
Therapeutic Uses. In cancer treatment, 2 dosage schedules for HU (HYDREA, DROXIA, others), alone or in combination with other drugs, are most commonly used in a variety of solid tumors: (1) intermittent therapy with 80 mg/kg administered orally as a single dose every third day or (2) continuous therapy with 20-30 mg/kg administered as a single daily dose. In patients with essential thrombocythemia and in sickle cell disease, HU is given in a daily dose of 15 mg/kg, adjusting that dose upward or downward according to blood counts. The neutrophil count responds within 1-2 weeks to discontinuation of the drug. In treating subjects with sickle cell and related diseases, a neutrophil count of at least 2500 cells/mL should be maintained. Treatment typically is continued for 6 weeks to determine effectiveness; if satisfactory results are obtained, therapy can be continued indefinitely, although leukocyte counts at weekly intervals are advisable.
The principal use of HU has been as a myelosuppressive agent in various myeloproliferative syndromes, particularly CML, polycythemia vera, myeloid metaplasia, and essential thrombocytosis, for controlling high platelet or white cell counts. Many of the myeloproliferative syndromes harbor activating mutations of JAK2, a gene that is downregulated by HU. In essential thrombocythemia, it is the drug of choice for patients with a platelet count >1.5 million cells/mm3 or with a history of arterial or venous thrombosis. In CML, HU has been largely replaced by imatinib. HU is a potent radiosensitizer as a consequence of its inhibition of RNR and has been incorporated into several treatment regimens with concurrent irradiation (i.e., cervical carcinoma, primary brain tumors, head and neck cancer, non–small-cell lung cancer).
Clinical Toxicity. Leukopenia, anemia, and occasionally thrombocytopenia are the major toxic effects; recovery of the bone marrow is prompt if the drug is discontinued for a few days. Other adverse reactions include a desquamative interstitial pneumonitis, GI disturbances, and mild dermatological reactions, and, more rarely, stomatitis, alopecia, and neurological manifestations. Increased skin and fingernail pigmentation may occur, as well as painful leg ulcers, especially in elderly patients or in those with renal dysfunction. HU does not increase the risk of secondary leukemia in patients with myeloproliferative disorders or sickle cell disease. It is a potent teratogen in animals and should not be used in women with childbearing potential.
One of the hallmarks of malignant transformation is a block in differentiation. A number of chemical entities (vitamin D and its analogs, retinoids, benzamides and other inhibitors of histone deacetylase, various cytotoxics and biological agents, and inhibitors of DNA methylation) can induce differentiation in tumor cell lines.
The biology and pharmacology of retinoids are discussed in Chapter 65. The most important of these for cancer treatment is tretinoin (all-trans retinoic acid [ATRA]), which induces a high rate of complete remission in acute promyelocytic leukemia (APL) as a single agent and, in combination with anthracyclines, cures most patients with this disease.
Mechanism of Action. Under physiological conditions, the retinoic acid receptor-α (RAR-α) dimerizes with the retinoid X receptor to form a complex that binds ATRA tightly. ATRA binding displaces a repressor from the complex and promotes differentiation of cells of multiple lineages. In APL cells, physiological concentrations of retinoid are inadequate to displace the repressor but pharmacological concentrations, are effective in activating the differentiation program and in promoting degradation of the PML–RAR-α fusion gene. The PML gene encodes a transcription factor (promyelocytic leukemia factor) important in inhibiting proliferation and promoting myeloid differentiation. The oncogenic PML–RAR-α gene produces a protein that binds retinoids with much decreased affinity, lacks PML regulatory function, and fails to upregulate transcription factors (C/EBP and PU.1) that promote myeloid differentiation. ATRA also binds and activates RAR-γ and thereby promotes stem-cell renewal, and this action may help restore normal bone marrow renewal. Resistance to ATRA arises by further mutation of the fusion gene, abolishing ATRA binding; by induction of the CYP26A1; or by loss of expression of the PML–RAR-α fusion gene.
Clinical Pharmacology. The dosing regimen of orally administered ATRA (VESANOID, others) is 45 mg/m2/day until 30 days after remission is achieved (maximum course of therapy is 90 days). ATRA as a single agent reverses the hemorrhagic diathesis associated with APL and induces a high rate of temporary remission. ATRA in combination with an anthracycline induces remission with ≥80% relapse-free long-term survival.
ATRA is cleared by a CYP3A4-mediated elimination with a t1/2 of <1 h. Treatment with inducers of CYP3A4 leads to more rapid drug disappearance and resistance to ATRA. Inhibitors of CYPs, such as antifungal imidazoles, block ATRA degradation and may lead to hypercalcemia and renal failure, which responds to diuresis, bisphosphonates, and ATRA discontinuation. Corticosteroids and chemotherapy sharply decrease the occurrence of “retinoic acid syndrome,” which is characterized by fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions. When used as a single agent for remission induction, especially in patients with >5000 leukemic cells/mm3 in the peripheral blood, ATRA induces an outpouring of cytokines and mature-appearing neutrophils of leukemic origin. These cells express high concentrations of integrins and other adhesion molecules on their surface and clog small vessels in the pulmonary circulation, leading to significant morbidity in 15-20% of patients. The syndrome of respiratory distress, pleural and pericardial effusions, and mental status changes may have a fatal outcome. Retinoids also cause dry skin, cheilitis, reversible hepatic enzyme abnormalities, bone tenderness, pseudotumor cerebri, hypercalcemia, and hyperlipidemia.
ARSENIC TRIOXIDE (ATO)
ATO is a highly effective treatment for relapsed APL, producing complete responses in >85% of such patients. The chemistry and toxicity of arsenic are considered in Chapter 67.
Mechanism of Action. The basis for ATO’s antitumor activity remains uncertain. APL cells have high levels of reactive oxygen species (ROS) and are quite sensitive to further ROS induction. ATO inhibits thioredoxin reductase and thereby generates ROS. It inactivates glutathione and other sulfhydryls that scavenge ROS and thereby aggravates ROS damage. Cells exposed to ATO also upregulate p53, Jun kinase, and caspases associated with the intrinsic pathway of apoptosis and downregulate anti-apoptotic proteins such as bcl-2. ATO’s cytotoxic effects are antagonized by cell survival signals emanating from activation of components of the PI3 kinase cell survival pathway, including Akt kinase, S6 kinase, and mammalian target of rapamycin (mTOR). ATO also induces differentiation of leukemic cell lines and in experimental and human leukemias.
Clinical Pharmacology. ATO (TRISENOX) is well absorbed orally but in cancer treatment is administered as a 2-h intravenous infusion in dosages of 0.15 mg/kg/day for up to 60 days, until remission is documented. The drug enters cells via one of several glucose transporters. The primary mechanism of elimination is through enzymatic methylation. Multiple methylated metabolites form rapidly and are excreted in urine. Less than 20% of administered drug is excreted unchanged in the urine. No dose reductions are indicated for hepatic or renal dysfunction.
Toxicity. Pharmacological doses of ATO are well tolerated. Patients may experience reversible side effects, including hyperglycemia, hepatic enzyme elevations, fatigue, dysesthesias, and light-headedness. Fewer than 10% of patients experience a leukocyte maturation syndrome similar to that seen with ATRA, including pulmonary distress, effusions, and mental status changes. Oxygen, corticosteroids, and temporary discontinuation of ATO lead to full reversal of this syndrome. Lengthening of the QT interval on the electrocardiogram occurs in 40% of patients, but rarely do patients develop torsade de pointes. Simultaneous treatment with other QT-prolonging drugs should be avoided. Monitoring of serum electrolytes and repletion of serum K+ in patients with hypokalemia are precautionary measures in patients receiving ATO therapy. In patients exhibiting a significantly prolonged QT (>470 msec), treatment should be suspended, K+ supplemented, and therapy resumed only if the QT returns to normal.
HISTONE DEACETYLASE INHIBITORS
Vorinostat (ZOLINZA), also known as suberoylanilide hydroxamic acid (SAHA), is unique as an epigenetic modifier that directly affects histone function.
Mechanism of Action. Acetylation of lysine residues on histones increases the spatial distance between DNA strands and the protein core, allowing access for transcription factor complexes, and enhancing transcriptional activity. Acetyl groups are added by histone acetyltransferases (HACs) and removed by histone deacetylases (HDACs). HDAC inhibitors such as vorinostat increase histone acetylation and thus enhance gene transcription. Many nonhistone proteins also are subject to lysine acetylation and thus are affected by treatment with HDAC inhibitors; the role of their acetylation status in the antitumor action of HDAC inhibitors is unclear.
Vorinostat is a hydroxamic acid modeled after hybrid polar compounds that cause differentiation of malignant cells in vitro, as do other classes of compounds with HDAC-inhibitory activity. These compounds bind to a critical Zn++ ion in the active site of HDAC enzymes. An important distinction between vorinostat and other HDAC inhibitors is that vorinostat and the hydroxymates are pan-HDAC inhibitors, whereas other compounds have selectivity for HDAC isoenzyme subsets. HDAC inhibitors induce cell-cycle arrest, differentiation, and apoptosis of cancer cells; nonmalignant cells are relatively resistant to these effects. These agents increase transcription of cell-cycle regulators, affect levels of nuclear transcription factors, and induce pro-apoptotic genes. HDAC inhibition directly blocks function of the chaperone HSP90 and stabilizes the tumor suppressor p53.
ADME. Vorinostat is administered as a once-daily oral dose of 400 mg. It is inactivated by glucuronidation of the hydroxyl amine group, followed by hydrolysis of the terminal carboxamide bond and further oxidation of the aliphatic side chain. The metabolites are pharmacologically inactive. The terminal t1/2 in plasma is 2 h. Histones remain hyperacetylated up to 10 h after an oral dose of vorinostat, suggesting that its effects persist beyond its measurable presence in the plasma.
Therapeutic Uses. In patients with refractory cutaneous T-cell lymphoma (CTCL), vorinostat produces an overall response rate of 30%, with a median time to progression of 5 months. Vorinostat and other HDAC inhibitors, including romidepsin (depsipeptide; FK228) and MGCD 0103, have shown activity in CTCL, other B- and T-cell lymphomas, and myeloid leukemia.
Toxicity. The most common side effects include fatigue, nausea, diarrhea, and thrombocytopenia. Deep venous thrombosis and pulmonary embolism are infrequent but serious adverse events. Caution is advised in patients with underlying cardiac abnormalities, and careful monitoring of the QTc interval and of electrolytes (K+, Mg++) is necessary.