Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 54. Cancer Chemotherapy

Cancer Chemotherapy: Introduction

Cancer chemotherapy remains an intriguing area of pharmacology. On the one hand, use of anticancer drugs produces high rates of cure of diseases, which, without chemotherapy, result in extremely high mortality rates (eg, acute lymphocytic leukemia in children, testicular cancer, and Hodgkin's lymphoma). On the other hand, some types of cancer are barely affected by currently available drugs. Furthermore, as a group, the anticancer drugs are more toxic than any other pharmaceutic agents, and thus their benefit must be carefully weighed against their risks. Many of the available drugs are cytotoxic agents that act on all dividing cells, cancerous or normal. The ultimate goal in cancer chemotherapy is to use advances in cell biology to develop drugs that selectively target specific cancer cells. A few such agents are in clinical use, and many more are in development.

High-Yield Terms to Learn

Cell cycle-nonspecific (CCNS) drug An anticancer agent that acts on tumor stem cells when they are traversing the cell cycle and when they are in the resting phase Cell cycle-specific (CCS) drug An anticancer agent that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they are in the G0 phase

Growth fraction The proportion of cells in a tumor population that are actively dividing Myelosuppressant A drug that suppresses the formation of mature blood cells such as erythrocytes, leukocytes, and platelets. This effect is also known as "bone marrow suppression" Oncogene A mutant form of a normal gene that is found in naturally occurring tumors and which, when expressed in noncancerous cells, causes them to behave like cancer cells

Cancer Cell Cycle Kinetics

Cell Cycle Kinetics

Cancer cell population kinetics and the cancer cell cycle are important determinants of the actions and clinical uses of anticancer drugs. Some anticancer drugs exert their actions on cells undergoing cycling (cell cycle-specific [CCS] drugs), and others (cell cycle-nonspecific [CCNS] drugs) kill tumor cells in both cycling and resting phases of the cell cycle (although cycling cell are more sensitive). CCS drugs are usually most effective when cells are in a specific phase of the cell cycle (Figure 54-1). Both types of drugs are particularly effective when a large proportion of the tumor cells are proliferating (ie, when the growth fraction is high).

FIGURE 54-1

Phases of the cell cycle that are susceptible to the actions of cell cycle-specific (CCS) drugs. All dividing cells—normal and neoplastic—must traverse these cell cycle phases before and during cell division. Tumor cells are usually most responsive to specific drugs (or drug groups) in the phases indicated. Cell cycle-nonspecific (CCNS) drugs act on tumor cells while they are actively cycling and while they are in the resting phase (G0).

(Reproduced and modified, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 54-2.)

The Log-Kill Hypothesis

Cytotoxic drugs act with first-order kinetics in a murine model of leukemia. In this model system, in which all the cells are actively progressing through the cell cycle, a given dose kills a constant proportionof a cell population rather than a constant number of cells. The log-kill hypothesis proposes that the magnitude of tumor cell kill by anticancer drugs is a logarithmic function. For example, a 3-log-kill dose of an effective drug reduces a cancer cell population of 1012 cells to 109 (a total kill of 999 x 109 cells); the same dose would reduce a starting population of 106 cells to 103 cells (a kill of 999 x 103 cells). In both cases, the dose reduces the numbers of cells by 3 orders of magnitude, or "3 logs." A key principle that stems from this finding and that is applicable to hematologic malignancies is an inverse relationship between tumor cell number and curability (Figure 54-2). Mathematical modeling data suggest that most human solid tumors do not grow in such an exponential manner and rather that the growth fraction of the tumor decreases with time owing to blood supply limitations and other factors. In drug-sensitive solid tumors, the response to chemotherapy depends on where the tumor is in its growth curve.

FIGURE 54-2

Relationship, based on the log-kill hypothesis, of tumor cell number to 3 approaches to drug treatment and to no treatment (dashed line). In the protocol diagrammed at the top, infrequent treatment (indicated by arrows) prolongs survival but with recurrence of symptoms between treatments and eventual death. With the regimen diagrammed in the middle section that is more intensive and begun earlier, cure results after many cycles of therapy. In the treatment diagrammed near the bottom of the graph, early surgery removes much of the tumor burden, and intensive adjuvant chemotherapy has been used long enough to produce a cure.

(Reproduced with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 54-1.)

Resistance to Anticancer Drugs

Drug resistance is a major problem in cancer chemotherapy. Mechanisms of resistance include the following:

Increased DNA Repair

An increased rate of DNA repair in tumor cells can be responsible for resistance and is particularly important for alkylating agents and cisplatin.

Formation of Trapping Agents

Some tumor cells increase their production of thiol trapping agents (eg, glutathione), which interact with anticancer drugs that form reactive electrophilic species. This mechanism of resistance is seen with the alkylating agent bleomycin, cisplatin, and the anthracyclines.

Changes in Target Enzymes

Changes in the drug sensitivity of a target enzyme, dihydrofolate reductase, and increased synthesis of the enzyme are mechanisms of resistance of tumor cells to methotrexate.

Decreased Activation of Prodrugs

Resistance to the purine antimetabolites (mercaptopurine, thioguanine) and the pyrimidine antimetabolites (cytarabine, fluorouracil) can result from a decrease in the activity of the tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites.

Inactivation of Anticancer Drugs

Increased activity of enzymes capable of inactivating anticancer drugs is a mechanism of tumor cell resistance to most of the purine and pyrimidine antimetabolites.

Decreased Drug Accumulation

This form of multidrug resistance involves the increased expression of a normal gene (MDR1) for a cell surface glycoprotein (P-glycoprotein). This transport molecule is involved in the accelerated efflux of many anticancer drugs in resistant cells.

Strategies in Cancer Chemotherapy

Cancer Treatment Modalities

Chemotherapy is used in three main clinical settings:

Primary Induction Chemotherapy

Drug therapy is administered as the primary treatment for many hematologic cancers and for advanced solid tumors for which no alternative treatment exists. Although primary induction can be curative in a small number of patients who present with advanced metastatic disease (eg, lymphoma, acute myelogenous leukemia, germ cell cancer, choriocarcinoma, and several childhood cancers), in many cases the goals of therapy are palliation of cancer symptoms, improved quality of life, and increased time to tumor progression.

Neoadjuvant Chemotherapy

The use of chemotherapy in patients who present with localized cancer for which alternative local therapy, such as surgery, exist is known as neoadjuvant chemotherapy. The goal is to render the local therapy more effective.

Adjuvant Chemotherapy

In the treatment of many solid tumors, chemotherapy serves as an important adjuvant to local treatment procedures such as surgery or radiation. The goal is to reduce the risk of local and systemic recurrence and to improve disease-free and overall survival.

Principles of Combination Therapy

Chemotherapy with combinations of anticancer drugs usually increases log-kill markedly, and in some cases synergistic effects are achieved. Combinations are often cytotoxic to a heterogeneous population of cancer cells and may prevent development of resistant clones. Drug combinations using CCS and CCNS drugs may be cytotoxic to both dividing and resting cancer cells. The following principles are important for selecting appropriate drugs to use in combination chemotherapy:

(1) Each drug should be active when used alone against the particular cancer.

(2) The drugs should have different mechanisms of action.

(3) Cross-resistance between drugs should be minimal.

(4) The drugs should have different toxic effects (Table 54-1).

TABLE 54-1 Selected examples of cancer chemotherapy.

Diagnosis Examples of Commonly-Used Anticancer Drugs Acute lymphocytic leukemia in children Prednisone, vincristine, and asparaginase or an anthracycline, plus intrathecal methotrexate Acute myelogenous leukemia in adults Cytarabine and idarubicin or daunorubicin Breast carcinoma Cytotoxic agents, hormonal therapy with tamoxifen or an aromatase inhibitor (eg, anastrozole), trastuzumab Chronic myelogenous leukemia Imatinib, newer tyrosine kinase inhibitors, interferon Colon carcinoma Fluorouracil plus leucovorin plus oxaliplatin Hodgkin's lymphoma ABVD regimen: doxorubicin (Adriamycin), bleomycin, vincristine, dacarbazine, and prednisone Non-Hodgkin's lymphoma CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab Ovarian carcinoma Paclitaxel and carboplatin Pancreatic carcinoma Gemcitabine and erlotinib Prostate carcinoma GnRH agonist (eg, leuprolide) or antagonist (eg, abarelix) and androgen receptor antagonist (eg, flutamide) Lung carcinoma Carboplatin, paclitaxel, and bevacizumab Testicular carcinoma PEB regimen: cisplatin (Platinol), etoposide, and bleomycin

GnRH, gonadotropin-releasing hormone.

Rescue Therapy

Toxic effects of anticancer drugs can sometimes be alleviated by rescue strategy. For example, high doses of methotrexate may be given for 36-48 h to cells of the gastrointestinal tract and bone marrow and terminated before severe toxicity occurs. Leucovorin, a form of tetrahydrofolate that is accumulated more readily by normal than by neoplastic cells, is then administered. This results in rescue of the normal cells because leucovorin bypasses the dihydrofolate reductase step in folic acid synthesis.

Mercaptoethanesulfonate ( mesna ) "traps" acrolein released from cyclophosphamide and thus reduces the incidence of hemorrhagic cystitis. Dexrazoxane inhibits free radical formation and affords protection against the cardiac toxicity of anthracyclines (eg, doxorubicin).

Alkylating Agents

The alkylating agents include nitrogen mustards ( chlorambucil, cyclophosphamide, mechlorethamine ), nitrosoureas ( carmustine, lomustine ), and alkyl sulfonates ( busulfan ). Other drugs that act in part as alkylating agents include cisplatin, dacarbazine, and procarbazine.

The alkylating agents are CCNS drugs. They form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine. This leads to cross-linking of bases, abnormal base-pairing, and DNA strand breakage. Tumor cell resistance to the drugs occurs through increased DNA repair, decreased drug permeability, and the production of trapping agents such as thiols.

Cyclophosphamide

Pharmacokinetics

Hepatic cytochrome P450-mediated biotransformation of cyclophosphamide is needed for antitumor activity. One of the breakdown products is acrolein.

Clinical Use

Uses of cyclophosphamide include leukemia, non-Hodgkin's lymphoma, breast and ovarian cancers, and neuroblastoma.

Toxicity

Gastrointestinal distress, myelosuppression, and alopecia are expected adverse effects of cyclophosphamide. Hemorrhagic cystitis resulting from the formation of acrolein may be decreased by vigorous hydration and by use of mercaptoethanesulfonate ( mesna ). Cyclophosphamide may also cause cardiac dysfunction, pulmonary toxicity, and a syndrome of inappropriate antidiuretic hormone (ADH) secretion.

Mechlorethamine

Mechanism and Pharmacokinetics

Mechlorethamine spontaneously converts in the body to a reactive cytotoxic product.

Clinical Use

Mechlorethamine is best known for use in regimens for Hodgkin's and non-Hodgkin's lymphoma.

Toxicity

Gastrointestinal distress, myelosuppression, alopecia, and sterility are common. Mechlorethamine has marked vesicant actions.

Platinum Analogs (Cisplatin, Carboplatin, Oxaliplatin)

Pharmacokinetics

Cisplatin is used intravenously; the drug distributes to most tissues and is cleared in unchanged form by the kidney.

Clinical Use

Cisplatin is commonly used as a component of regimens for testicular carcinoma and for cancers of the bladder, lung, and ovary. Carboplatin has similar uses. Oxaliplatin is used in advanced colon cancer.

Toxicity

Cisplatin causes gastrointestinal distress and mild hematotoxicity and is neurotoxic (peripheral neuritis and acoustic nerve damage) and nephrotoxic. Renal damage may be reduced by the use of mannitol with forced hydration. Carboplatin is less nephrotoxic than cisplatin and is less likely to cause tinnitus and hearing loss, but it has greater myelosuppressant actions. Oxaliplatin causes dose-limiting neurotoxicity.

Procarbazine

Mechanisms

Procarbazine is a reactive agent that forms hydrogen peroxide, which generates free radicals that cause DNA strand scission.

Pharmacokinetics

Procarbazine is orally active and penetrates into most tissues, including the cerebrospinal fluid. It is eliminated via hepatic metabolism.

Clinical Use

The primary use of the drug is as a component of regimens for Hodgkin's and non-Hodgkin's lymphoma, and brain tumors.

Toxicity

Procarbazine is a myelosuppressant and causes gastrointestinal irritation, CNS dysfunction, peripheral neuropathy, and skin reactions. Procarbazine inhibits many enzymes, including monoamine oxidase and those involved in hepatic drug metabolism. Disulfiram-like reactions have occurred with ethanol. The drug is leukemogenic.

Other Alkylating Agents

Busulfan is sometimes used in chronic myelogenous leukemia. It causes adrenal insufficiency, pulmonary fibrosis, and skin pigmentation. Carmustine and lomustine are highly lipid-soluble drugs used as adjuncts in the management of brain tumors. Dacarbazine is used in regimens for Hodgkin's lymphoma. It causes alopecia, skin rash, gastrointestinal distress, myelosuppression, phototoxicity, and a flu-like syndrome.

Antimetabolites

The antimetabolites are structurally similar to endogenous compounds and are antagonists of folic acid ( methotrexate ), purines ( mercaptopurine, thioguanine ), or pyrimidines ( fluorouracil, cytarabine, gemcitabine ). Antimetabolites are CCS drugs acting primarily in the S phase of the cell cycle. In addition to their cytotoxic effects on neoplastic cells, the antimetabolites also have immunosuppressant actions (see Chapters 36, 54, and 55).

Methotrexate

Mechanisms of Action and Resistance

Methotrexate is an inhibitor of dihydrofolate reductase. This action leads to a decrease in the synthesis of thymidylate, purine nucleotides, and amino acids and thus interferes with nucleic acid and protein metabolism (see Figure 33-2 for folate-dependent enzymatic reactions). The formation of polyglutamate derivatives of methotrexate appears to be important for cytotoxic actions. Tumor cell resistance mechanisms include decreased drug accumulation, changes in the drug sensitivity or activity of dihydrofolate reductase, and decreased formation of polyglutamates.

Pharmacokinetics

Oral and intravenous administration of methotrexate affords good tissue distribution except to the CNS. Methotrexate is not metabolized, and its clearance is dependent on renal function. Adequate hydration is needed to prevent crystallization in renal tubules.

Clinical Use

Methotrexate is effective in choriocarcinoma, acute leukemias, non-Hodgkin's and primary central nervous system lymphomas, and a number of solid tumors, including breast cancer, head and neck cancer, and bladder cancer. Methotrexate is used also in rheumatoid arthritis psoriasis (Chapter 36) and ectopic pregnancy.

Toxicity

Common adverse effects of methotrexate include bone marrow suppression and toxic effects on the skin and gastrointestinal mucosa (mucositis). The toxic effects of methotrexate on normal cells may be reduced by administration of folinic acid (leucovorin); this strategy is called leucovorin rescue. Long-term use of methotrexate has led to hepatotoxicity and to pulmonary infiltrates and fibrosis.

Mercaptopurine (6-MP) and Thioguanine (6-TG)

Mechanisms of Action and Resistance

Mercaptopurine and thioguanine are purine antimetabolites. Both drugs are activated by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine metabolism. Resistant tumor cells have a decreased activity of HGPRTase, or they may increase their production of alkaline phosphatases that inactivate the toxic nucleotides.

Pharmacokinetics

Mercaptopurine and thioguanine have low oral bioavailability because of first-pass metabolism by hepatic enzymes. The metabolism of 6-MP by xanthine oxidase is inhibited by the xanthine oxidase inhibitors allopurinol and febuxostat.

Clinical Use

Purine antimetabolites are used mainly in the acute leukemias and chronic myelocytic leukemia.

Toxicity

Bone marrow suppression is dose limiting, but hepatic dysfunction (cholestasis, jaundice, necrosis) also occurs.

Fluorouracil (5-FU)

Mechanisms

Fluorouracil is converted in cells to 5-fluoro-2'-deoxyuridine-5'-monophosphate (5-FdUMP), which inhibits thymidylate synthase and leads to "thymineless death" of cells. Incorporation of FdUMP into DNA inhibits DNA synthesis and function while incorporation of 5-fluorouridine-5'-triphosphate (FUTP), another 5-FU metabolite, into RNA interferes with RNA processing and function. Tumor cell resistance mechanisms include decreased activation of 5-FU, increased thymidylate synthase activity, and reduced drug sensitivity of this enzyme.

Pharmacokinetics

When given intravenously, fluorouracil is widely distributed, including into the cerebrospinal fluid. Elimination is mainly by metabolism.

Clinical Use

Fluorouracil is used in bladder, breast, colon, anal, head and neck, liver, and ovarian cancers. The drug can be used topically for keratoses and superficial basal cell carcinoma.

Toxicity

Gastrointestinal distress, myelosuppression, and alopecia are common.

Cytarabine (ARA-C)

Mechanisms of Action and Resistance

Cytarabine (cytosine arabinoside) is a pyrimidine antimetabolite. The drug is activated by kinases to AraCTP, an inhibitor of DNA polymerases. Of all the antimetabolites, cytarabine is the most specific for the S phase of the cell cycle. Resistance to cytarabine can occur as a result of its decreased uptake or its decreased conversion to AraCTP.

Gemcitabine

Mechanisms

Gemcitabine is a deoxycytidine analog that is converted into the active diphosphate and triphosphate nucleotide form. Gemcitabine diphosphate appears to inhibit ribonucleotide reductase and thereby diminish the pool of deoxyribonucleoside triphosphates required for DNA synthesis. Gemcitabine triphosphate can be incorporated into DNA, where it causes chain termination.

Pharmacokinetics

Elimination is mainly by metabolism.

Clinical Use

Gemcitabine was initially approved for pancreatic cancer and now is used widely in the treatment of non-small cell lung cancer, bladder cancer, and non-Hodgkin's lymphoma.

Toxicity

Primarily myelosuppression occurs, mainly as neutropenia. Pulmonary toxicity has been observed.

Natural Product Anticancer Drugs

The most important of these plant-derived, CCS drugs are the vinca alkaloids (vinblastine, vincristine, vinorelbine), the podophyllotoxins (etoposide, teniposide), the camptothecins (topotecan, irinotecan),the taxanes (paclitaxel, docetaxel).

Vinblastine, Vincristine, and Vinorelbine

Mechanisms

The vinca alkaloids block the formation of the mitotic spindle by preventing the assembly of tubulin dimers into microtubules. They act primarily in the M phase of the cancer cell cycle. Resistance can occur from increased efflux of the drugs from tumor cells via the membrane drug transporter.

Pharmacokinetics

These drugs must be given parenterally. They penetrate most tissues except the cerebrospinal fluid. They are cleared mainly via biliary excretion.

Clinical Use

Vincristine is used in acute leukemias, lymphomas, Wilms' tumor, and neuroblastoma. Vinblastine is used for lymphomas, neuroblastoma, testicular carcinoma, and Kaposi's sarcoma. Vinorelbine is used in non-small cell lung cancer and breast cancer.

Toxicity

Vinblastine and vinorelbine cause gastrointestinal distress, alopecia, and bone marrow suppression. Vincristine does not cause serious myelosuppression but has neurotoxic actions and may cause areflexia, peripheral neuritis, and paralytic ileus.

Etoposide and Teniposide

Mechanisms

Etoposide , a semisynthetic derivative of podophyllotoxin, induces DNA breakage through its inhibition of topoisomerase II. The drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics.

Pharmacokinetics

Etoposide is well absorbed after oral administration and distributes to most body tissues. Elimination of etoposide is mainly via the kidneys, and dose reductions should be made in patients with renal impairment.

Clinical Use

These agents are used in combination drug regimens for therapy of lymphoma, and lung, germ cell, and gastric cancers.

Toxicity

Etoposide and teniposide are gastrointestinal irritants and cause alopecia and bone marrow suppression.

Topotecan and Irinotecan

Mechanisms

The 2 camptothecins, topotecan and irinotecan , produce DNA damage by inhibiting topoisomerase I. They damage DNA by inhibiting an enzyme that cuts and relegates single DNA strands during normal DNA repair processes.

Pharmacokinetics

Irinotecan is a prodrug that is converted in the liver into an active metabolite. Topotecan is eliminated renally, whereas irinotecan and its metabolite are eliminated in the bile and feces.

Clinical Use

Topotecan is used as second-line therapy for advanced ovarian cancer and for small cell lung cancer. Irinotecan is used for metastatic colorectal cancer.

Toxicity

Myelosuppression and diarrhea are the 2 most common toxicities.

Paclitaxel and Docetaxel

Mechanisms

Paclitaxel and docetaxel interfere with the mitotic spindle. They act differently from vinca alkaloids, since they prevent microtubule disassembly into tubulin monomers.

Pharmacokinetics

Paclitaxel and docetaxel are given intravenously.

Clinical Use

The taxanes have activity in a number of solid tumors, including breast, ovarian, lung, gastroesophageal, prostate, bladder, and head and neck cancers.

Toxicity

Paclitaxel causes neutropenia, thrombocytopenia, a high incidence of peripheral neuropathy, and possible hypersensitivity reactions during infusion. Docetaxel causes neurotoxicity and bone marrow depression.

Antitumor Antibiotics

This category of antineoplastic drugs is made up of several structurally dissimilar microbial products and includes the anthracyclinesbleomycin, and mitomycin.

Anthracyclines

Mechanisms

The anthracyclines ( doxorubicin , daunorubicinidarubicin , epirubicin , mitoxantrone ) intercalate between base pairs, inhibit topoisomerase II, and generate free radicals. They block the synthesis of RNA and DNA and cause DNA strand scission. Membrane disruption also occurs. Anthracyclines are CCNS drugs.

Pharmacokinetics

Doxorubicin and daunorubicin must be given intravenously. They are metabolized in the liver, and the products are excreted in the bile and the urine.

Clinical Use

Doxorubicin is used in Hodgkin's and non-Hodgkin's lymphoma, myelomas, sarcomas, and breast, lung, ovarian, and thyroid cancers. The main use of daunorubicin is in the treatment of acute leukemias. Idarubicin, a newer anthracycline, is approved for use in acute myelogenous leukemia. Epirubicin is used in breast cancer and gastroesophageal cancer. Mitoxantrone is used in acute myeloid leukemias, non-Hodgkin's lymphoma, breast cancer, and gastroesophageal cancer.

Toxicity

These drugs cause bone marrow suppression, gastrointestinal distress, and severe alopecia. Their most distinctive adverse effect is cardiotoxicity, which includes initial electrocardiographic abnormalities (with the possibility of arrhythmias) and slowly developing, dose-dependent cardiomyopathy and congestive heart failure. Dexrazoxane, an inhibitor of iron-mediated free radical generation, may protect against the dose-dependent form of cardiotoxicity. Liposomal formulations of doxorubicin may be less cardiotoxic.

Bleomycin

Mechanisms

Bleomycin is a mixture of glycopeptides that generates free radicals, which bind to DNA, cause strand breaks, and inhibit DNA synthesis. Bleomycin is a CCS drug active in the G2 phase of the tumor cell cycle.

Pharmacokinetics

Bleomycin must be given parenterally. It is inactivated by tissue aminopeptidases, but some renal clearance of intact drug also occurs.

Clinical Use

Bleomycin is a component of drug regimens for Hodgkin's lymphoma and testicular cancer. It is also used for treatment of lymphomas and for squamous cell carcinomas.

Toxicity

The toxicity profile of bleomycin includes pulmonary dysfunction (pneumonitis, fibrosis), which develops slowly and is dose limiting. Hypersensitivity reactions (chills, fever, anaphylaxis) are common, as are mucocutaneous reactions (alopecia, blister formation, hyperkeratosis).

Mitomycin

Mechanisms and Pharmacokinetics

Mitomycin is a CCNS drug that is metabolized by liver enzymes to form an alkylating agent that cross-links DNA. Mitomycin is given intravenously and is rapidly cleared via hepatic metabolism.

Clinical Use

Mitomycin acts against hypoxic tumor cells and is used in combination regimens for adenocarcinomas of the cervix, stomach, pancreas, and lung.

Toxicity

Mitomycin causes severe myelosuppression and is toxic to the heart, liver, lung, and kidney.

Miscellaneous Anticancer Agents

Tyrosine Kinase Inhibitors

Imatinib is an example of a selective anticancer drug whose development was guided by knowledge of a specific oncogene. It inhibits the tyrosine kinase activity of the protein product of the bcr-abloncogene that is commonly expressed in chronic myelogenous leukemia (CML). In addition to its activity in CML, imatinib is effective for treatment of gastrointestinal stromal tumors that express the c-kittyrosine kinase, which is also inhibited. Resistance may occur from mutation of the bcr-abl gene. Toxicity of imatinib includes diarrhea, myalgia, fluid retention, and congestive heart failure. Dasatinib and nilotinib are newer anticancer kinase inhibitors.

Growth Factor Receptor Inhibitors

Trastuzumab , a monoclonal antibody, recognizes a surface protein in breast cancer cells that overexpress the HER-2/neu receptor for epidermal growth factor. Acute toxicity of this antibody includes nausea and vomiting, chills, fevers, and headache. Trastuzumab may cause cardiac dysfunction, including congestive heart failure.

Several drugs inhibit the epidermal growth factor receptor (EGFR), which is distinct from the HER-2/neu receptor for epidermal growth factor that is targeted by trastuzumab. The EGFR regulates signaling pathways involved in cellular proliferation, invasion and metastasis, and angiogenesis. It is also implicated in inhibiting the cytotoxic activity of some anticancer drugs and radiation therapy. Cetuximab is a chimeric monoclonal antibody directed to the extracellular domain of the EGFR. It is used in combination with irinotecan and oxaliplatin for metastatic colon cancer and is used in combination with radiation for head and neck cancer. Its primary toxicity is skin rash and a hypersensitivity infusion reaction. Panitumumab is a fully human monoclonal antibody directed against the EGFR; it is approved for refractory metastatic colorectal cancer. Gefitinib and erlotinib are small molecule inhibitors of the EGFR's tyrosine kinase domain. Both are used as second-line agents for non-small cell lung cancer, and erlotinib is also used in combination therapy of advanced pancreatic cancer. Rash and diarrhea are the main toxicities.

Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and prevents it from interacting with VEGF receptors. VEGF plays a critical role in the angiogenesis required for tumor metastasis. Bevacizumab has activity in colorectal, breast, non-small cell lung, and renal cancer. Adverse effects include hypertension, infusion reactions, arterial thrombosis, impaired wound healing, gastrointestinal perforation, and proteinuria.

Rituximab

Rituximab is a monoclonal antibody that binds to a surface protein in non-Hodgkin's lymphoma cells and induces complement-mediated lysis, direct cytotoxicity, and induction of apoptosis. It is currently used with conventional anticancer drugs (eg, cyclophosphamide plus vincristine plus prednisone) in low-grade lymphomas. Rituximab is associated with hypersensitivity reactions and myelosuppression.

Interferons

The interferons are endogenous glycoproteins with antineoplastic, immunosuppressive, and antiviral actions. Alpha-interferons (see Chapter 55) are effective against a number of neoplasms, including hairy cell leukemia, the early stage of chronic myelogenous leukemia, and T-cell lymphomas. Toxic effects of the interferons include myelosuppression and neurologic dysfunction.

Asparaginase

Asparaginase is an enzyme that depletes serum asparagine; it is used in the treatment of T-cell auxotrophic cancers (leukemia and lymphomas) that require exogenous asparagine for growth. Asparaginase is given intravenously and may cause severe hypersensitivity reactions, acute pancreatitis, and bleeding.

Hormonal Anticancer Agents

Glucocorticoids

Prednisone is the most commonly used glucocorticoid in cancer chemotherapy and is widely used in combination therapy for leukemias and lymphomas. Toxicity is described in Chapter 39.

Gonadal Hormone Antagonists

Tamoxifen, a selective estrogen receptor modulator (see Chapter 40), blocks the binding of estrogen to receptors of estrogen-sensitive cancer cells in breast tissue. The drug is used in receptor-positive breast carcinoma and has been shown to have a preventive effect in women at high risk for breast cancer. Because it has agonist activity in the endometrium, tamoxifen increases the risk of endometrial hyperplasia and neoplasia. Other adverse effects include nausea and vomiting, hot flushes, vaginal bleeding, and venous thrombosis. Toremifene is a newer estrogen receptor antagonist used in advanced breast cancer. Flutamide is an androgen receptor antagonist used in prostatic carcinoma (see Chapter 40). Adverse effects include gynecomastia, hot flushes, and hepatic dysfunction.

Gonadotropin-Releasing Hormone (GnRH) Analogs

Leuprolide, goserelin, and nafarelin are GnRH agonists, effective in prostatic carcinoma. When administered in constant doses so as to maintain stable blood levels, they inhibit release of pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Leuprolide may cause bone pain, gynecomastia, hematuria, impotence, and testicular atrophy (see Chapters 37 and 40).

Aromatase Inhibitors

Anastrozole and letrozole inhibit aromatase, the enzyme that catalyzes the conversion of androstenedione (an androgenic precursor) to estrone (an estrogenic hormone). Both drugs are used in advanced breast cancer. Toxicity includes nausea, diarrhea, hot flushes, bone and back pain, dyspnea, and peripheral edema.

Skill Keeper: Management of Anticancer Drug Hematotoxicity

(See Chapter 33)

Bone marrow suppression is a characteristic toxicity of most cytotoxic anticancer drugs. What agents are available for the treatment of anemia and neutropenia, and for platelet restoration in patients undergoing cancer chemotherapy? The Skill Keeper Answer appears at the end of the chapter.

Skill Keeper Answer: Management of Anticancer Drug Hematotoxicity

(See Chapter 33)

Recombinant DNA technology has provided several agents that have value in the management of hematotoxicity caused by anticancer drugs. Erythropoietin stimulates red cell formation by interaction with receptors on erythroid progenitors in bone marrow. Myeloid growth factors filgrastim (G-CSF) and sargramostim (GM-CSF) stimulate the production and function of neutrophils. Megakaryocyte growth factor oprelvekin (IL-11) stimulates the growth of platelet progenitors.

Checklist

When you complete this chapter, you should be able to:

 Name 3 anticancer drugs that are cell cycle-specific and act at different phases of the cell cycle.

 Describe the relevance of cell cycle kinetics to the modes of action and clinical uses of anticancer drugs.

 List the mechanisms by which tumor cells develop drug resistance.

 Describe the rationale underlying strategies of combination drug chemotherapy and rescue therapies.

 Identify the major subclasses of anticancer drugs and describe the mechanisms of action of the main drugs in each subclass.

Identify a distinctive "characteristic" toxicity for each of the following anticancer drugs: bleomycin, cisplatin, cyclophosphamide, doxorubicin, and vincristine.

Drug Summary Table: Cancer Chemotherapy Drugs

Subclass Mechanism of Action Clinical Applications Acute Toxicities Chronic Toxicities Alkylating agents Cyclophosphamide Forms DNA cross-links, resulting in inhibition of DNA synthesis and function Breast cancer, ovarian cancer, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, neuroblastoma Nausea and vomiting Myelosuppression, alopecia, hemorrhagic cystitis Other major alkylating agents: Mechlorethamine, procarbazine, busulfan carmustine, lomustine, dacarbazine Platinum analogs: Cisplatin, carboplatin, oxaliplatin Antimetabolites Methotrexate Inhibits DHFR, resulting in inhibition of synthesis of thymidylate, purine nucleotides, serine, and methionine Breast cancer, head and neck cancer, primary CNS lymphoma, non-Hodgkin's lymphoma, bladder cancer, choriocarcinoma Mucositis, diarrhea Myelosuppression 6-Mercaptopurine Inhibits de novo purine synthesis Acute myelogenous leukemia Nausea and vomiting Myelosuppression, immunosuppression, hepatotoxicity 5-Fluorouracil Inhibits thymidylate synthase, and its metabolites are incorporated into RNA and DNA, all resulting in inhibition of DNA synthesis and function and in RNA processing GI cancers, breast cancer, head and neck cancer, hepatocellular cancer Nausea, mucositis, diarrhea Myelosuppression, neurotoxicity Other antimetabolites: Cytarabine, gemcitabine Vinca alkaloids Vincristine Interferes with microtubule function, resulting in impaired mitosis Acute lymphocytic leukemia, Hodgkin's and non-Hodgkin's lymphoma, Wilms' tumor, neuroblastoma None Neurotoxicity with peripheral neuropathy, paralytic ileus, myelosuppression, alopecia, inappropriate ADH secretion Other vinca alkaloids: Vinblastine, vinorelbine Podophyllotoxins Etoposide Inhibits topoisomerase II, resulting in DNA damage Lung cancer, non-Hodgkin's lymphoma, gastric cancer Nausea, vomiting Alopecia, myelosuppression Other podophyllotoxins: Teniposide Camptothecins Topotecan Inhibits topoisomerase I, resulting in DNA damage Small cell lung cancer, ovarian cancer Nausea, vomiting, diarrhea Myelosuppression Other camptothecins: Irinotecan Taxanes Paclitaxel Interferes with microtubule function, resulting in impaired mitosis Breast, lung, ovarian, gastroesophageal, prostate, bladder, and head and neck cancers Nausea, vomiting, hypotension, arrhythmias, hypersensitivity Myelosuppression, peripheral sensory neuropathy Other taxanes: Docetaxel Anthracyclines Doxorubicin Oxygen free radicals bind to DNA causing strand breakage; inhibits topoisomerase II; intercalates into DNA Lymphomas, myelomas, sarcomas, and breast, lung, ovarian and thyroid cancers Nausea, arrhythmias Alopecia, myelosuppression, cardiomyopathy, myelosuppression Other anthracyclines: Daunorubicin, idarubicin, epirubicin, mitoxantrone Other antitumor antibiotics: Bleomycin, mitomycin Tyrosine kinase inhibitors Imatinib Inhibits bcr-abl tyrosine kinase and other receptor tyrosine kinases Chronic myelogenous leukemia, gastrointestinal stromal tumor Nausea, vomiting Fluid retention with ankle and periorbital edema, diarrhea, myalgias, congestive heart failure Other tyrosine kinase inhibitors: Dasatinib, nilotinib Growth factor receptor inhibitorsTrastuzumab Inhibits the binding of EGF to the HER-2/neu growth receptor HER-2/neu receptor + breast cancer Nausea, vomiting, chills, fever, headache Cardiac dysfunction Other growth factor receptor inhibitors: Cetuximab, panitumumab, gefitinib, erlotinib Vascular endothelial growth factor (VEGF) inhibitors Bevacizumab Inhibits binding of VEGF to its receptor, resulting in inhibition of tumor vascularization Colorectal, breast, non-small cell lung, and renal cancer Hypertensin, infusion reaction Arterial thromboembolic events, gastrointestinal perforations, wound healing complications, proteinuria Hormone agonists Prednisone See Chapter 39 Hormone antagonists Tamoxifen See Chapter 40 Other hormonal antagonists: Aromatase inhibitors, GnRH agonist and antagonists, androgen receptor antagonists (see Chapter 40)

DHFR, dihydrofolate reductase; EGF, epidermal growth factor; GnRH, gonadotropin-releasing hormone; VEGF, vascular endothelial growth factor.



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