34.1 General Principles of Cancer Chemotherapy
Tumor development
Tumors develop when the normal regulation of the balance between cell proliferation (mitosis) and programmed cell death (apoptosis) is lost. Tumor initiation is the process by which normal cells are changed so that they are able to form tumors. This involves DNA damage of multiple genes (6–10). Substances that cause cancer can be tumor initiators. Tumor promotion is the process by which existing tumors are stimulated to grow. Tumor promoters are not able to cause tumors to form, but increase the frequency of tumor formation in tissue previously exposed to the tumor initiator.
Chemical carcinogenesis
Many chemicals that are present as industrial or environmental pollutants, dietary components, combustion by-products, or therapeutic agents may increase the risk of cancer development. Genotoxic carcinogens are thought to initiate tumorigenesis by interacting with DNA. Chemicals may be inherently genotoxic, but many chemical carcinogens are metabolized to highly reactive metabolites, which in turn damage DNA. Alternatively, chemicals could act by altering DNA replication or repair. Epigenetic carcinogens do not appear to interact directly with DNA, but instead appear to augment neoplastic growth by poorly defined mechanisms. This class of carcinogens includes various hormones (e.g., estrogen and diethylstilbestrol), immunosuppressive drugs (e.g., azathioprine), solid-state carcinogens (e.g., asbestos), and promoting agents (agents that increase tumor development when given after a genotoxic chemical).
Cell Cycle
An understanding of the cell cycle is essential for the effective use of anticancer agents (Fig. 34.1). Most anticancer drugs kill dividing cells (they are proliferation dependent); thus, tumors with a high cell turnover are most susceptible (certain leukemias and lymphomas, small proliferating tumors, “recruited” tumor cells, and micrometastases). The killing of tumor cells follows first-order kinetics. To produce a cure, therapy must continue until the final tumor cell has been eradicated. Agents that act preferentially on tumor cells in a given phase of the cell cycle are called cell cycle specific. Agents that act during several stages of the cell cycle are called cell cycle nonspecific.
Cancer critical genes
The two main types of genes that are now recognized as playing a role in cancer are oncogenes and tumor suppressor genes. Most oncogenes are mutations of normal genes called proto-oncogenes. The mutant proteins coded by oncogenes (oncoproteins) are overactive and allow cells to proliferate when they should not. The protein products of tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, and tells when to undergo apoptosis (programmed cell death). These genes are deleted or inactivated in cancer cells, allowing unregulated proliferation.
P53 gene
P53 is a tumor suppressor gene that codes for a transcription factor that regulates the expression of other genes and arrests the cell cycle. It is the most frequently mutated gene in human cancers. Mutations in p53 have been associated with carcinogenesis at multiple sites within the body.
Tumor markers
Tumor markers are substances that can be detected in the peripheral blood and are derived from neoplastic populations, but lack functional hormonal or other physiologic activity. They include carcinoembryonic antigen (CEA), seen in colon, gastric, pancreatic, and breast carcinoma; prostate-specific antigen (PSA), seen in prostate carcinoma; cancer antigen 125 (CA-125), seen in ovarian carcinoma; alpha fetoprotein (AFP), seen in hepatocellular carcinoma and germ cell neoplasms, especially yolk sac carcinoma; and human chorionic gonadotropin (hCG), seen in choriocarcinoma testicular germ cell neoplasms. In general, serum tumor markers are characterized by low sensitivity and low specificity. Nonetheless, they are employed routinely for several purposes, including screening, monitoring therapy, and detection of recurrences.
Anticancer Drugs
Several neoplastic diseases can be cured with drugs alone or with a combination of drugs and other treatment modalities. Examples of these neoplastic diseases include choriocarcinoma, Hodgkin disease, acute lymphocytic leukemia, Burkitt lymphoma, and testicular carcinoma. Adjuvant chemotherapy in combination with surgery and/or radiotherapy has increased survival rates for several solid tumors; however, the most prevalent forms of human cancer respond poorly or not at all to chemotherapy.
Drug treatment regimens for cancer usually involve combinations of agents given intermittently. Combining drugs with different mechanisms of action can produce larger therapeutic effects with fewer side effects. Intermittent therapy allows the patient to recover from drug toxicities, such as bone marrow suppression, between courses.
Fig. 34.1 
Cell cycle.
The cell cycle describes the cellular events that take place, cumulating in cell division. It is divided into four phases: G1, S, G2, and M. Fully differentiated cells are in the G0 stage when further cell division does not usually occur (hence, it is not part of the cell cycle). However, cells in the G0phase can reenter the G1 phase if acted upon by certain mitotic signals (e.g., tumor viruses and cytokines). In the G1 phase, the cell is growing and accumulating proteins and RNA. The restriction point in the G1 phase is a control point that ensures that everything is ready for DNA synthesis, which occurs in the S phase. In the G2 phase, the cell is preparing for mitosis, which occurs in the M phase, producing two daughter cells.
Radiotherapy and its systemic effects
Radiotherapy involves the use of focused ionizing radiation to treat malignant cancer cells by damaging their DNA. It can be curative, used as an adjuvant therapy, or employed in palliative therapy to limit disease progression or to provide symptomatic relief. The systemic effects of radiation include several syndromes. Hematopoietic syndrome (200−500 rads) is development of a pancytopenia within a few weeks of exposure. Bleeding and infection are the major complications. Gastrointestinal (GI) syndrome (500−1000 rads) reflects injury to the GI epithelium, resulting in the development of nausea, vomiting, and severe diarrhea within several days of exposure. This may lead to severe metabolic disturbances, vascular collapse, sepsis, and death. Cerebral syndrome (> 2500 rads) is caused by vascular endothelial damage, resulting in cerebral edema, convulsions, coma, and death within hours of exposure.
Local effects of radiotherapy
Depending on the tissues involved, acute radiation injury may manifest as an acute dermatitis, pneumonitis, and/or enteritis. Chronic changes reflect organ ischemia due to vasculopathy (endothelium is highly radiation sensitive). Neoplasms (primarily sarcomas) may develop even after an interval of 10 years or more. Acutely, blood vessels may dilate, thrombose, or rupture. Over time, however, reactive endothelial cell proliferation and mural scarring may lead to narrowing or even obliteration of the vessel lumens, causing tissue ischemia. The chronic effects of radiation injury, therefore, include interstitial fibrosis of various tissues and strictures of hollow organs.
Toxicity of Anticancer Drugs
Anticancer drugs generally have low therapeutic indices and potentially lethal toxicities. Many of the toxic effects of anticancer drugs are due to cytotoxic effects on normal tissues that have high proportions of dividing cells (Fig. 34.2).
– Anticancer drugs frequently produce nausea and vomiting, which can be ameliorated with phenothiazines or cannabinoids.
– The release of nucleic acid breakdown products following a very large cell kill from anticancer drugs can result in hyperuricemia and renal damage. Hyperuricemia is prevented with allopurinol (see Chapter 33 for details of this drug).
– Many anticancer drugs are mutagenic and carcinogenic.
Combination Therapy
When selecting a combination of anticancer drugs, they should ideally have the following attributes:
– They should be effective when used alone.
– They should have different mechanisms of action.
Fig. 34.2 Chemotherapy of tumors: principle and adverse effects.
Chemotherapeutic agents lack specificity and thus affect both malignant and endogenous cells. Because cytostatic agents act on proliferating or dividing (mitotic) cells, rapidly dividing malignant cells are preferentially injured (growth is retarded, and apoptosis is initiated). Endogenous tissues with a high mitotic rate (hair and epithelial cells) are also injured. In bone marrow, inhibition of mitosis causes neutropenia (producing a lowered resistance to infection), thrombocytopenia (producing an increased bleeding tendency), and anemia (producing fatigue, shortness of breath, dizziness, etc.). Infertility is also common due to suppression of spermatogenesis and follicle maturation. Healthy tissues and those with a low mitotic rate are largely unaffected by cytostatic agents.
— They should have minimally overlapping toxicities.
– There should be no cross-resistance.
This means that doses close to the regular doses for each drug as a single agent can be used to optimize the cytotoxic effects without additive toxicity. Drug resistance is the greatest obstacle to successful chemotherapy.
Drug Resistance
When tumor cells lack sensitivity to a drug, the drug resistance is termed primary or natural. Acquired drug resistance occurs when tumor cells undergo genotypic and phenotypic changes during therapy that render them insensitive to the drug (Fig. 34.3).
The Goldie–Coldman hypothesis states that the probability of tumor containing a cell resistant to a specific drug is related to both tumor size and mutation frequency. Even the smallest detectable cancer would be expected to contain at least one drug-resistant cell. Drug exposure then provides the selection pressure for growth of a resistant cell population. Drug resistance may be to a single or multiple drugs. Common mechanisms include decreased drug uptake, increased drug metabolism, and increased drug efflux from the cell. Increased drug efflux results from increased expression of P-glycoprotein and multidrug resistance protein and leads to multidrug resistance.
Fig. 34.3 Mechanisms of cytostatic resistance.
The initial success of cytostatic agents can be followed by diminution of effect because of the emergence of resistant tumor cells. Genotypic and phenotypic changes may lead to reduced uptake of the drug into cancer cells, increased efflux of the drug from cells, diminished activation of prodrugs, and increased DNA repair.
Benign versus malignant neoplasms
The distinction between benign and malignant tumors is based on their microscopic appearance, which predicts clinical behavior. It reflects the degree of cellular differentiation, the extent to which neoplastic cells resemble their mature counterparts. Benign neoplasms are well differentiated (i.e., closely resemble mature cells of origin); hence, features such as gland formation are retained. Malignant cells, however, exhibit incomplete or lack of differentiation (anaplasia), and thus resemble stem cells. Anaplasia is characterized by cellular and nuclear pleomorphism (due to alterations in the cell cytoskeleton), increased nuclear/cytoplasmic ratio, increased nuclear chromatin density and bizarre mitoses (due to chromosomal aneuploidy), and loss of cellular orientation. Rate of growth tends to parallel the degree of differentiation of the neoplastic cells, as well as the cell turnover rate of the cell of origin. Thus, benign neoplasms have slow growth. Malignant neoplasms are characterized by a wide range of growth rates. Neoplasms derived from rapidly cycling populations (e.g., bone marrow and GI tract) grow much more rapidly than slowly proliferating tissues (e.g., prostate and salivary gland).
34.2 Cancer Chemotherapy Drugs
Alkylating Agents
Mechanism of action. Alkylating agents bind covalently to guanine nucleotides of DNA and cross-link DNA strands. This prevents DNA replication and transcription to produce cytotoxicity (Fig. 34.4). They are proliferation dependent but cell cycle nonspecific.
Fig. 34.4 Cytostatics: alkylating agents and cytostatic antibiotics (1), inhibitors of tetrahydrofolate synthesis (2), and antimetabolites (3).
Mitosis is preceded by protein synthesis (RNA synthesis) and chromosomal replication (DNA synthesis). Existing DNA (gray) acts as a template for new DNA (blue). Alkylating agents (1) form covalent bonds with DNA, cross-linking it, and thus rendering it impossible to “unzip” and replicate. DNA strand breakage may also occur with some cytostatic antibiotics and topoisomerase inhibitors. Methotrexate is an antimetabolite (2) that inhibits dihydrofolate reductase, suppressing the production of purine and thymine nucleotides. Other antimetabolites (3) are purine and pyrimidine analogues that inhibit DNA/RNA synthesis or lead to the production of incorrect nucleic acids.
Resistance. High rates of DNA repair may be a cause of resistance.
Mechlorethamine
Mechlorethamine was the first anticancer drug to be used clinically, but it has largely been replaced by drugs that are better tolerated.
Pharmacokinetics
– Administered intravenously (IV)
– Highly reactive (the active drug has a very short half-life)
– A potent vesicant (i.e., it can cause chemical burns, resulting in large water blisters on contact with skin)
Uses. Mechlorethamine's main use is in the mechlorethamine, oncovin, procarbazine, and prednisone (MOPP) regimen for treatment of Hodgkin disease.
Hodgkin disease
Hodgkin disease is a type of lymphoma (tumor of lymphocytes). On histological examination, there are characteristic cells (Reed–Sternberg cells) that have mirror image nuclei. Patients present with enlarged, painless lymph nodes in the neck or axillae, as well as fever, weight loss, night sweats, and general malaise (in 25%). Treatment depends on the stage of the disease but may involve radiotherapy and/or chemotherapy. This is one of the more treatable forms of cancer, with survival rates of up to 90% if detected early.
Side effects
– Bone marrow depression (leading to leucopenia and thrombocytopenia) is dose-limiting.
– Severe nausea and vomiting may occur.
Bone marrow function
There are two types of bone marrow: red and yellow. Red bone marrow contains myeloid tissue and produces red blood cells, most white blood cells, and platelets. Yellow bone marrow is largely made up of fat cells. At birth, all bone marrow is red, but in adults, it has been reduced by approximately half and is generally found in the flat bones, such as the hip, skull, vertebrae, and sternum, along with the cancellous ends of the long bones.
Cyclophosphamide and Ifosfamide
Cyclophosphamide is the most widely used alkylating agent. Ifosfamide is an analogue of cyclophosphamide.
Pharmacokinetics
– Effective orally or IV
– Require cytochrome P-450−mediated metabolism for activation
– Nonvesicant
Uses
– Leukemia, lymphoma, ovarian cancer, breast cancer, and for solid tumors in children (cyclophosphamide in combination with other drugs)
– Prevention of organ rejection after transplantation (cyclophosphamide)
– Immune disorders, such as Wegener granulomatosis, rheumatoid arthritis, and systemic lupus erythematosus (cyclophosphamide)
– Ifosfamide is approved as third-line therapy for testicular cancer, but it can also be used to treat the diseases for which cyclophosphamide is indicated.
Side effects
– Bone marrow depression is dose-limiting.
– Alopecia and immunosuppression are prominent.
– Renal excretion of metabolites causes hemorrhagic cystitis. This can be prevented with adequate prophylactic hydration.
– Isofosfamide has greater myelosuppressant, renal, and neurologic side effects.
Carmustine and Lomustine
These drugs have a nitrosoureas structure.
Pharmacokinetics
– These agents are highly lipophilic and cross the blood–brain barrier.
– Carmustine is given IV, and lomustine is given orally.
Uses
– Central nervous system (CNS) malignancies
– Hodgkin disease
Side effects. Bone marrow depression is delayed and may be prolonged.
Chemotherapy wafer implants
Chemotherapy wafer implants are a new way of administering chemotherapy for certain brain tumors (gliomas and glioblastoma multiforme). Brain surgery is performed to remove all or most of the tumor, and the wafer is placed in the resulting space, where the drug (carmustine) slowly leaches out and treats the tumor locally. All of the usual chemotherapy side effects are still seen with this method of drug delivery.
Cisplatin, Carboplatin, and Oxaliplatin
Mechanism of action. Each of these agents consists of a complex of inorganic platinum ions. They act by forming DNA cross-links, which prevents DNA replication and transcription.
Pharmacokinetics
– Administered IV
– Bind to plasma proteins (90%)
– Concentrate in the liver, kidneys, intestines, and ovaries
– Excreted in the urine
Uses. Solid tumors, especially testicular, ovarian, and bladder cancer.
Side effects
– Renal damage (dose-limiting). This can be decreased by prehydration and concomitant mannitol diuresis.
– Moderate bone marrow depression, ototoxicity (damage to the inner ear by a toxin), hypomagnesemia, and hypocalcemia
Busulfan
Pharmacokinetics
– Given orally
Uses
– Chronic granulocytic leukemia
Side effects
– Bone marrow depression is selective for granulocytes (neutrophils, basophils, and eosinophils).
– Leukopenia (decreased number of white blood cells) and skin pigmentation may occur.
Procarbazine
Mechanism of action. Procarbazine's mechanism of action is unclear.
Pharmacokinetics
– Administered orally
– It must undergo metabolic activation.
– It is not cross-resistant with other alkylating agents.
Side effects
– Bone marrow depression is dose-limiting.
– CNS depression may occur (synergistic with phenothiazines and barbiturates).
Antimetabolites
Mechanism of action. These drugs include purine, pyrimidine, and folate analogues that act primarily by inhibiting DNA synthesis. They inhibit cells in the S phase (except fluorouracil, which has no clear-cut phase specificity) and may be incorporated into DNA and RNA. These drugs are converted by the cells to lethal metabolites (Fig. 34.4).
Methotrexate
Methotrexate is also discussed in Chapters 27 and 33.
Mechanism of action. Methotrexate is a folic acid analogue that competitively inhibits dihydrofolate reductase, the enzyme that normally converts folate to tetrahydrofolate, which is needed for purine and thymidine synthesis. This results in reduced DNA, RNA, and protein synthesis (Fig. 34.4).
Pharmacokinetics
– Administered orally, IV, or intrathecally
– It is poorly transported across the blood–brain barrier unless given in high concentrations or administered intrathecally.
– Fifty percent is bound to plasma proteins (displaced by salicylates, sulfonamides, etc.).
– Excreted unchanged in urine (so it should be used with caution in patients with renal damage)
Uses
– Drug of choice for gestational choriocarcinoma
– Acute lymphocytic leukemia (in children)
– Burkitt lymphoma
– Breast cancer
– Psoriasis
– Rheumatoid arthritis
– Inflammatory bowel disease
Note: It is sometimes used in very high doses with leucovorin, an active form of folate, to prevent damage to normal cells.
Side effects
– Bone marrow depression (dose-limiting toxicity)
– Oral and GI ulceration
– Hepatic damage
– Renal damage (due to precipitation of crystallized metabolites in the kidney)
Tumor grading
Grade refers to a microscopic pathologic determination of tumor aggressiveness based on the degree of differentiation of the neoplastic cells and the number of mitoses. Most tumors are graded from 1 (low grade, well differentiated) through 3 (high grade, undifferentiated). Some malignant neoplasms progress to a higher grade over time as less differentiated clones of cells become dominant. Criteria for grading include mitotic rate, nuclear pleomorphism, and architectural features (e.g., preservation of gland formation).
Tumor staging
Stage refers to a clinical and pathologic determination of tumor extent based on the size of the neoplasm, the presence or absence of regional lymph node metastases, and the presence or absence of distant metastases. This is the basis of the tumor size, node involvement, metastasis (TNM) staging system. Tumors are staged numerically from 0 through IV as follows:
0: in situ
I: small, organ confined
II: large or regional node metastases
III: invasion of adjacent organs
IV: distant metastases In general, stage has greater prognostic value than grade.
Mercaptopurine
Mechanisms of action. Mercaptopurine is a purine analogue that causes pseudofeedback inhibition of the first step in purine biosynthesis and inhibition of purine interconversions. This leads to the insertion of the incorrect bases into DNA (Fig. 34.4).
Pharmacokinetics
– Administered orally
– Metabolism to inactive products is inhibited by allopurinol.
Uses
– Acute lymphoid leukemia
Side effects. Side effects include bone marrow depression (major toxicity) and liver damage.
Thioguanine
Thioguanine has similar pharmacological properties to mercaptopurine except that allopurinol does not interfere with its inactivation.
Fluorouracil
Mechanism of action. Fluorouracil is a pyrimidine analogue that is converted to 5-fluodeoxyuridine monophosphate, causing inhibition of thymidylate synthesis. DNA synthesis is therefore reduced due to a lack of thymidine. It also forms 5-fluodeoxyuridine triphosphate, which is incorporated into RNA and blocks translation. There is no cell cycle phase specificity.
– Leucovorin is also used in combination with fluorouracil. While it protects normal cells from damage by methotrexate, leucovorin potentiates the effectiveness of fluorouracil, presumably by providing active folate as a cofactor for the interaction of fluorouracil with thymidylate synthase.
Pharmacokinetics
– Administered IV
– Able to enter the cerebrospinal fluid (CSF)
– Rapidly metabolized in the liver
Uses
– Breast, pancreatic, colorectal, and gastric cancer
Side effects
– Oral and GI ulcers
– Bone marrow depression (dose-limiting toxicity)
– Neurologic defects (cerebellar)
– Hyperpigmentation
– Alopecia
Capecitabine
Mechanism of action. Capecitabine is a prodrug for fluorouracil and therefore acts similarly.
Uses
– Advanced colon and breast cancer
Fludarabine and Cladribine
Mechanism of action. These agents are purine analogue antagonists that cause a reduction in DNA synthesis.
Uses
– Chronic lymphocytic leukemia and some non–Hodgkin lymphomas (fludarabine)
– Hairy cell leukemia (cladribine)
Cytarabine and Gemcitabine
Mechanism of action. Cytarabine and gemcitabine are metabolized to cytidine analogues that block DNA synthesis by inhibiting DNA polymerases and by becoming incorporated into DNA, preventing further elongation of the DNA.
Pharmacokinetics
– Administered IV
– Rapidly deaminated in the liver, plasma, and other tissues
Uses
– Acute lymphoid leukemia, acute myeloid leukemia, chronic myeloid leukemia, and meningeal leukemia (cytarabine)
– Advanced pancreatic, breast, ovarian, and non–small cell lung cancers (gemcitabine)
Side effects
– Bone marrow depression (major toxicity)
– Oral ulceration
– Liver dysfunction
Antibiotics
Antibiotic treatment of infections is discussed in Chapter 29. The agents discussed in this section are used to treat cancer. They act by binding to DNA (noncovalently by intercalation) and altering its function. They are cycle nonspecific (Fig. 34.4).
Dactinomycin (Actinomycin D)
Mechanisms of action. Dactinomycin intercalates between G-C pairs in double-stranded DNA and inhibits DNA-directed RNA synthesis. It is equally cytotoxic to proliferating and stationary cells.
Pharmacokinetics
– Administered IV (can cause local inflammation and phlebitis)
Side effects. Side effects include bone marrow depression (toxicity is dose limiting), oral and GI ulceration, and alopecia.
Doxorubicin
Mechanisms of action
– Inhibition of DNA and RNA synthesis due to intercalation
– DNA fragmentation from reactive oxygen species
– Inhibition of DNA topoisomerase II
– Interaction with cell membranes, causing a broad spectrum of antitumor activity
Pharmacokinetics
– Administered IV (extravasation leads to severe local reaction and necrosis)
– Extensively metabolized in the liver and excreted into the bile (decreased dose in the presence of hepatic dysfunction)
– Drug and metabolites color urine red.
Uses. Doxorubicin has a broad spectrum of activity and is used in the following cancers:
– Acute lymphoid leukemia, chronic lymphoid leukemia, and acute myeloid leukemia
– Breast, stomach, bone, thyroid, kidney, liver, and pancreatic cancers
Side effects
– Bone marrow depression is their major toxicity (except for bleomycin). This is dose-limiting.
– Cardiotoxicity (refractory congestive heart failure). This is due to avid uptake by and oxidative damage to heart muscle. The damage caused is potentially irreversible and can be delayed many months. It is related to the total dose administered.
– Alopecia, stomatitis (inflammation of the mucosa of the mouth), fever, and chills
Daunorubicin
Daunorubicin is similar to doxorubicin but has a narrower spectrum of activity.
Idarubicin
Idarubicin is an analogue of daunorubicin used in combination with therapy for acute lymphoid leukemia.
Bleomycin
Mechanism of action. Bleomycin is a mixture of complex glycopeptides that causes strand scission of DNA by producing reactive oxygen species. It is unusual in that it produces very little bone marrow depression.
Pharmacokinetics
– Administered IV
– Enzymatically inactivated in several tissues (toxicity occurs in tissues with low inactivating activity, i.e., lungs and skin)
– Fifty percent is excreted unchanged in the urine.
Uses
– Hodgkin and non–Hodgkin lymphomas
– Testicular cancer
– Squamous cell carcinomas of the head, neck, nasopharynx, penis, vulva, and cervix
Side effects
– Pulmonary toxicity (pneumonitis and fibrosis) is dose-limiting.
– The more common toxic effects involve the skin and mucous membranes.
– Alopecia and stomatitis
Topoisomerase Inhibitors
Topoisomerase
DNA is arranged as in a double helix formation, which is then supercoiled or knotted in chromosomes. This is a very stable and efficient way to store our genetic information. To avoid having to uncoil and unwind entire lengths of DNA, topoisomerase enzymes bind to DNA and cut the phosphate backbone, thus allowing specific sections to uncoil and unwind for transcription and replication to occur. They reconnect the DNA strands when the process is finished.
Etoposide and Teniposide
Mechanism of action. These agents inhibit topoisomerase II, which acts on single-stranded DNA to cause strand breakage (Fig. 34.4).
Uses
– Small cell lung cancer, testicular carcinoma, acute nonlymphocytic leukemia, and malignant lymphoma (etoposide)
– First-line therapy for neuroblastoma and retinoblastoma in combination with other agents
– Refractory leukemias (teniposide)
Side effects
– Nausea and vomiting (short term)
– Alopecia and myelosuppression (longer term)
Irinotecan and Topotecan
Mechanism of action. Irinotecan and topotecan inhibit topoisomerase I, which acts on double-stranded DNA to induce strand breakage.
Uses
– Metastatic colorectal cancer (irinotecan)
– Ovarian and small cell lung cancers (topotecan)
Side effects. Side effects are the same as for etoposide and teniposide.
Antimitotics
Mechanism of action. Antimitotic agents bind to tubulin, inhibiting mitotic spindles and arresting cell development in the M phase of the cell cycle.
The vinca alkaloids vincristine and vinblastine are structurally similar but have different activities and toxicities and show no cross-resistance.
Pharmacokinetics
– Administered IV (extravasation and subsequent local reactions may occur)
– Excreted into bile (use with caution in patients with obstructive jaundice)
Vincristine
Uses
– Acute leukemia
– Hodgkin disease
– Nephroblastoma (Wilms tumor)
– Rhabdomyosarcoma
Nephroblastoma (Wilms tumor)
Nephroblastoma (Wilms tumor) is a malignant renal tumor composed of mixed embryonal cell elements. Increased mature elements and decreased anaplastic cells are indicative of the best prognosis. Signs and symptoms include painless hematuria, abdominal pain, an enlarged abdomen, and a palpable abdominal mass. Computed tomography scans or magnetic resonance imaging of the abdomen is diagnostic for a mass. Hematuria is seen with urinalysis. Treatment includes surgery (nephrectomy), radiation therapy, and chemotherapy. The prognosis for 2-year survival (with favorable histology) is 95% for stage I, II, and III tumors and 50% for stage IV tumors.
Side effects
– Neurologic toxicities are dose-limiting. Suppression of the Achilles tendon reflex and paresthesias appear first, followed by other peripheral neuropathies, neuritic pain, constipation, and disorders of cranial nerve function.
– Alopecia
– Mild bone marrow depression (vincristine is considered to be marrow-sparing compared with other agents)
Achilles tendon reflex
The Achilles tendon reflex is plantar (downward) flexion extension of the foot resulting from contraction of the calf muscles following a sharp blow to the Achilles tendon. This reflex is suppressed by vincristine.
Vinblastine
Uses
– Some lymphomas and solid tumors
Side effects
– Bone marrow depression (dose-limiting)
– Neuropathy is less frequent and less serious than with vincristine
– Alopecia, stomatitis, and peripheral neuropathy
Vinorelbine
Vinorelbine is a semisynthetic derivative of vinblastine.
Pharmacokinetics
– Given orally
Uses
– Non–small cell lung cancer
Side effects. They are similar to vinblastine.
Taxanes
Paclitaxel and Docetaxel
Mechanism of action. These drugs promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization. This prevents reorganization of the microtubule network for mitosis.
Uses
– Breast cancer
– Lung cancer
– Ovarian cancer
Side effects
– Bone marrow suppression
– Moderate nausea and vomiting
– Alopecia
– Sensory neuropathy
– Hypersensitivity to the drug
Monoclonal Antibodies
Mechanism of action. Monoclonal antibodies bind specifically to proteins on cancer cells, resulting in inhibition of growth and antibody-dependent cellular cytotoxicity. Labeling the antibodies with radioactive isotopes allows the bound antibody to specifically deliver the radioactivity to target cells.
Pharmacokinetics. These agents must be given IV.
Rituximab
Mechanism of action. Rituximab binds to CD20, which is found on pre-B and mature B lymphocytes. It is also expressed on > 90% of B cell non–Hodgkin lymphomas, but not expressed on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues.
Pharmacokinetics
– Given by slow IV infusion to prevent adverse reactions
Uses
– B-cell lymphoma
– Chronic lymphoblastic leukemia
Side effects
– Changes in blood pressure
– GI upset: nausea and vomiting
– Neurologic effects including weakness, dizziness, headache, and sensory neuropathy
– Fever and shivering
Tositumomab and Iodine 131 Tositumomab
Mechanism of action. Tositumomab and iodine 131 tositumomab bind to CD20.
Uses
– B-cell lymphoma
Side effects
– Diarrhea
Indium 111 Ibritumomab and Yttrium 90 Ibritumomab Tiuxetan
Mechanism of action. Indium 111 ibritumomab and yttrium 90 ibritumomab tiuxetan bind to CD20.
Uses
– B-cell lymphoma
Side effects
– Severe allergic reactions have been observed.
– Severe hematological reactions, including anemia, leukopenia, thrombocytopenia, and bone marrow suppression
– Nausea and vomiting
– Weakness, dizziness, headache, and sensory neuropathy
– Fever and shivering
Alemtuzumab
Mechanism of action. Alemtuzumab binds to CD52, which is present on the surface of essentially all B and T lymphocytes, a majority of monocytes, macrophages, and NK cells, and a subpopulation of granulocytes.
Uses
– B-cell chronic lymphocytic leukemia
– T-cell lymphoma
Side effects
– Changes in blood pressure
– Severe hematological reactions, including anemia, leukopenia, thrombocytopenia, and bone marrow suppression
– Diarrhea, nausea, and vomiting
— Weakness, dizziness, and headache
– Fever and shivering
– Infection and viremia
Trastuzumab
Mechanism of action. Trastuzumab binds to HER2/neu (ErbB-2) protein, which is overexpressed in 25 to 30% of primary breast cancers.
Uses
– Breast cancer
Side effects
– Edema
– Rash
– Diarrhea, nausea, and vomiting
– Weakness, dizziness, headache, and backache or muscle pain
– Fever and shivering
– Cough, dyspnea, rhinitis, and pharyngitis
Cetuximab
Mechanism of action. Cetuximab binds to epidermal growth factor receptor (EGFR), which has been detected in many human cancers, including those of the colon and rectum.
Uses
– Colorectal cancer
– Head and neck cancers
Side effects
– Rash
– Hypomagnesemia
– Constipation, diarrhea, nausea, and vomiting
– Fatigue, pain, headache, and insomnia
– Fever and shivering
– Cough, dyspnea, and pharyngitis
Bevacizumab
Mechanism of action. Bevacizumab binds to vascular endothelial growth factor (VEGF) prevents the proliferation of endothelial cells and formation of new blood vessels, thus starving tumors of their blood supply.
Uses
– Colorectal cancer
– Lung cancer
– Breast cancer
– Pancreatic cancer
Side effects
– Hypertension
– Alopecia
– Hypokalemia
– Constipation, diarrhea, nausea, anorexia, and stomatitis
– Fatigue, pain, headache, and sensory neuropathy
– Epistaxis
– Hemorrhage
Gemtuzumab Ozogamicin
Mechanism of action. Gemtuzumab ozogamicin binds to CD33 expressed on hematopoietic cells. The receptor is then internalized. Upon internalization, the ozogamicin portion of the molecule is released inside the lysosomes of the myeloid cell and binds to DNA to cause cell death.
Uses
– Acute myeloid leukemia
Side effects
– Shivering, nausea, fever, and bone marrow suppression
Table 34.1 provides a summary of the monoclonal antibody agents, the antigen on cancer cells that they bind to, and their uses.
|
Table 34.1 |
||
|
Agent |
Antigen |
Uses |
|
Rituximab |
CD20 |
B-cell lymphoma and chronic lymphoblastic leukemia |
|
Tositumomab and iodine 131 tositumomab |
CD20 |
B-cell lymphoma |
|
Indium 111 ibritumomab and yttrium 90 ibritumomab tiuxetan |
CD20 |
B-cell lymphoma |
|
Alemtuzumab |
CD52 |
B-cell CLL and T-cell lymphoma |
|
Trastuzumab |
HER2/neu (ErbB-2) |
Breast cancer |
|
Cetuximab |
EGFR (ErbB-1) |
Colorectal, head and neck |
|
Bevacizumab |
VEGF |
Colorectal, lung, breast, pancreatic |
|
Gemtuzumab ozogamicin |
CD33 |
Acute myeloid leukemia |
|
Abbreviations: CLL, chronic lymphocytic leukemia; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor. |
||
Tyrosine Kinase Inhibitors
Tyrosine kinase inhibitors target receptor tyrosine kinases on the membranes of cancer cells, inhibiting their activity and thus decreasing cancer cell growth.
Imatinib
Mechanism of action. Imatinib is a selective inhibitor of the tyrosine kinase activity of the bcr-abl protein, which is the product of the Philadelphia chromosome. It is present in virtually all patients with chronic myelogenous leukemia and some patients with acute lymphoblastic leukemia (Fig. 34.5).
Pharmacokinetics
– Given orally
Uses
– Chronic myelogenous leukemia
– Acute lymphoblastic leukemia
Side effects
– Edema, nausea, and vomiting
Dasatinib
Mechanism of action. Dasatinib is a tyrosine kinase inhibitor active against bcr-abl and Src family kinases. Dasatinib is more potent than imatinib, and it inhibits mutated forms of bcr-abl that are resistant to imatinib.
Fig. 34.5 Targeting of the chemotherapeutic drug imatinib.
Targeted treatment of cancer can occur when cancer cells display metabolic properties that are different from those of healthy cells. Patients with chronic myelogenous leukemia almost always possess the Philadelphia chromosome. This recombinant gene encodes a tyrosine kinase mutant with unregulated, enhanced activity, causing cell proliferation. Imatinab specifically inhibits this mutant tyrosine kinase, thus inhibiting cell proliferation.
Uses
– Acute lymphoblastic leukemia and chronic myelogenous leukemia that is resistant to imatinib
Gefitinib and Erlotinib
Mechanism of action. Gefitinib and erlotinib are selective EGFR tyrosine kinase inhibitors. They block EGFR-mediated signal transduction pathways involved in tumor growth.
Uses
– Non–small cell lung cancer in patients with advanced forms who have failed both platinum and docetaxel-based chemotherapies
– Pancreatic cancer (erlotinib)
Side effects
– Rash
– Diarrhea, nausea, and vomiting
Sorafenib
Mechanism of action. Sorafenib is a multiple kinase inhibitor that blocks the receptor tyrosine kinases VEGFR (vascular endothelial growth factor receptor) and PDGFR (platelet-derived growth factor receptor) and the Raf serine/threonine kinases along the RAF/MEK/ERK pathway.
Uses
– Liver and kidney cancers
Side effects
– Hypertension
– Alopecia, rash, and chemotherapy-induced acral erythema (hand-foot syndrome)
– Abdominal pain, diarrhea, nausea, and anorexia
– Headache and fatigue
– Hemorrhage
Sunitinib
Mechanism of action. Sunitinib is a multitargeting tyrosine kinase inhibitor that decreases tumor cell proliferation and angiogenesis.
Uses
– Advanced stomach and kidney cancers
Side effects
– Hypertension and heart failure
– Abdominal pain, constipation, diarrhea, nausea, anorexia, and stomatitis
– Anemia, leukopenia, lymphocytopenia, and hemorrhage
– Yellow discoloration of skin, hand-foot syndrome, and dry skin
Bortezomib
Mechanism of action. Bortezomib is an inhibitor of the 26S proteasome, a protease important for intracellular degradation of proteins involved in cell cycle control and cellular apoptosis. Disruption of the degradation of these proteins results in disruption of cell proliferation and increases cell death.
Uses
– Patients with multiple myeloma who have not responded to prior therapies
Side effects. Serious dose-limiting effects on cardiovascular and hematological systems, along with the common skin, GI, neurologic, and respiratory effects of anticancer agents.
Differentiating Agents
Tretinoin
Tretinoin is an all trans retinoic acid, which is a derivative of vitamin A.
Mechanism of action. Tretinoin induces terminal maturation of leukemic promyelocytes into polymorphonuclear monocytes in acute promyelocytic leukemia.
Uses
– Acute promyelocytic leukemia
Side effects
– Edema, arrhythmia, and blood pressure changes
– Headache, pain, fatigue, and dizziness
– Rash and dry skin
– Hypercholesterolemia and hypertriglyceridemia
– Abdominal pain, constipation, diarrhea, nausea, and vomiting
– Leukocytosis
– Upper respiratory tract disorders, dyspnea, and pneumonia
Arsenic Trioxide
Mechanism of action. Arsenic trioxide causes differentiation and apoptosis in acute promyelocytic leukemia refractory to tretinoin.
Uses
– Acute promyelocytic leukemia refractory to tretinoin
Side effects
– Chest pain, edema, and hypotension
– Headache, pain, fatigue, dizziness, and insomnia
– Rash and dry skin
– Hypo- or hyperkalemia, hyperglycemia, and hypomagnesemia
– Abdominal pain, constipation, diarrhea, nausea, vomiting, and anorexia
– Leukocytosis, anemia, and thrombocytopenia
– Upper respiratory tract disorders, cough, dyspnea, and epistaxis
Hormones and Hormone Inhibitors
Hormonal therapy is effective for some cancers (e.g., breast cancer). They may inhibit tumor growth directly or oppose the effects of endogenous hormones. Toxicities are due to hormonal effects rather than cytotoxic effects.
Corticosteroids
Corticosteroids are also discussed in Chapters 16, 26, 27, and 32.
Prednisone
Mechanism of action. Corticosteroids are useful in cancer chemotherapy due to their lymphocytic and antimitotic actions.
Uses
– Lymphomatous cancers (in conjunction with other agents)
Antiestrogens
Testing for the presence of estrogen receptors and progesterone receptors in tumor specimens from biopsy or surgery is recommended for all patients with primary invasive breast cancer. Up to 60% of patients with metastatic breast cancer will respond to hormonal therapy if their tumors contain estrogen receptors; however, < 10% of patients with metastatic tumors that are estrogen receptor–negative respond to hormonal therapy. Up to 80% of patients with metastatic progesterone receptor–positive tumors respond to hormonal manipulation. The presence or absence of these receptors does not correlate with the response to other chemotherapies. Thus, adjuvant hormonal therapy, in combination with surgery, radiation, and/or chemotherapy, is recommended for all women whose breast cancer expresses hormone receptors.
Tamoxifen
Mechanism of action. Tamoxifen is a partial agonist at the estrogen receptor. Its primary effect is to block the cell-proliferative effects of estrogen, but it also may inhibit replication by additional mechanisms (see Fig. 17.3, page 164). Many proteins and transcription factors interact with the estrogen receptor, so there are many downstream effects that occur because of tamoxifen's acting at the estrogen receptor, resulting in inhibition of growth-stimulatory factors, as well as activation of growth-inhibitory effects, including transforming growth factor beta (TGF-β).
Pharmacokinetics
– Given orally
Uses
– Adjuvant hormonal therapy in premenopausal women with invasive breast cancer, with or without ovarian suppression or ablation therapy
– Adjuvant hormonal therapy in postmenopausal women with invasive breast cancer
Side effects. Nausea and vomiting, hot flashes, and hypercalcemia
Aromatase Inhibitors
Anastrozole, Letrozole, and Exemestane
Mechanism of action. Aromatase converts the adrenal androgen androstenedione in peripheral tissue to estrone and estradiol, the main source of estrogens in postmenopausal women.
– Anastrozole and letrozole are nonsteroidal competitive inhibitors.
Fig. 34.6 Aromatase inhibitors.
Aromatase inhibitors block the conversion of androgens (testosterone and androstenedione) to estrone and estradiol in extragonadal tissue after menopause (when ovarian estrogen production ceases). In doing so, these agents inhibit the growth of estrogen-dependent breast cancers.
– Exemestane is a derivative of androstenedione; thus, it is a steroidal compound that acts as a false substrate for the enzyme, binding to the active site and resulting in irreversible inactivation (Fig. 34.6).
Uses
– For adjuvant treatment of postmenopausal women with hormone receptor–positive early breast cancer or for treatment of advanced breast cancer
Note: When an aromatase inhibitor is used in premenopausal women, a luteinizing hormone–releasing hormone (LHRH) agonist (goserelin, leuprolide, or triptorelin) is given to block ovarian estrogen production, or the ovaries are removed surgically.
Side effects. Nausea and vomiting, hot flashes, and musculoskeletal problems
Functions of the prostate gland
The prostate gland is responsible for producing a significant portion of the fluid that makes up semen. This fluid contains substances that aid sperm on their journey to the fallopian tubes during reproduction (e.g., fructose provides sperm with energy). Seminal fluid is alkaline, which neutralizes the acidity of the vagina and stops sperm death on contact. The prostate gland also plays a part in ejaculation and sealing off the urethra so that no urine is expelled at this time.
GnRH Agonist Agents
Leuprolide and Goserelin
Mechanism of action. These agents are GnRH agonists that desensitize pituitary GnRH receptors and inhibit the release of gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]).
Uses
– Prostate cancer treatment (in combination with an antiandrogen) to prevent the initial flare-up of the disease
Antiandrogens
Bicalutamide, Flutamide, and Nilutamide
Mechanism of action. These agents are competitive inhibitors of dihydrotestosterone (DHT) and testosterone at receptor binding sites.
Side effects
– Hot flashes are common.
– Gynecomastia, nausea and vomiting, edema, and thrombophlebitis
34.3 Immunosuppressants
Immunosuppressants are used to prevent rejection in patients receiving organ transplants and in autoimmune diseases. Although effective in such cases, they increase the risk of infections and cancers. Figure 34.7 illustrates the normal immune reaction and the general steps that the immunosuppressant drugs may inhibit.
Immunosuppressants have been discussed in the sections on inflammatory bowel disease, cancer chemotherapy, and rheumatoid arthritis. Those agents that have not been discussed elsewhere are included below. Table 34.2 provides page and figure cross-references for all immunosuppressant drugs.
|
Table 34.2 |
|||
|
Drug class |
Drugs |
Chapter/page reference(s) |
Figure reference(s) |
|
Antimetabolites |
Cyclophosphamide |
Chapter 34/p. 369 |
34.7 |
|
Methotrexate Chapter 27/p. 276 Chapter 33/p. 351 Chapter 34/p. 370 |
27.13 33.3 34.4 34.7 |
||
|
Azathioprine |
Chapter 27/p. 276 |
27.13 34.4 34.7 |
|
|
Calcineurin inhibitors |
Cyclosporine |
Chapter 27/p. 276 |
33.3 34.8 |
|
Tacrolimus |
Chapter 34/p. 384 |
34.8 |
|
|
Corticosteroids |
Prednisone Budesonide Hydrocortisone (Cortisol) Methylprednisolone Triamcinolone Dexamethasone Betamethasone Beclomethasone Fluocinonide Ciclesonide Flunisolide Fluticasone |
Chapter 16/pp. 149, 151–155 Chapter 26/p. 250 Chapter 27/p. 276 Chapter 32/p. 350 Chapter 34/p. 381 |
16.8–16.11 27.12 34.7 |
|
Monoclonal antibodies |
Basiliximab |
Chapter 34/p. 387 |
34.7 |
|
Infliximab |
Chapter 27/p. 274 Chapter 33/p. 358 Chapter 34/p. 387 |
33.4 |
|
|
Muromonab-CD3 |
Chapter 34/p. 387 |
34.7 |
|
|
Other |
Sirolimus |
Chapter 34/p. 385 |
34.7 |
|
Mycophenolate mofetil |
Chapter 34/p. 385 |
34.7 |
|
Humoral and cell-mediated immunity
Humoral immunity refers to the adaptive immune responses mediated by antigen-specific antibodies and cell-mediated immunity to those mediated by T cells. Both these responses begin with the binding of antigen by lymphocytes (B cells or T cells). B cells bind free antigen. Activated B cells differentiate into plasma cells and secrete antibodies that travel around the body and attack and destroy antigens identical to those that stimulated their production.
T cells require that antigens be on the surface of macrophages (for helper T cells) or other cells (for cytotoxic T cells) in conjunction with the major histocompatibility complex and CD proteins (MHC I and CD8 for cytotoxic T cells and MHC II and CD4 for helper T cells) to be recognized and bound. Following activation, cytotoxic T cells proliferate and travel to, bind, and destroy antigens identical to those that stimulated their production. Helper T cells do not attack antigens but instead assist in the activation and function of B cells and cytotoxic T cells. Once activated by binding antigen, helper T cells release cytokines which act on activated B and cytotoxic T cells. In most cases, this is essential for activated B cells and cytotoxic T cells to proliferate and function. In addition, some of the cytokines that helper T cells release mediate the inflammatory response.
Fig. 34.7 Immune reaction and immunosuppressant drugs.
Humoral immunity (left column) and cell-mediated immunity (middle two columns) are described in the call-out boxes, on p. 383. The far right column lists the actions of immunosuppressant drugs in inhibiting immune responses. (MHC, major histocompatibility complex)
Tacrolimus
Tarcrolimus is a macrolide antibiotic produced by Streptomyces tsukubaensis.
Mechanism of action. Tarcrolimus inhibits calcineurin, thus inhibiting T-cell activation (Fig. 34.8).
Pharmacokinetics
– Given orally or IV
Uses
– Prophylaxis of organ transplant rejection
Side effects
– Cardiovascular: hypertension and edema
– Endocrine/metabolic: hypomagnesemia, hyperglycemia, and diabetes
– GI: nausea, vomiting, constipation, and diarrhea
– Hematologic: anemia, leukopenia, and thrombocytopenia
– Neurologic: headache, insomnia, pain, paresthesia, and tremor
Sirolimus
Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus.
Mechanism of action. Sirolimus inhibits T-lymphocyte activation and proliferation stimulation by interleukin cytokines (IL-2, IL-4, and IL-15) (Fig. 34.8).
Pharmacokinetics
– Given orally
Uses
– Prophylaxis of kidney transplant rejection
Side effects
– Cardiovascular: hypertension and edema
– Dermatologic: acne and rash
– Endocrine/metabolic: hyperlipidemias
– GI: nausea, vomiting, constipation, and diarrhea
– Hematologic: anemia and thrombocytopenia
– Neurologic: headache, insomnia, and pain
Mycophenolate Mofetil
Mycophenolate mofetil is a semisynthetic derivative of mycophenolic acid from the mold Penicillium glaucum.
Mechanism of action. Mycophenolate mofetil inhibits T- and B-lymphocyte responses.
Pharmacokinetics
– Given orally or IV
Uses
– Prophylaxis of organ transplant rejection
Side effects
– Cardiovascular: hypertension and edema
– Endocrine/metabolic: hyperlipidemias
– GI: nausea, vomiting, constipation, and diarrhea
– Hematologic: anemia, severe neutropenia, and thrombocytopenia
– Neurologic: asthenia, headache, insomnia, pain, and tremor
Fig. 34.8 Calcineurin inhibitors and sirolimus (rapamycin).
In T-helper cells, nuclear factor of activated T cell (NFAT) promotes the expression of interleukin 2 (IL-2). NFAT is able to enter the nucleus following dephosphorylation of its phosphorylated precursor by the phosphatase calcineurin. Cyclosporine binds to the protein cyclophillin in the cell interior; this complex inhibits calcineurin, and thus the transcription and production of IL-2 are inhibited. Tarcrolimus acts like cyclosporine, but it attaches to a so-called FK-binding protein instead of cyclophillin. Sirolimus forms a complex with the FK-binding protein, changing its conformation. This complex then inhibits mTOR (mammalian target of rapamycin), which operates the signaling path leading from the IL-2 receptor to the activation of mitosis in lymphocytes, thus inhibiting lymphocyte proliferation.
Basiliximab
Mechanism of action. Basiliximab is a recombinant anti-IL-2 receptor antibody that binds to the CD25 antigen on the IL-2 receptor and prevents IL-2 binding, thus preventing IL-2-mediated activation of lymphocytes.
Pharmacokinetics
– Given IV
Uses
– Prophylaxis of kidney transplant rejection
Side effects
– Cardiovascular: hypertension and edema
– GI: pain and vomiting
– Hematologic: anemia
– Neurologic: headache and insomnia
Infliximab
Mechanism of action. Infliximab is an antibody to tumor necrosis factor-α (TNF-α; see page 358) that blocks TNF-α from binding to TNF receptors on inflammatory cell surfaces, resulting in suppression of downstream inflammatory cytokines such as IL-1 and IL-6 and adhesion molecules involved in leukocyte activation and migration.
Muromonab-CD3
Mechanism of action. Muromonab-CD3 binds to the CD3 component of the T-cell receptor complex involved in antigen recognition, leading to rapid internalization of the T-cell receptor, thereby preventing subsequent antigen recognition.
Pharmacokinetics
– Given IV
Uses
– Acute organ transplant rejection
Side effects
– Cytokine release reactions: fever, chills, nausea, vomiting, diarrhea, tachycardia, and changes in blood pressure. These reactions occur in many patients following the first few doses. Anaphylactic and anaphylactoid reactions may also occur, but fatalities are rare.
– GI: nausea, vomiting, and diarrhea
– Neurologic: fever, headache, insomnia, and pain
Summary of Monoclonal Antibodies