Anticancer Drugs: MONOCLONAL ANTIBODIES
Focus topic: Anticancer Drugs
Monoclonal antibodies have become an active area of drug development for anticancer therapy and other nonneoplastic diseases, because they are directed at specific targets and often have fewer adverse effects. They are created from B lymphocytes (from immunized mice or hamsters) fused with “immortal” B-lymphocyte tumor cells. The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed against a single antigen type. Recombinant technology has led to the creation of “humanized” antibodies that overcome the immunologic problems previously observed following administration of mouse (murine) antibodies. The use of the monoclonal antibodies trastuzumab, rituximab, bevacizumab, and cetuximab in the treatment of cancer is described below. Many other monoclonal antibody treatments are available, examples of which include alemtuzumab, which is used in the treatment of refractory B-cell chronic lymphocytic leukemia, panitumumab, which is effective in metastatic colorectal tumors, and I131-tositumomab, which is used in relapsed non-Hodgkin lymphoma. [Note: Monoclonal antibodies also find application in a number of other disorders, such as inflammatory bowel disease, psoriasis, and rheumatoid arthritis.]
In patients with metastatic breast cancer, overexpression of transmembrane human epidermal growth factor receptor protein 2 (HER2) is seen in 25% to 30% of patients. HER2 overexpression is also noted in gastric and gastroesophageal cancers. Trastuzumab [tra-STEWzoo-mab], a humanized monoclonal antibody, specifically targets the extracellular domain of the HER2 growth receptor that has intrinsic tyrosine kinase activity. [Note: At least 50 tyrosine kinases mediate cell growth or division by phosphorylating signaling proteins. They have been implicated in the development of many neoplasms by an unknown mechanism.]
- Mechanism of action: Trastuzumab binds to HER2 sites in breast cancer, gastric cancer, and gastroesophageal tissues and inhibits the proliferation of cells that overexpress the HER2 protein, thereby decreasing the number of cells in the S-phase. By binding to HER2, it blocks downstream signaling pathways, induces antibody-dependent cytotoxicity, and prevents the release of HER2.
- Adverse effects: The most serious toxicity associated with the use of trastuzumab is congestive heart failure. The toxicity is worsened if given in combination with anthracyclines. Extreme caution should be exercised when giving the drug to patients with preexisting cardiac dysfunction.
Rituximab [ri-TUCKS-ih-mab] was the first monoclonal antibody to be approved for the treatment of cancer. It is a genetically engineered, chimeric monoclonal antibody directed against the CD20 antigen that is found on the surfaces of normal and malignant B lymphocytes. CD20 plays a role in the activation process for cell cycle initiation and differentiation. The CD20 antigen is expressed on nearly all B-cell non-Hodgkin lymphomas but not in other bone marrow cells. Rituximab is effective in the treatment of lymphomas, chronic lymphocytic leukemia, and rheumatoid arthritis.
- Mechanism of action: The Fab domain of rituximab binds to the CD20 antigen on the B lymphocytes, and its Fc domain recruits immune effector functions, inducing complement and antibodydependent, cell-mediated cytotoxicity of the B cells. The antibody is commonly used with other combinations of anticancer agents, such as cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (CHOP).
- Adverse effects: Severe adverse reactions have been fatal. It is important to infuse rituximab slowly. Hypotension, bronchospasm, and angioedema may occur. Chills and fever commonly accompany the first infusion (especially in patients with high circulating levels of neoplastic cells), because of rapid activation of complement which results in the release of tumor necrosis factor-α and interleukins. Pretreatment with diphenhydramine, acetaminophen, and corticosteroids can ameliorate these problems. Tumor lysis syndrome has been reported within 24 hours of the first dose of rituximab. This syndrome consists of hyperkalemia, hypocalcemia, hyperuricemia, hyperphosphatasemia (an abnormally high content of alkaline phosphatase in the blood), and acute renal failure that may require dialysis.
The monoclonal antibody bevacizumab [be-vah-SEE-zoo-mab] is an IV antiangiogenesis agent. Bevacizumab is approved for use as a first-line drug against metastatic colorectal cancer and is given with 5-FU–based chemotherapy. It attaches to and stops vascular endothelial growth factor from stimulating the formation of new blood vessels (neovascularization). Without new blood vessels, tumors do not receive the oxygen and essential nutrients necessary for growth and proliferation.
D. Cetuximab and panitumumab
Cetuximab [see-TUX-i-mab] is another chimeric monoclonal antibody infused intravenously and approved to treat KRAS wild-type metastatic colorectal cancer and head and neck cancers. [Note: KRAS is a form of RAS proteins, which are mediators of proliferation and differentiation.] It exerts its antineoplastic effect by targeting the epidermal growth factor receptor (EGFR) on the surface of cancer cells and interfering with their growth. Cetuximab, panitumumab [pan-i-TUE-moo-mab], and other agents that target this receptor cause a distinct acneiform-type rash. The appearance of this rash has been associated with a positive response to therapy.
Anticancer Drugs: PLATINUM COORDINATION COMPLEXES
Focus topic: Anticancer Drugs
A. Cisplatin, carboplatin, and oxaliplatin
Cisplatin [SIS-pla-tin] was the first member of the platinum coordination complex class of anticancer drugs, but because of its severe toxicity, carboplatin [KAR-boe-pla-tin] was developed. The mechanisms of action of the two drugs are similar, but their potency, pharmacokinetics, patterns of distribution, and dose-limiting toxicities differ significantly. Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. It has found wide application in the treatment of solid tumors, such as metastatic testicular carcinoma in combination with VBL and bleomycin, ovarian carcinoma in combination with cyclophosphamide, or alone for bladder carcinoma. Carboplatin is used when patients cannot be vigorously hydrated, as is required for cisplatin treatment, or if they suffer from kidney dysfunction or are prone to neuro- or ototoxicity. Oxaliplatin [ox-AL-ih-pla-tin] is a closely related analog of carboplatin used in the setting of colorectal cancer.
- Mechanism of action: The mechanism of action for this class of drugs is similar to that of the alkylating agents. In the high-chloride milieu of the plasma, cisplatin persists as the neutral species, which enters the cell and loses its chlorides in the low-chloride milieu. It then binds to guanine in DNA, forming inter- and intrastrand crosslinks. The resulting cytotoxic lesion inhibits both polymerases for DNA replication and RNA synthesis. Cytotoxicity can occur at any stage of the cell cycle, but cells are most vulnerable to the actions of these drugs in the G1 and S-phases.
- Pharmacokinetics: These agents are administered via IV infusion. Cisplatin and carboplatin can also be given intraperitoneally for ovarian cancer and intra-arterially to perfuse other organs. The highest concentrations of the drugs are found in the liver, kidney, and intestinal, testicular, and ovarian cells, but little penetrates into the CSF. The renal route is the main avenue for excretion.
- Adverse effects: Severe, persistent vomiting occurs for at least 1 hour after administration of cisplatin and may continue for as long as 5 days. Premedication with antiemetic agents is required. The major limiting toxicity is dose-related nephrotoxicity, involving the distal convoluted tubule and collecting ducts. This can be prevented by aggressive hydration. Other toxicities include ototoxicity with high-frequency hearing loss and tinnitus. Unlike cisplatin, carboplatin causes only mild nausea and vomiting, and it is rarely nephro-,neuro-, or ototoxic. Its dose-limiting toxicity is myelosuppression. Oxaliplatin has a distinct side effect of cold-induced peripheral neuropathy that usually resolves within 72 hours of administration. It also causes myelosuppression and cumulative peripheral neuropathy. Hepatotoxicity has also been reported. These agents may cause hypersensitivity reactions ranging from skin rashes to anaphylaxis.
Anticancer Drugs: TOPOISOMERASE INHIBITORS
Focus topic: Anticancer Drugs
These agents exert their mechanism of action via inhibition of topoisomerase enzymes, a class of enzymes that reduce supercoiling of DNA.
Camptothecins are plant alkaloids originally isolated from the Chinese tree Camptotheca. Irinotecan [eye-rin-oh-TEE-kan] and topotecan [toe-poe-TEE-kan] are semisynthetic derivatives of camptothecin [camp-toe-THEE-sin]. Topotecan is used in metastatic ovarian cancer when primary therapy has failed and also in the treatment of small cell lung cancer. Irinotecan is used with 5-FU and leucovorin for the treatment of colorectal carcinoma.
- Mechanism of action: These drugs are S-phase specific and inhibit topoisomerase I, which is essential for the replication of DNA in human cells. SN-38 (the active metabolite of irinotecan) is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I. The topoisomerases relieve torsional strain in DNA by causing reversible, single-strand breaks.
- Adverse effects: Bone marrow suppression, particularly neutropenia, is the dose-limiting toxicity for topotecan. Frequent blood counts should be performed on patients taking this drug. Myelosuppression is also seen with irinotecan. Acute and delayed diarrhea may be severe and require treatment with atropine during the infusion or high doses of loperamide in the days following the infusion.
Etoposide [e-toe-POE-side] is a semisynthetic derivative of the plant alkaloid, podophyllotoxin. It blocks cells in the late S- to G2 phase of the cell cycle. Its major target is topoisomerase II. Binding of the drug to the enzyme–DNA complex results in persistence of the transient, cleavable form of the complex and, thus, renders it susceptible to irreversible double-strand breaks. Etoposide finds its major clinical use in the treatment of lung cancer and in combination with bleomycin and cisplatin for testicular carcinoma. Etoposide may be administered either IV or orally. Dose-limiting myelosuppression (primarily leukopenia) is the major toxicity.
Anticancer Drugs: TYROSINE KINASE INHIBITORS
Focus topic: Anticancer Drugs
The tyrosine kinases are a family of enzymes that are involved in several important processes within a cell, including signal transduction and cell division. Many tyrosine kinase inhibitors are available, and these agents have a wide variety of applications in the treatment of cancer.
A. Imatinib, dasatinib, and nilotinib
Imatinib [i-MAT-in-ib] mesylate is used for the treatment of chronic myelogenous leukemia (CML) as well as GI stromal tumors. It acts as a signal transduction inhibitor, used specifically to inhibit tumor tyrosine kinase activity. A deregulated BCR-ABL kinase is present in the leukemia cells of almost every patient with CML. In the case of GI stromal tumors, an unregulated expression of tyrosine kinase is associated with a growth factor. The ability of imatinib to occupy the “kinase pocket” prevents the phosphorylation of tyrosine on the substrate molecule and, hence, inhibits subsequent steps that lead to cell proliferation. Nilotinib [ni-LOT-in-ib] and dasatinib [da-SAT-in-ib] are also first-line options for CML. These agents are all available in oral formulations, and they are associated with notable toxicities, such as fluid retention and QT prolongation (Figure 46.33).
Erlotinib [er-LOT-tih-nib] is an inhibitor of the epidermal growth factor receptor tyrosine kinase. It is an oral agent approved for the treatment of non–small cell lung cancer and pancreatic cancer. Erlotinib is absorbed after oral administration and undergoes extensive metabolism in the liver by the CYP3A4 isoenzyme. The most common adverse effects are diarrhea, nausea, acne-like skin rashes, and ocular disorders. A rare but potentially fatal adverse effect is interstitial lung disease, which presents as acute dyspnea with cough.
C. Sorafenib and sunitinib
Sorafenib [SOR-af-i-nib] and sunitinib [su-NIT-ti-nib] are oral serine/ threonine and tyrosine kinase inhibitors used mainly in renal cell carcinoma. Sorafenib is also part of the treatment strategy for hepatocellular carcinoma, and sunitinib is used in GI stromal tumors and pancreatic neuroendocrine tumors. These agents target cell surface kinases that are involved in tumor signaling, angiogenesis, and apoptosis, thus slowing tumor growth. Adverse effects include diarrhea, fatigue, hand and foot syndrome, and hypertension.
Anticancer Drugs: MISCELLANEOUS AGENTS
Focus topic: Anticancer Drugs
Procarbazine [proe-KAR-ba-zeen] is used in the treatment of Hodgkin disease and other cancers. Procarbazine rapidly equilibrates between the plasma and the CSF after oral administration. It must undergo a series of oxidative reactions to exert its cytotoxic action that causes inhibition of DNA, RNA, and protein synthesis. Metabolites and the parent drug are excreted via the kidney. Bone marrow depression is the major toxicity, and nausea, vomiting, and diarrhea are common. The drug is also neurotoxic, causing symptoms ranging from drowsiness to hallucinations to paresthesias. Because it inhibits monoamine oxidase, patients should be warned against ingesting foods that contain high levels of tyramine (for example, aged cheeses, beer, and wine) as this could cause a hypertensive crisis. Ingestion of alcohol leads to a disulfiram-like reaction. Procarbazine is both mutagenic and teratogenic. Nonlymphocytic leukemia has developed in patients treated with the drug.
B. Asparaginase and pegaspargase
Some neoplastic cells require an external source of asparagine because of limited capacity to synthesize sufficient amounts of the amino acid to support growth and function. l-Asparaginase [ah-SPAR-a-gi-nase] and the pegylated formulation pegaspargase [pegah-SPAR-jase] catalyze the deamination of asparagine to aspartic acid and ammonia, thus depriving the tumor cells of this amino acid, which is needed for protein synthesis. The form of the enzyme used chemotherapeutically is derived from bacteria. l-Asparaginase is used to treat childhood acute lymphocytic leukemia in combination with VX and prednisone. The enzyme must be administered either IV or intramuscularly, because it is destroyed by gastric enzymes. Toxicities include a range of hypersensitivity reactions (because it is a foreign protein), a decrease in clotting factors, liver abnormalities, pancreatitis, seizures, and coma due to ammonia toxicity.
Human interferons are biological response modifiers and have been classified into the three types α, β, and γ on the basis of their antigenicity. The α interferons are primarily leukocytic, whereas the β and γ interferons are produced by connective tissue fibroblasts and T lymphocytes, respectively. Recombinant DNA techniques in bacteria have made it possible to produce large quantities of pure interferons, including two species designated interferon-α-2a and 2b that are employed in treating neoplastic diseases. Interferon-α-2a is currently approved for the management of hairy cell leukemia, CML, and acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma. Interferon-α-2b is approved for the treatment of hairy cell leukemia, melanoma, AIDS-related Kaposi sarcoma, and follicular lymphoma. Interferons interact with surface receptors on other cells, at which site they exert their effects. Bound interferons are neither internalized nor degraded. As a consequence of the binding of interferon, a series of complex intracellular reactions take place. These include synthesis of enzymes, suppression of cell proliferation, activation of macrophages, and increased cytotoxicity of lymphocytes. However, the exact mechanism by which the interferons are cytotoxic is unknown. Interferons are well absorbed after intramuscular or subcutaneous injections. An IV form of interferon-α-2b is also available. Interferons undergo glomerular filtration and are degraded during reabsorption, but liver metabolism is minimal. Flu-like symptoms and GI upset are common with these agents. Suicidal ideation and seizures have been reported.
D. Abiraterone acetate
Abiraterone [ab-er-AT-er-own] acetate is an oral agent used in the treatment of metastatic castration–resistant prostate cancer. Abiraterone acetate is used in conjunction with prednisone to inhibit the CYP17 enzyme (an enzyme required for androgen synthesis), resulting in reduced testosterone production. Coadministration with prednisone is required to help lessen the effects of mineralocorticoid excess resulting from CYP17 inhibition. Hepatotoxicity may occur, and patients should be closely monitored for hypertension, hypokalemia, and fluid retention. Joint and muscle discomfort, hot flushes, and diarrhea are common side effects with this agent.
Enzalutamide [enz-a-LOOT-a-mide] is an oral agent that works at the level of the androgen-signaling pathway in the treatment of metastatic castrate-resistant prostate cancer in patients that have previously received docetaxel chemotherapy. Enzalutamide inhibits the binding of androgen to receptors and inhibits androgen receptor nuclear translocation and interaction with DNA. Notable adverse effects include asthenia, back pain, fluid retention, and risk of seizure. Multiple drug interactions potentially exist, as this drug is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19.
Anticancer therapy strives to cure disease, prolong life, and ameliorate symptoms caused by tumor invasion. These agents may have severe, life-threatening side effects, but with careful consideration and monitoring, these agents can be very useful in the treatment of cancer. “Chemo Man” is a useful tool to help remember the most common toxicities of these drugs.