42: Antineoplastic Drugs

CHAPTER 42 Antineoplastic Drugs

The role of antineoplastic drugs in cancer treatment has greatly expanded in the past few decades. These drugs can cure numerous advanced tumors and are the treatment of choice for many widely disseminated malignancies that cannot be reached by surgery or are beyond the limits of safety of radiotherapy. They are also used as adjuncts to surgery and irradiation in the prevention of metastasis from locally treated primary tumors. Research has resulted in the development of new agents, more effective applications of existing agents, and the use of adjunctive drugs to overcome resistance and minimize drug toxicity.

The past decade has also brought about a greater depth of research and understanding of the molecular biology of cancer cell growth. Many mechanisms of growth stimulation and retardation and the actions of growth modulators have been discovered. Gene rearrangements and mutations and their resultant influences on cell growth are being elucidated. These discoveries provide many new targets for the management of abnormal cell growth, and with that have come multiple new approaches to cancer therapy and several new classes of drugs. Antineoplastic regimens that contribute to the goal of eliminating and destroying tumor cells now include traditional chemotherapeutic drugs (i.e., alkylators, antimetabolites, antibiotics, steroids, plant alkaloids, and other agents), biologic response modifiers, novel targeting agents, and agents used specifically to protect the patient from the toxic effects of these drugs. In the last few years, several newer chemotherapy drugs, such as nelarabine, ixabepilone, and others, have been introduced as the antineoplastic agents, and some older therapeutic agents, such as arsenic trioxide, and thalidomide, are experiencing a resurgence of interest in their actions.

Other newer groups of drugs used in managing cancer include specific hormonal agents, such as letrozole, anastrozole, and fulvestrant; differentiating agents, such as tretinoid; and monoclonal antibodies (MAbs), which have a variety of different targets and potential mechanisms of action. Additional groups include drugs that target signal transduction, such as imatinib mesylate; drugs that block crucial cellular receptors, including epidermal growth factor receptors (EGFRs) such as erlotinib; and drugs that inhibit angiogenesis, such as bevacizumab, a MAb that blocks vascular endothelial growth factor (VEGF). There are also groups that include proteasome inhibitors, such as bortezomib, and drugs that may enhance or remove blocks to apoptosis (programmed cell death). As the choices in therapeutic agents, combinations, and approaches increase, the ability to successfully eradicate cancer is improving.

HISTORY OF CANCER CHEMOTHERAPY

The cytotoxic effects of drugs were observed well before the turn of the twentieth century, but their usefulness in the treatment of disease was not appreciated until the mid-1940s. Chemical warfare with sulfur mustard gas in World War I resulted in shrinkage of lymph nodes and myeloid tissues in the victims. The application of these nitrogen mustard compounds for the medical treatment of Hodgkin’s disease, malignant lymphomas, and chronic leukemia followed these observations but was not reported until the end of World War II. In 1944, glucocorticoids were shown to have a profound effect on the volume, structure, and function of lymphoid tissue.17 Subsequently, this effect was used in the control of human leukemia, and since then prednisone and prednisolone have been incorporated in drug protocols designed to ablate lymphoproliferative and myeloproliferative diseases.

In 1948, Farber and colleagues20 obtained temporary remissions in children with acute leukemia who were given the folic acid antagonist 4-aminopteroylglutamic acid (aminopterin). This specially tailored molecule was the first antimetabolite to produce unequivocally beneficial results in a human neoplastic disease.

The folate antagonist approach led to the development of competitive inhibitors of purines and pyrimidines that interfered with the synthesis of nucleic acids in rapidly multiplying neoplastic cells. Observations in animal tumor models of selective uptake of uracil by colon tumor cells resulted in the development of a “designer” antimetabolite, 5-fluorouracil.

The first antibiotic with activity against human tumors was actinomycin D. Introduced as an anticancer agent in 1952, dactinomycin (actinomycin D) is curative in many patients with Wilms’ tumor and uterine choriocarcinoma. The anticancer effects of the vinca alkaloids, extracted from the periwinkle plant (Vinca rosea), were initially shown in animals with experimental leukemia in 1960.40 In the same year, vinblastine was found to be valuable in the treatment of acute forms of leukemia, Hodgkin’s disease, and adenocarcinoma of the colon.35 The earliest reports of the use of carmustine, the prototype of the nitrosourea group of cytotoxic compounds, against human malignancies appeared in 1966.

In 1967, the enzyme l-asparaginase was found to produce remissions in some patients with acute leukemia. The first of the heavy metal complexes to have significant success in the treatment of human cancer was cisplatin, introduced in 1969. The 1950s and 1960s brought rapid development of new agents, and continued refinements in their use occurred in the 1970s and early 1980s with additional combination chemotherapy regimens and a better understanding of the cytokinetics of tumor cells and the pharmacokinetics of the drugs.13,15 The late 1980s and early 1990s contributed several new agents, such as taxanes, topoisomerase I inhibitors, and others with measurable efficacy and decreased toxicity; biologic response modifiers such as interferon and interleukin-2; and chemoprotective agents and newer technologies for the application of these antineoplastic agents.

The late 1990s brought the commercial availability of some MAbs for the treatment of several cancers, as well as important research on the role of angiogenesis, which had started in the 1960s. Angiogenesis, which is the formation of new blood vessels, plays a role in supporting existing tumors with required nutrients and oxygen and in forming metastatic tumors. The identification of angiogenic factors such as VEGF, basic fibroblastic growth factor, and other regulators and inhibitors of angiogenesis is leading to the development of new drugs to target these factors and evaluate their role in starving cancer cells and preventing the formation of metastatic disease.44

Several novel strategies are being considered in clinical trials, applying newer drug entities for newly identified targets. Drugs being studied include angiogenesis factors, inhibitors of matrix metalloproteinase, and drugs that affect intracellular signaling pathways (e.g., tyrosine kinase [TK] inhibitors). Many drugs have been developed that can promote apoptosis, target cyclin-dependent kinases, and inhibit the family of enzymes that plays a role in cell cycle progression. The challenge of these clinical trials is to identify agents specific to the cancer cell process and determine the appropriate role of these agents, combined with existing therapies, in enhancing responses to cancer treatment and minimizing side effects.

PRINCIPLES OF CANCER CHEMOTHERAPY

The goal of chemotherapy is to eradicate every viable tumor cell without significantly damaging normal host tissue. Attaining this goal requires that the tumor be inherently sensitive to the chemotherapy agents, that the tumor receptor sites be exposed to adequate concentrations of active drug for sufficient periods, and that the host cells be resistant to the effects of the chemotherapy drugs. Classic chemotherapy agents are not tumor cell specific and kill all cells actively undergoing cell division. In addition to killing the abnormal or malignant cells, normal cells in the gastrointestinal tract, bone marrow, and hair follicles and other tissues are affected.

Chemotherapy drugs kill or impair susceptible tumor cells by blocking a drug-sensitive biochemical or metabolic pathway. Some, such as cell cycle phase–specific antimetabolites, act by inhibiting DNA synthesis and are most effective against rapidly dividing cells. Others, including alkylating agents, act by interfering with nucleic acid function and protein production throughout the cell division cycle and are effective against both proliferating and resting cells (Figures 42-1 and 42-2). All chemotherapy drugs are extremely cytotoxic with low margins of safety. Incorporating the current understanding of tumor biology, the patient’s physiologic status, and the drug’s pharmacologic features, the principles that govern the useful application of cancer chemotherapy include the following:

CHEMOTHERAPEUTIC DRUGS

Antineoplastic Alkylating Agents

Alkylating agents (Table 42-1) are composed of six major chemical classes: (1) nitrogen mustards (chlorambucil, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, and melphalan), (2) alkyl sulfonates (busulfan), (3) ethylenimines (thiotepa), (4) triazines (dacarbazine), (5) tetrazines (temozolomide), and (6) nitrosoureas (carmustine, lomustine, and streptozocin). They all share the common chemical characteristic of forming alkyl radicals, which form covalent linkages with nucleophilic moieties such as the phosphate, sulfhydryl, hydroxyl, carboxyl, amino, and imidazole groups. This radical formation allows them to react with organic compounds such as DNA and RNA and proteins essential for cell metabolism and protein synthesis. By binding these groups, they also prevent cell division by cross-linking strands of DNA.

Alkylating agents are not cell cycle specific, although they are most destructive to rapidly proliferating tissues and seem to cause cellular death only when the cell attempts to divide. Because they produce irreversible changes in the DNA molecule, alkylating agents are mutagenic, teratogenic, and carcinogenic in addition to being oncolytic. Alkylating agents are also radiomimetic because they produce morphologic damage in cells similar to the damage caused by radiation injury. Because most of these agents are myelosuppressive, immunosuppression and susceptibility to infection are common outcomes. They vary greatly in lipid solubility, membrane transport, and pharmacokinetic properties and differ in clinical use. The molecular structures of representative alkylating agents are shown in Figure 42-3; adverse effects and clinical applications are summarized in Table 42-1.

Nitrogen mustards

Bendamustine hydrochloride

Bendamustine hydrochloride (Treanda) is an intravenously administered bifunctional mechlorethamine derivative with alkylator and purine antimetabolite activity. This bifunctional agent may have an advantage to overcome cross-resistance with other alkylating agents. Bendamustine has been studied in combination with rituximab in the management of patients with indolent or mantle cell lymphoma and has shown significant activity.59 It has been approved more recently for the treatment of chronic lymphocytic leukemia and continues to be studied in many other tumor types, including breast cancer and sarcomas. The most common adverse effects (occurring 15% to 20% of the time) include neutropenia, thrombocytopenia, anemia, pyrexia, nausea, and vomiting.

Tetrazines

Temozolomide

Temozolomide is the first imidazotetrazinone derivative used in clinical practice. Similar to DTIC, temozolomide is metabolized to monomethyl 5-triazinoimidazole carboxamide (MTIC), which is ultimately converted to the cytotoxic methyldiazonium ion. Temozolomide has advantages over DTIC: it can be administered orally, and it does not require hepatic conversion to MTIC because temozolomide is spontaneously converted to the active metabolite at physiologic pH.29 Temozolomide penetrates tissues well and is able to cross the blood-brain barrier, allowing it to be used to treat brain tumors such as astrocytoma69 and glioblastoma multiforme, an aggressive primary brain tumor. Temozolomide has also been used to treat malignant melanoma. The major toxic effects associated with this alkylating agent include myelosuppression, nausea, vomiting, headache, and fatigue.

Nitrosoureas

Antimetabolite Agents

Antimetabolites bear a marked structural resemblance to folic acid and to the purine and pyrimidine bases involved in the synthesis of DNA, RNA, and certain coenzymes (Figure 42-4). They differ in molecular arrangement from the corresponding metabolite to a degree sufficient to serve as fraudulent substrates for biochemical reactions, either inhibiting synthetic steps or becoming incorporated into molecules and interfering with cellular function or replication. Antimetabolites characteristically exert their major effects during the S (DNA synthesis) phase of the cell cycle. This activity interferes with the growth of rapidly proliferating cells throughout the body—the bone marrow, germinal cells, hair follicles, and lining of the alimentary tract. Oral manifestations are an especially prominent feature of the toxicity of these agents. Three classes of antimetabolites exist: folic acid analogues, purine analogues, and pyrimidine analogues.

Methotrexate

Methotrexate is the 4-amino, 10-methyl analogue of folic acid and a potent inhibitor of dihydrofolate reductase. This inhibition results in the decreased conversion of dihydrofolate to tetrahydrofolate and impaired synthesis of thymidylic acid and inosinic acid. Deficiencies of these acids retard DNA and RNA synthesis. Protein synthesis is also inhibited because reduced folates are cofactors in the conversion of glycine to serine and homocysteine to methionine.

Methotrexate is readily absorbed from the gastrointestinal tract and is primarily excreted in the urine. There is some enterohepatic recycling of methotrexate, which extends the elimination half-life of the drug and is responsible for most of the marrow and gastrointestinal toxicity. Methotrexate tends to distribute into “third spaces,” such as ascitic, pleural, or peritoneal fluids that can potentially act as a drug reservoir. The presence of these clinical features or renal failure or both contributes to increased toxicity. Depending on the indication, methotrexate may be administered by many different routes with a variable dosing range. Administered orally, the drug is often used to treat rheumatoid arthritis and psoriasis. Intrathecal administration is used to treat central nervous system (CNS) tumors, and intra-arterial administration is used for regional therapy of head and neck cancers. Given intravenously and intramuscularly, methotrexate is a valuable therapeutic agent in some forms of leukemia, choriocarcinoma, lymphoma, sarcoma, testicular tumors, and carcinoma of the breast and lung. The drug is also used in very high doses for adjuvant and salvage therapies for osteosarcoma and leukemia.

High-dose therapy with methotrexate requires monitoring of serum blood concentrations and the use of folinic acid “rescue.” The folinic acid (e.g., citrovorum factor, calcium folinate, leucovorin) bypasses the blockade of dihydrofolate reductase in normal cells and may reduce the incidence and severity of mucositis and myelosuppression. Other nontumoricidal applications of methotrexate include its use after allogeneic bone marrow transplants to prevent graft-versus-host disease, to treat systemic lupus erythematosus, and in steroid-dependent asthmatic patients to decrease asthmatic symptoms.

Methotrexate is subject to many important drug interactions. Highly plasma protein-bound drugs such as salicylates, sulfonamides, and phenytoin may displace methotrexate from its protein-binding sites and result in greater toxicity. Organic acids such as salicylate and probenecid inhibit the tubular secretion of methotrexate, resulting in increased concentrations of methotrexate and toxicity. Penicillins can also compete with methotrexate for renal tubular secretion.32 In patients receiving large gram doses of methotrexate, the concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided because this drug class can also reduce renal blood flow and increase the risk of nephrotoxicity.

Dose-limiting toxic effects of methotrexate include bone marrow depression manifested by leukopenia and thrombocytopenia, which are conducive to secondary infection and hemorrhage; a very painful stomatitis with mucosal and epithelial ulceration; pharyngitis and dysphagia; esophagitis; gastroenterocolitis; and proctitis with associated watery and bloody diarrhea. Large doses can be nephrotoxic, and long-term treatment with methotrexate can lead to changes in hepatic function.

Purine analogues

Historically, the most commonly used purine analogues in cancer chemotherapy have been mercaptopurine and thioguanine. Newer agents include fludarabine, pentostatin, cladribine, clofarabine, and nelarabine.

Mercaptopurine and thioguanine

The mechanisms of action of the thiopurines mercaptopurine and thioguanine have not yet been fully established. Presumably, they affect the incorporation of purine derivatives into nucleic acids. The analogues are converted in the body to the ribonucleotide form, which interferes with the conversion of inosinic acid to the nucleotides of adenine and guanine, resulting in the inhibition of DNA and RNA synthesis. They also inhibit de novo biosynthesis of purines from the small molecule precursors (glycine, formate, and phosphate), which ultimately leads to fraudulent DNA.

Orally administered mercaptopurine is readily absorbed but undergoes extensive first-pass metabolism by the liver. After intravenous injection, the plasma half-life is approximately 90 minutes. The drug is metabolized by methylation in the liver and by the hepatic enzyme xanthine oxidase. Concurrent administration with allopurinol, a xanthine oxidase inhibitor originally developed to increase the anticancer effect of mercaptopurine, requires a 50% reduction in the dose of mercaptopurine. Allopurinol is of little clinical value in this setting because it also increases the toxicity of mercaptopurine. The use of allopurinol in the treatment of gout is described in Chapter 21. Currently, mercaptopurine is used mainly for maintenance of remission in acute lymphocytic leukemia. The chief toxic effect is myelosuppression. Pulmonary fibrosis and pancreatitis may also occur. Thioguanine has activity, toxicity, and clinical applications similar to those of mercaptopurine.

Fludarabine

Fludarabine (2-fluoro-ara-AMP) is an analogue of adenosine. This injectable purine antagonist is quickly dephosphorylated in the plasma, enters the cell, and is converted to the triphosphate form. This false nucleotide inhibits ribonucleotide reductase and DNA polymerase, which results in the inhibition of DNA synthesis.37 Fludarabine is indicated for the treatment of B-cell chronic lymphocytic leukemia in patients who have not responded to traditional therapy with an alkylating agent. Fludarabine is primarily excreted by the kidneys and has a long plasma half-life of approximately 10 hours. Transient myelosuppression and immunosuppression, with an increased risk of opportunistic infection, seems to be the major toxicity at current doses. Fludarabine has also been used for treatment of non-Hodgkin’s lymphoma, hairy cell leukemia, and cutaneous T-cell lymphoma and in salvage regimens for the treatment of acute myeloid leukemia.

Clofarabine and nelarabine

Clofarabine and nelarabine are the newest purine nucleoside antimetabolites approved for the treatment of acute lymphocytic leukemias. Clofarabine is converted intracellularly by deoxycytidine kinase to the 5′-monophosphate metabolite, then via monophosphokinases and diphosphokinases to the active 5′-triphosphate form. The clofarabine 5′-triphosphate inhibits DNA synthesis through its action on ribonucleotide reductase and DNA polymerases. Clofarabine is approved by the U.S. Food and Drug Administration (FDA) for the treatment of pediatric patients with relapsed or refractory acute lymphocytic leukemia after at least two prior treatment regimens.24 It is also being studied for other malignancies, including the treatment of acute myeloid leukemias in adults. The principal toxicities associated with clofarabine are nausea, vomiting, hematologic toxicity, febrile neutropenia, hepatobiliary toxicity, infections, and renal toxicity. Clofarabine can also produce a syndrome manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multiorgan failure called systemic inflammatory response syndrome, which is similar to a capillary leak syndrome. Cardiac effects include tachycardia and left ventricular systolic dysfunction.

Nelarabine is a prodrug of the deoxyguanosine analogue-9-beta-D-arabinofuranosylguanine (ara-G). Nelarabine is demethylated to ara-G and activated to the active 5′-triphosphate, ara-GTP. The active ara-G is incorporated into the DNA resulting in inhibition of DNA synthesis and cell death. There is a differential accumulation in T cells, and nelarabine is approved for the treatment of patients with T-cell acute lymphoblastic leukemia and lymphoma who have not responded to or have relapsed after treatment with at least two other chemotherapy regimens.9 A major adverse effect associated with nelarabine resulting in a “black box” warning involves neurologic events that include severe somnolence, convulsions, peripheral neuropathies, and paralysis. Other adverse effects include fatigue, bone marrow suppression, gastrointestinal side effects, and some pulmonary complaints of cough and dyspnea. Rarely, patients have complained of blurred vision while receiving nelarabine. The combination of nelarabine and adenosine deaminase inhibitors such as pentostatin should be avoided because this combination may result in a decreased conversion of nelarabine to its active substrate, decreasing its efficacy and potentially changing the adverse profile of both drugs.

Pyrimidine analogues

Several pyrimidine congeners have been examined for antineoplastic activity. These drugs exert multiple effects on cellular growth and are among the most useful agents for solid tumors and leukemia.

Fluorouracil and floxuridine

The fluorinated pyrimidines fluorouracil and floxuridine are prepared by substituting a stable fluorine atom for hydrogen in position 5 of the uracil and deoxyuridine molecules. These compounds, after intracellular conversion to 5-fluoro-2′-deoxyuridine monophosphate, are potent antimetabolites that bind to and inhibit thymidylate synthetase, inhibiting formation of thymidylic acid and impairing DNA synthesis. Fluorouracil metabolism also produces a critical intermediate, 5-fluorouridine triphosphate, which is incorporated into RNA and interferes with its function. 5-Fluorodeoxyuridine triphosphate (5-FdUTP) may also be incorporated into DNA, producing single-strand breaks contributing to the cytotoxicity.54

Fluorouracil is used most often for treatment of gastrointestinal adenocarcinomas, breast cancer, and ovarian cancer. Activity has also been reported in bladder and prostate cancer. The drug is usually given intravenously as a bolus or short infusion or as a prolonged continuous infusion daily, over several days, or for months. Continuous infusion is advantageous because the plasma half-life of the drug is short (10 to 20 minutes), and the drug (similar to other antimetabolites) works primarily in the S phase of the cell cycle. Continuous infusion provides for prolonged exposure of the cells to the drug and the opportunity for cell populations not in the S phase to cycle into that sensitive phase. The toxicity profile of fluorouracil depends on the method of administration. Given as a continuous infusion over a 96-hour period, the dose-limiting toxicity is mucositis, whereas intravenous bolus results in bone marrow suppression. Fluorouracil can be administered topically to treat actinic keratoses and noninvasive skin cancers and, commonly, to improve efficacy of radiation therapy in head and neck cancers by working as a radiosensitizer. Folinic acid (leucovorin) has been combined with fluorouracil to enhance the inhibition of thymidylate synthetase in resistant disease.

Floxuridine, the deoxyribonucleoside of fluorouracil, exerts a more direct inhibition of thymidylate synthetase than fluorouracil. The drug must be given by continuous infusion because it is rapidly catabolized in vivo. Floxuridine administered intra-arterially is indicated for gastrointestinal adenocarcinomas metastatic to the liver and has produced beneficial results in the treatment of head and neck carcinoma, although fluorouracil is now the preferred agent. The adverse effects of fluorinated pyrimidines may be quite severe. Stomatitis, pharyngitis, dysphagia, enteritis, and diarrhea can be life-threatening. Myocardial ischemia caused by coronary artery vasospasm has been described with fluorouracil.

Gemcitabine

Gemcitabine (difluorodeoxycytidine) is a newer antimetabolite useful in many experimental tumor models, with clinical responses in NSCLC and breast cancer. It is currently indicated for first-line treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.31 Recent trials support the use of gemcitabine in combination with cisplatin to treat metastatic NSCLC. Its dose-limiting side effect is myelosuppression characterized by thrombocytopenia. Transient febrile episodes and a flulike syndrome have been commonly reported.

Antibiotics

Numerous substances originally isolated as antibiotics have been found to exert antineoplastic activity because of their cytotoxic properties. These substances, produced naturally by various Streptomyces species, operate by binding with DNA to produce irreversible complexes that inhibit cell division. Various other possible mechanisms for cytotoxicity have been proposed for these agents. Antibiotics can work on cells in different phases of the cell cycle, behaving as non–phase-specific agents. Semisynthetic derivatives of some of the antibiotics are being prepared and tested clinically in an effort to reduce toxicity but retain the oncolytic potency of the parent compound.

Daunorubicin

Daunorubicin is a cytotoxic anthracycline antibiotic produced by Streptomyces peucetius subsp. caesius, which is also the source of doxorubicin and idarubicin (Figure 42-5). The drug combines with DNA in an intercalative mode by slipping into the helical structure between stacked bases. Synthesis of DNA and RNA is inhibited, and preformed DNA is damaged. Other possible mechanisms are postulated, including metabolism to form cytotoxic free radicals, a cell membrane surface cytotoxic action, and inhibition of topoisomerase II. The killing effect of daunorubicin is at a maximum in the DNA synthesis S phase of the cell cycle, but damage is not phase specific. Experimental evidence exists for synergy between these antibiotics and drugs such as etoposide.

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Jan 5, 2015 | Posted by in General Dentistry | Comments Off on 42: Antineoplastic Drugs
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