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Chapter: Modern Pharmacology with Clinical Applications: Antineoplastic Agents

Antimetabolites: Folate Antagonists

In general, antimetabolites used in cancer chemother-apy are drugs that are structurally related to naturally occurring compounds, such as vitamins, amino acids, and nucleotides.




Folate Antagonists


In general, antimetabolites used in cancer chemother-apy are drugs that are structurally related to naturally occurring compounds, such as vitamins, amino acids, and nucleotides. These drugs can compete for binding sites on enzymes or can themselves become incorpo-rated into DNA or RNA and thus interfere with cell growth and proliferation. The antimetabolites in clinical use include the folic acid analogue methotrexate, the pyrimidines (fluorouracil and cytarabine), and the purines (thioguanine, mercaptopurine, fludarabine, pen-tostatin, and cladribine).





Methotrexate competitively inhibits the binding of folic acid to the enzyme dihydrofolate reductase.This enzyme catalyzes the formation of tetrahydrofolate, as follows:

Tetrahydrofolate is in turn converted to N5,N10-methylenetetrahydrofolate, which is an essential cofac-tor for the synthesis of thymidylate, purines, methio-nine, and glycine. The major mechanism by which methotrexate brings about cell death appears to be in-hibition of DNA synthesis through a blockage of the biosynthesis of thymidylate and purines.


Cells in S-phase are most sensitive to the cytotoxic ef-fects of methotrexate. RNA and protein synthesis also may be inhibited to some extent and may delay pro-gression through the cell cycle, particularly from G1 to S.




Mammalian cells have several mechanisms of resist-ance to methotrexate. These include an increase in intracellular dihydrofolate reductase levels, appearance of altered forms of dihydrofolate reductase with de-creased affinity for methotrexate, and a decrease in methotrexate transport into cells . The relative importance of each of these mechanisms of re-sistance in various human tumors is not known.


Cellular uptake of the drug is by carrier-mediated active transport. Drug resistance due to decreased transport can be overcome by greatly increasing extra-cellular methotrexate concentration, which provides a rationale for high-dose methotrexate therapy. Since bone marrow and gastrointestinal cells do not have im-paired folate methotrexate transport, these normal cells can be selectively rescued with reduced folate, bypass-ing the block of dihydrofolate reductase. Leucovorin (citrovorum factor, folinic acid, 5-formyltetrahydrofo-late) is the agent commonly used for rescue.


Absorption, Metabolism, and Excretion


Methotrexate is well absorbed orally and at usual dosages is 50% bound to plasma proteins. The plasma decay that follows an intravenous injection is triphasic, with a distribution phase, an initial elimination phase, and a prolonged elimination phase. The last phase is thought to reflect slow release of methotrexate from tis-sues. The major routes of drug excretion are glomerular filtration and active renal tubular secretion.


The formation of polyglutamic acid conjugates of methotrexate has been observed in tumor cells and in the liver and may be an important determinant of cyto-toxicity. These methotrexate polyglutamates are re-tained in the cell and are also potent inhibitors of dihy-drofolate reductase.



Clinical Uses


Methotrexate is part of curative combination chemotherapy for acute lymphoblastic leukemias, Burkitt’s lymphoma, and trophoblastic choriocarci-noma. It is also useful in adjuvant therapy of breast car-cinoma; in the palliation of metastatic breast, head, neck, cervical, and lung carcinomas; and in mycosis fungoides.


High-dose methotrexate administration with leu-covorin rescue has produced remissions in 30% of pa-tients with metastatic osteogenic sarcoma.


Methotrexate is one of the few anticancer drugs that can be safely administered intrathecally for the treat-ment of meningeal metastases. Its routine use as pro-phylactic intrathecal chemotherapy in acute lym-phoblastic leukemia has greatly reduced the incidence of recurrences in the CNS and has contributed to the cure rate in this disease. Daily oral doses of methotrex-ate are used for severe cases of the nonneoplastic skin disease psoriasis , and methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis.

Adverse Effects


Myelosuppression is the major dose-limiting toxicity associated with methotrexate therapy. Gastrointestinal toxicity may appear in the form of ulcerative mucositis and diarrhea. Nausea, alopecia, and dermatitis are com-mon with high-dose methotrexate. The greatest danger of high-dose therapy is renal toxicity due to precipita-tion of the drug in the renal tubules, and the drug should not be used in patients with renal impairment. Intra-thecal administration may produce neurological toxic-ity ranging from mild arachnoiditis to severe and pro-gressive myelopathy or encephalopathy. Chronic low-dose methotrexate therapy, as used for psoriasis, may result in cirrhosis of the liver. Occasionally meth-otrexate produces an acute, potentially lethal lung toxi-city that is thought to be allergic or hypersensitivity pneumonitis. Additionally, methotrexate is a potent te-ratogen and abortifacient.



Drug Interactions


Salicylates, probenecid, and sulfonamides inhibit the renal tubular secretion of methotrexate and may dis-place it from plasma proteins. Asparaginase inhibits protein synthesis and may protect cells from methotrex-ate cytotoxicity by delaying progression from G1-phase to S-phase. Methotrexate may either enhance or inhibit the action of fluorouracil, depending on its sequence of administration.




Gemcitabine (Gemzar), an antimetabolite, undergoes metabolic activation to difluorodeoxycytidine triphos-phate, which interferes with DNA synthesis and repair. It is the single most active agent for the treatment of metastatic pancreatic cancer, and it is used as a first-line treatment for both pancreatic and small cell lung can-cer. It is administered by intravenous infusion. The dose-limiting toxicity is bone marrow suppression.


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