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 inhibition of DNA synthesis through a blockage of the biosynthesis of thymidylate and purines.
Cells in S-phase are most sensitive to the cytotoxic effects of methotrexate. RNA and protein synthesis also may be inhibited to some extent and may delay progression through the cell cycle, particularly from G1 to S.
Mammalian cells have several mechanisms of resistance to methotrexate. These include an increase in in-
tracellular dihydrofolate reductase levels, appearance of altered forms of dihydrofolate reductase with decreased affinity for methotrexate, and a decrease in methotrexate transport into cells (see Chapter 55). The relative importance of each of these mechanisms of resistance 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 extracellular methotrexate concentration, which provides a rationale for high-dose methotrexate therapy. Since bone marrow and gastrointestinal cells do not have impaired folate methotrexate transport, these normal cells can be selectively rescued with reduced folate, bypassing 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 tissues. 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 retained in the cell and are also potent inhibitors of dihy-drofolate reductase.
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 carcinoma; 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 patients with metastatic osteogenic sarcoma.
Methotrexate is one of the few anticancer drugs that can be safely administered intrathecally for the treatment of meningeal metastases. Its routine use as prophylactic 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 (see Chapter 41), and methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis.
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