Methotrexate, amethopterin

Inhibitors. Aside from its role in providing reduced folate coenzymes for cells, this enzyme has attracted a great deal of attention because it appears to be a site of action of the important anticancer drugs methotrexate (amethopterin) and aminopterin.293 364 365 These compounds inhibit dihydrofolate reductase in concentrations as low as 10 8 to 10 9 M. Methotrexate is also widely used as an immunosuppresant drug and in the treatment of parasitic infections. 

Methotrexate (Amethopterin) is a folic acid antagonist that binds to dihydrofolate reductase, thus interfering with the synthesis of the active cofactor tetrahydrofolic acid, which is necessary for the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. 

Figure 6.3 Antitumor agents methotrexate (amethopterin) and aminopterin. They inhibit dihydrofolate reductase competitively.

Inhibition of nudeobase synthesis (2). Tet-rahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 274). The folate analogues aminopterin and methotrexate (amethopterin) inhibit enzyme activity. Cellular stores of THF are depleted. The effect of these antimetabolites can be reversed by administration of folinic acid (5-formyl-THF, leucovorin, citrovorum factor). Hydroxyurea (hydroxycarbamide) inhibits ribonucleotide reductase that normally converts ribonucleotides into deoxyribonucleotides subsequently used as DNA building blocks. 

The synthesis of TMP can also be blocked by inhibiting the regeneration of tetrahydrofolate. Analogs of dihydrofolate, such as aminopterin and methotrexate (amethopterin), are potent competitive inhibitors (.ST < 1 nM) of dihydrofolate reductase. 

Methotrexate (amethopterin Rheumatrex, trexall, others) has been used in the treatment of severe, disabling psoriasis in doses of 2.5 mg orally for 5 days, followed by a rest period of at least 2 days, or 10-25 mg intravenously weekly. It also is used intermittently at low dosage to induce remission in rheumatoid arthritis. 

Aminopterin 4-amino-4-deoxyfolic acid (see Vitamins, folic acid), a cytostatic agent used in the management of some caneers. It inhibits the enzyme dihy-drofolate reductase, which reduces the folate coenzymes required for Purine biosynthesis (see) and thymine production (see Pyrimidine biosynth is), and thus prevents DNA synthesis However, it is toxic to nondividing cells as well, and cannot be tolerated indefinitely. Methotrexate (amethopterin) has similar activity. 

The folic acid analogues, methotrexate (amethopterin) and aminop-terin, prevent the utilization of folic acid and of one-carbon units, and produce in animals symptoms of deficiency of this vitamin. 

It was found in early studies that the folic acid analogues, methotrexate (amethopterin) and aminopterin very effectively blocked the incorporation of labeled deoxyuridine and of labeled formate into DNA thymine however, the incorporation of thymidine was not blocked. It was apparent, therefore, that the analogues interfered with the introduction of the methyl group into thymine, a process known to involve H -folate. When it became established that the antifolic agents were exceedingly potent inhibitors of tetrahydrofolate dehydrogenase (see Chapter 5), the mechanism of their inhibition of DNA synthesis was apparent. 

Cancer. Methotrexate (amethopterin), a drug closely related to aminopterin, is currently being used in cancer chemotherapy. Its action is to bind the enzyme dihydrofolate... 

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