Biological and Biochemical Properties of New Anticancer Folate Antagonists

Overview

Journal Cancer Metastasis Rev

Specialty Oncology

Date 1987 Jan 1

PMID 3549036

Citations 6

Authors

D W FRY

R C Jackson

Affiliations

Soon will be listed here.

Abstract

We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development. Toxicology and clinical data are not discussed. 10-Ethyl-10-deazaaminopterin (10-EdAM) is a classical antifolate, structurally related to methotrexate (MTX) but with greater activity against murine tumors. 10-EdAM has more efficient membrane transport, and relatively greater polyglutamylation in murine tumors than in normal mouse tissues, and these differential effects are greater for 10-EdAM than for other 10-deaza antifolates or for MTX. Trimetrexate and piritrexim are nonclassical antifolates, lacking a glutamate substitution. They are lipophilic, cross cell membranes more rapidly than does MTX, and retain activity against tumors resistant to MTX because of impaired drug transport. These nonclassical antifolates are active against several MTX-insensitive murine tumors, and both have demonstrated clinical anticancer activity. 10-EdAM, trimetrexate and piritrexim all inhibit dihydrofolate reductase (DHFR) as their primary site of action. As such, they deplete cellular thymidylate and purine pools, and inhibit DNA replication. N10-Propargyl-5,8-dideazafolic acid (CB3717) differs from the first three compounds in acting primarily on thymidylate synthase. Like DHFR inhibitors, it blocks DNA replication through depletion of dTTP, but it does not exert an antipurine effect. CB3717 retains activity against transport-defective MTX-resistant cells, and also against cells that overproduce DHFR. 5,10-Dideazatetrahydrofolic acid (DDATHF) is a selective inhibitor of glycinamide ribotide transformylase, and its biochemical pharmacology may differ appreciably from that of the other antifolates under study. DDATHF has strong antitumor activity in several murine systems.

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References

Hurlbert B, Valenti B . Studies on condensed pyrimidine systems. XXIV. The condensation of 2,4,6-triaminopyrimidine with malondialdehyde derivatives. J Med Chem. 1968; 11(4):708-10. DOI: 10.1021/jm00310a016. View

Jackman A, Alison D, Calvert A, HARRAP K . Increased thymidylate synthase in L1210 cells possessing acquired resistance to N10-propargyl-5,8-dideazafolic acid (CB3717): development, characterization, and cross-resistance studies. Cancer Res. 1986; 46(6):2810-5. View

Hurlbert B, FERONE R, Herrmann T, HITCHINGS G, Barnett M, Bushby S . Studies on condensed pyrimidine systems. XXV. 2,4-diaminopyrido[2,3-d]pyrimidines. Biological data. J Med Chem. 1968; 11(4):711-7. DOI: 10.1021/jm00310a017. View

Hill B, Price L, Goldie J, HARRISON S . Methotrexate resistance and uptake of DDMP by L5178Y cells. Selective protection with folinic acid. Eur J Cancer (1965). 1975; 11(8):545-53. DOI: 10.1016/0014-2964(75)90126-7. View

TAYLOR I, Tattersall M . Methotrexate cytotoxicity in cultured human leukemic cells studied by flow cytometry. Cancer Res. 1981; 41(4):1549-58. View

Ohnuma T, Lo R, Scanlon K, Kamen B, Ohnoshi T, WOLMAN S . Evolution of methotrexate resistance of human acute lymphoblastic leukemia cells in vitro. Cancer Res. 1985; 45(4):1815-22. View

Hill B, Price L . DDMP (2,4-diamino-5-(3',4'-dichlorophenyl)-methylpyrimidine). Cancer Treat Rev. 1980; 7(2):95-112. DOI: 10.1016/s0305-7372(80)80019-3. View

Margolis S, PHILIPS F, Sternberg S . The cytotoxicity of methotrexate in mouse small intestine in relation to inhibition of folic acid reductase and of DNA synthesis. Cancer Res. 1971; 31(12):2037-46. View

Samuels L, Moccio D, Sirotnak F . Similar differential for total polyglutamylation and cytotoxicity among various folate analogues in human and murine tumor cells in vitro. Cancer Res. 1985; 45(4):1488-95. View

10.

Balis F, Lester C, Poplack D . Pharmacokinetics of trimetrexate (NSC 352122) in monkeys. Cancer Res. 1986; 46(1):169-74. View

11.

Goldman I, Matherly L . The cellular pharmacology of methotrexate. Pharmacol Ther. 1985; 28(1):77-102. DOI: 10.1016/0163-7258(85)90083-x. View

12.

Klohs W, Steinkampf R, Besserer J, FRY D . Cross resistance of pleiotropically drug resistant P338 leukemia cells to the lipophilic antifolates trimetrexate and BW 301U. Cancer Lett. 1986; 31(3):253-60. DOI: 10.1016/0304-3835(86)90145-x. View

13.

Moccio D, Sirotnak F, Samuels L, Ahmed T, Yagoda A, DeGraw J . Similar specificity of membrane transport for folate analogues and their metabolites by murine and human tumor cells: a clinically directed laboratory study. Cancer Res. 1984; 44(1):352-7. View

14.

Jackson R, Jackman A, Calvert A . Biochemical effects of a quinazoline inhibitor of thymidylate synthetase, N-(4-(N-(( 2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoyl)-L-glutamic acid (CB3717), on human lymphoblastoid cells. Biochem Pharmacol. 1983; 32(24):3783-90. DOI: 10.1016/0006-2952(83)90150-8. View

15.

Duch D, Edelstein M, Bowers S, Nichol C . Biochemical and chemotherapeutic studies on 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW 301U), a novel lipid-soluble inhibitor of dihydrofolate reductase. Cancer Res. 1982; 42(10):3987-94. View

16.

Weir E, Cashmore A, Dreyer R, Graham M, Hsiao N, Moroson B . Pharmacology and toxicity of a potent "nonclassical" 2,4-diamino quinazoline folate antagonist, trimetrexate, in normal dogs. Cancer Res. 1982; 42(5):1696-702. View

17.

Sirotnak F, DeGraw J, Moccio D, Dorick D . Antitumor properties of a new folate analog, 10-deaza-aminopterin, in mice. Cancer Treat Rep. 1978; 62(7):1047-52. View

18.

Hamrell M, Laszlo J, BROWN O, Sedwick W . Toxicity of methotrexate and metoprine in a dihydrofolate reductase gene-amplified mouse cell line. Mol Pharmacol. 1981; 20(3):637-43. View

19.

Greco W, HAKALA M . Cellular pharmacokinetics of lipophilic diaminopyrimidine antifolates. J Pharmacol Exp Ther. 1980; 212(1):39-46. View

20.

Currie V, Warrell Jr R, Arlin Z, Tan C, Sirotnak F, Greene G . Phase I trial of 10-deaza-aminopterin in patients with advanced cancer. Cancer Treat Rep. 1983; 67(2):149-54. View