CYTO-TOXIC EFFECTS OF FOLATE ANTAGONISTS AGAINST METHOTREXATE-RESISTANT HUMAN-LEUKEMIC LYMPHOBLAST CCRF-CEM CELL-LINES

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  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (1) , 325-330
Abstract
A human T-lymphoblast cell line, CCRF-CEM/R1, resistant to methotrexate by virtue of increased dihydrofolate reductase activity, was grown in stepwise increasing concentrations of methotrexate. This additional selection pressure resulted in a cell line, CCRF-CEM/R2, resistant to methotrexate by virtue of both an elevation of dihydrofolate reductase activity and a marked decrease in methotrexate transport. The R1 and R2 cells were .apprx. 70- and 350-fold more resistant to methotrexate than were the parent cells. The effects of 3 folate antagonists were studied on these cell lines and also on CCRF-CEM/R3 cells, characterized by impaired methotrexate transport but normal levels of dihydrofolate reductase. The elevated reductase subline CCRF-CEM/R1 was cross-resistant to triazinate [Baker''s antifol, NSC 139105; ethanesulfonic acid compounded with .alpha.-(2-chloro-4-[4,6-diamino-2,2-dimethyl-S-triazine-1-(2H)-yl]phenoxy)-N,N-dimethyl-m-toluamide (1:1)] and trimetrexate (NSC 249008, JB-11, TMQ; 2,4-diamino-6-[(3,4,6-trimethoxyanilino)methyl]quinazoline), 2 nonclassical folate antagonists. In contrast, the transport defective subline, CCRF-CEM/R3 was not cross-resistant to these 2 compounds. In cells resistant to MTX by virtue of both mechanisms, CCRF-CEM/R2 triazinate and trimetrexate were partially cross-resistant. All 3 methotrexate-resistant sublines showed minor cross-resistance to isoaminohydroxyquinazoline (IAHQ, NSC 289517; 5,8-dideazaisopteroylglutamate), a folate antagonist inhibitor of thymidylate synthase. Methotrexate-resistant tumor cells may be effectively inhibited by antifolates with different route of entry into cells or with different enzyme targets.