Cytotoxic effects of folate antagonists against methotrexate-resistant human leukemic lymphoblast CCRF-CEM cell lines.
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 approximately 70- and 350-fold more resistant to methotrexate than were the parent cells. The effects of three 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] phenoxyl)-N,N-dimethyl-m-toluamide (1:1)] and trimetrexate (NSC 249008, JB-11, TMQ; 2,4-diamino-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline), two nonclassical folate antagonists. In contrast, the transport defective subline, CCRF-CEM/R3 was not cross-resistant to these two compounds. In cells resistant to MTX by virtue of both mechanisms, CCRF-CEM/R2, triazinate, and trimetrexate were partially cross-resistant. All three methotrexate-resistant sublines showed minor cross-resistance to isoaminohydroxyquinazoline (IAHQ, NSC 289517; 5,8-dideazaisopteroylglutamate), a folate antagonist inhibitor of thymidylate synthase. These data demonstrate that methotrexate-resistant tumor cells may be effectively inhibited by antifolates with different route of entry into cells or with different enzyme targets.
D000970:Antineoplastic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D007945:Leukemia, Lymphoid / Q000473:pathology*; D008727:Methotrexate / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate