N10-propargyl-5,8-dideazafolic acid (CB3717): inhibitory effects on human leukemia cell lines resistant to methotrexate or trimetrexate.
The inhibitory effects of N10-propargyl-5,8-dideazafolic acid (CB3717), a quinazoline antifolate and a potent thymidylate synthase inhibitor, were evaluated in human leukemia cell lines resistant to methotrexate (MTX) and trimetrexate (TMQ). MTX-resistant MOLT-3 cell lines, MOLT-3/MTX200 and MOLT-3/MTX10,000, were cross-resistant to CB3717; however, the degree of resistance was only tenfold for both cell lines, and increased dihydrofolate reductase activity in MOLT-3/MTX10,000 had little influence on the degree of CB3717 resistance. The MOLT-3 cell line made resistant to TMQ, MOLT-3/TMQ200, was as sensitive to CB3717 as the parent line. The cell growth inhibitory effect of CB3717 on MOLT-3 was reversed by the addition of thymidine. Leucovorin also partially reversed CB3717-induced growth inhibition. Cellular uptake of MTX and 5-methyl-tetrahydrofolate was hindered by the presence of a high concentration of CB3717, whereas TMQ uptake was not influenced by CB3717. CB3717 appears to enter the cells not only through reduced folate transport system, but by other route(s). CB3717 does not share the transport pathway with TMQ. Our observations that MTX-resistant cells with increased dihydrofolate reductase are not more resistant than cells without increased enzyme activity, and that TMQ-resistant cells are not cross-resistant to CB3717, may have clinical relevance.
Takemura
Y
Y
Department of Neoplastic Diseases, Mount Sinai School of Medicine (CUNY), NY.
Ohnuma
T
T
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D016597:Trimetrexate / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011799:Quinazolines; C031662:CB 3717; D005492:Folic Acid; D013940:Thymidylate Synthase; D016597:Trimetrexate; D008727:Methotrexate