Cell cycle effects of trimetrexate (CI-898).
The cell cycle phase specificity of trimetrexate (CI-898) was examined. CHO cells synchronized by mitotic selection were exposed to 50 microM trimetrexate for 2 h at various time points after release from Colcemid block. Only S phase cells were sensitive to trimetrexate when survival was measured by a cloning assay. Comparison of plateau phase and log phase cultures indicated that plateau phase CHO cells were relatively insensitive to 5 microM trimetrexate. Exponentially growing L1210 cells were continuously exposed to either 30 nM or 3 nM trimetrexate and analyzed by DNA flow cytometry. Incubation with 30 nM trimetrexate produced cell cycle arrest in late G1 or early S phase, while exposure to 3 nM trimetrexate caused only a delay in progression through S phase. In an in vivo schedule dependence study with mice bearing approximately 3 X 10(6) P388 leukemia cells, trimetrexate was most effective with frequent administration. Mice treated on the optimal schedule, every 3 h X 8 on days 1, 5, and 9 after tumor implant, had life-span increases in excess of 100%.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003703:Demecolcine; D004353:Drug Evaluation, Preclinical; D005260:Female; D005434:Flow Cytometry; D007274:Injections, Intraperitoneal; D007399:Interphase; D007939:Leukemia L1210 / Q000188:drug therapy; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010053:Ovary / Q000166:cytology*; D011799:Quinazolines / Q000627:therapeutic use* / Q000633:toxicity; D016597:Trimetrexate
D000970:Antineoplastic Agents; D011799:Quinazolines; D016597:Trimetrexate; D008727:Methotrexate; D003703:Demecolcine