Decreased cell kill of vincristine and methotrexate against 9L rat brain tumor cells in vitro caused by alpha-difluoromethylornithine-induced polyamine depletion.
The effect of polyamine depletion on the cell kill caused by the cell cycle-specific agents vincristine (VCR) and methotrexate (MTX) was studied in 9L rat brain tumor cells in vitro using a colony-forming efficiency assay as the experimental end point. The cell kill produced by a 24-hr treatment with VCR or MTX was decreased in 9L cells pretreated with 1 mM alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase. Reversal of the alpha-difluoromethylornithine-induced polyamine depletion with 1 mM exogenous putrescine prevented the decrease in VCR and MTX cytotoxicity. After a 48-hr treatment with 1 mM alpha-difluoromethylornithine, the number of mitotic cells in asynchronously growing 9L cell cultures was reduced markedly. The decreased cell kill of VCR and MTX appeared to be the result of polyamine depletion-induced inhibition of 9L cell cycle traverse, which reduced the number of cells in drug-sensitive phases of the cell cycle and thereby reduced the cell kill caused by the drugs.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000518:Eflornithine; D007700:Kinetics; D008727:Methotrexate / Q000633:toxicity*; D008940:Mitotic Index / Q000187:drug effects; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism*; D051381:Rats; D014750:Vincristine / Q000633:toxicity*
D000970:Antineoplastic Agents; D011073:Polyamines; D014750:Vincristine; D009952:Ornithine; D008727:Methotrexate; D000518:Eflornithine