Reversal of the growth inhibitory effect of alpha-difluoromethylornithine by putrescine but not by other divalent cations.
Treatment with alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase (ODC), depletes the putrescine and spermidine content, and reduces the growth rate of Ehrlich ascites tumor cells. The addition of putrescine, which is the immediate precursor of spermidine, promptly replenished the intracellular putrescine and spermidine pools and completely reversed the antiproliferative effect of DFMO. A sequential accumulation of spermine, spermidine and putrescine was observed. 1,3-diaminopropane, a lower homolog of putrescine, did not reverse the antiproliferative effect of DFMO, despite its structural similarity and identical positive charge. By inhibiting remaining ODC activity, resistant to 5 mM DFMO, and possibly by inhibiting spermine synthase activity, 1,3-diaminopropane produced a further decrease in total polyamine content by reducing the spermine content. Mg2+, which can replace putrescine in many in vitro reactions, completely lacked the capacity to reverse the antiproliferative effect of putrescine and spermidine deficiency.
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003959:Diamines / Q000494:pharmacology*; D000518:Eflornithine; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D009952:Ornithine / Q000031:analogs & derivatives* / Q000633:toxicity; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D011700:Putrescine / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D003959:Diamines; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; C009475:trimethylenediamine; D009952:Ornithine; D008274:Magnesium; D011700:Putrescine; D000518:Eflornithine