Inhibition of polyamine accumulation and cell proliferation by derivatives of diaminopropane in Ehrlich ascites cells grown in culture.
1. 1,3-Diaminopropane and some of its derivatives are potent inhibitors of ornithine decarboxylase (EC 4.1.1.17) in Ehrlich ascites cells grown in suspension culture. Among the amine derivatives tested, 1,3-diamino-2-propanol most effectively prevented any accumulation of spermidine and spermine in ascites cells when the proliferation was stimulated by diluting the cells with fresh medium. 2. The effectiveness of diaminopropanol in abolishing polyamine accumulation was primarily based on a rapid decay of ornithine decarboxylase activity following the exposure of the cells to the drug. 3. The mechanism of action of diaminopropanol on ornithine decarboxylase apparently involved a formation of macromolecular inhibitors or 'antizymes' to the enzyme. 4. Even though the inhibitory effect of 1,3-diaminopropane on polyamine accumulation approached that of diaminopropanol, the former compound only marginally inhibited the incorporation of [3H]thymidine into DNA and that of [14C]leucine into protein, in contrast to the marked depression of macromolecular synthesis produced by diaminopropanol. The apparent dissociation of polyamine depletion brought about by 1,3-diaminopropane from an antiproliferative action was apparently due to the fact that diaminopropane, unlike diaminopropanol, was partially capable of taking over the function of natural polyamines. 5. The inhibition of DNA and protein synthesis as well as the prevention of increase in cell number by diaminopropanol was closely associated with polyamine depletion and was fully comparable, as regards timing and magnitude, with that achieved with difluoromethylornithine. The antiproliferative effect of diaminopropanol, however, was only partly reversed by a simultaneous addition of putrescine (or spermidine) into the culture medium. The lack of a complete reversal of the action of diaminopropanol on cell growth by natural polyamines was apparently due to the fact that it was remarkably difficult or even impossible to increase intracellular polyamine concentrations by exogenous polyamines in the presence of diaminopropanol. Nevertheless, the diaminopropanol-induced arrest of growth was reversible as judged by a rapid increase in ornithine decarboxylase activity followed by restoration of DNA synthesis.
D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003959:Diamines / Q000494:pharmacology*; D004789:Enzyme Activation; D007700:Kinetics; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004273:DNA, Neoplasm; D003959:Diamines; D009363:Neoplasm Proteins; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D013096:Spermine; D003513:Cycloheximide; C009475:trimethylenediamine; D012437:Adenosylmethionine Decarboxylase; D013095:Spermidine