GROWTH-INHIBITION BY METHIONINE ANALOG INHIBITORS OF S-ADENOSYLMETHIONINE BIOSYNTHESIS IN THE ABSENCE OF POLYAMINE DEPLETION

Four methionine analog inhibitors of methionine adenosyltransferase, the enzyme which catalyzes S-adenosylmethionine biosynthesis, were tested in cultured [mouse leukemia] L1210 cells for their effects on cell growth, leucine incorporation, S-adenosylmethionine (AdoMet) formation and polyamine biosynthesis. The IC50 [median inhibitory concentration] values were: selenomethionine, 0.13 mM; L-2-amino-4-methoxy-cis-but-3-enoic acid (L-cis-AMB), 0.4 mM; cycloleucine, 5 mM and 2-aminobicyclo[2.1.1]hexane-2-carboxylic acid, 5 mM. At IC50 levels, the analogs significantly reduced AdoMet pools by .apprx. 50% while not similarly affecting leucine incorporation or polyamine biosynthesis. In combination with inhibitors of polyamine biosynthesis, growth inhibition was greatly increased with methylglyoxal bis (guanylhydrazone), an inhibitor of AdoMet decarboxylase, but only slightly increased with .alpha.-difluoromethylornithine, an inhibitor of ornithine decarboxylase. The methionine analogs, and particularly L-cis-AMB, seem to inhibit cell growth by interference with AdoMet biosynthesis. Since polyamine biosynthesis is not affected, the antiproliferative effect may be mediated through perturbations of certain transmethylation reactions. [Implications for cancer therapy are discussed].