Potentiation of 1,3-Bis(2-chloroethyl)-1-nitrosourea cytotoxicity in 9L rat brain tumor cells by methylglyoxal-bis(guanylhydrazone), an inhibitor of S-adenosyl- l-methionine decarboxylase

Abstract

Methylglyoxal-bis(guanylhydrazone) (MGBG), a potent inhibitor of the spermidine and spermine biosynthetic enzyme S-adenosyl- l-methionine decarboxylase, enhanced the cytotoxicity of 1,3-bis-(2-chlorethyl)-1-nitrosourea in 9L rat brain tumor cells in vitro, as measured by a colony-forming efficiency assay, by an amount that was approximately the same as the potentiation caused by the ornithine decarboxylase inhibitor α-difluoromethylornithine. Dose enhancement ratios at 10, 1 and 0.1% survival levels were approximately 1.3 for both inhibitors. 9L cells that were treated for 48 hr with 40 μ M MGBG had putrescine, spermidine and spermine levels that were 112, 41 and 21% respectively, of polyamine levels in control cells. MGBG treatment does not increase intracellular levels of decarboxylated S-adenosyl- l-methionine (AdoMet) as α-difluoromethylornithine treatment does. Elevated levels of decarboxylated AdoMet could modify intracellular methylation reactions and could affect the cytotoxicity of a chloroethylnitrosourea. Despite the fact that MGBG treatment caused a slight increase in intracellular levels of AdoMet, it is unlikely that this elevation will increase the amount of intracellular methylation. Thus it appears that effects caused by the decrease in polyamine levels are responsible for the potentiation of chloroethylnitrosourea cytotoxicity against 9L cells.