Effects of 2-amino-1,3,4-thiadiazole on ribonucleotide pools of leukemia L1210 cells.

The effects of 2-amino-1,3,4-thiadiazole [aminothiadiazole (NSC 4728)] on purine and pyrimidine ribonucleotide pools of L1210 ascites cells in vivo are presented and discussed as they relate to the site of action. Within 1 hr after administration of the drug, the levels of guanosine triphosphate, guanosine diphosphate, adenosine triphosphate, and adenosine diphosphate were reduced, whereas those of inosine monophosphate (IMP) and uridine triphosphate were increased. The most pronounced effects were the lowering of guanine ribonucleotide pools and the elevation of IMP. Aminothiadiazole produced a marked inhibition (approximately 95%) of the incorporation of [8-14C]inosine into guanine nucleotides, whereas only a slight inhibition (approximately 20%) of incorporation into adenine nucleotides was observed. These results suggest that the thiadiazole (or a metabolite thereof) inhibits the conversion of IMP to guanosine monophosphate; this conclusion is reinforced by the observation that mycophenolic acid, a known inhibitor of this conversion, produced effects on ribonucleotide pools similar to those produced by aminothiadiazole. Aminothiadiazole did not inhibit IMP dehydrogenase isolated from L1210 cells. The effects of the thiadiazole on nucleotide pools were prevented by simultaneous administration of nicotinamide. Since nicotinamide is known to prevent or reverse the antileukemic activity of aminothiadiazole, it is probable that the inhibition of synthesis of guanosine monophosphate is related to the antileukemic action of this agent.