The glutathione-activated thiopurine prodrugs trans-6-(2-acetylvinylthio)guanine and cis-6-(2-acetylvinylthio)purine cause less in vivo toxicity than 6-thioguanine after single- and multiple-dose regimens.

trans-6-(2-Acetylvinylthio)guanine (trans-AVTG) and cis-6-(2-acetylvinylthio)purine (cis-AVTP) are glutathione-activated prodrugs of 6-thioguanine (6-TG) and 6-mercaptopurine, respectively. In tumor cell lines, these prodrugs exhibit similar IC50 values that are comparable to or lower than those of 6-TG and 6-mercaptopurine, respectively. In this study, the in vivo toxicity and metabolism of the prodrugs were assessed. Mice given multiple treatments of 6-TG and, to a lesser extent, trans-AVTG exhibited decreased peripheral WBC and RBC counts and increased myeloid:erythroid ratios in bone marrow; no change was observed in mice given cis-AVTP. Similarly, intestinal epithelial crypt cell apoptosis was more extensive in mice treated with 6-TG than in those treated with trans-AVTG, whereas mice given cis-AVTP had little apoptosis. Epithelial crypt cell apoptosis was more extensive in the small intestine than in the large intestine in all treatment groups. Histopathological examination detected no kidney or liver toxicity, whereas mild increases in the activities of hepatocellular leakage enzymes were observed in mice treated with trans-AVTG. Only metabolites of trans-AVTG and cis-AVTP were recovered in urine. A higher fraction of the dose was recovered in urine as the parent thiopurine and the metabolites thiopurine riboside, thioxanthine, and thiouric acid after 6-TG treatment than after trans-AVTG treatment; cis-AVTP recovery was slightly less than that of 6-TG. Thioxanthine and thiouric acid comprised a higher fraction of the recovered dose after cis-AVTP treatment than after trans-AVTG or 6-TG treatment. Overall, the results suggest that the prodrugs exhibit less in vivo toxicity than 6-TG. Thus, investigations into their antitumor efficacy are warranted.