Cytotoxicity of the novel glutathione-activated thiopurine prodrugs cis-AVTP [cis-6-(2-acetylvinylthio)purine] and trans-AVTG [trans-6-(2-acetylvinylthio)guanine] results from the National Cancer Institute's anticancer drug screen.

cis-6-(2-Acetylvinylthio)purine (cis-AVTP) and trans-6-(2-acetylvinylthio)guanine (trans-AVTG) are glutathione-activated prodrugs of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), respectively. Previously, we showed that the prodrugs exhibited less in vivo toxicity in mice than did 6-TG, whereas their in vitro cytotoxicity in two renal cell carcinoma cell lines was comparable with or better than that of their respective thiopurines. To determine whether differences in sensitivity exist among different tissue types toward treatment with cis-AVTP and trans-AVTG, the cytotoxicity of the prodrugs was assessed in the National Cancer Institute's anticancer screening program, and the results were compared with the cytotoxicities of 6-MP and 6-TG obtained in the same screen. The results show that cis-AVTP was more cytotoxic than or equally cytotoxic as 6-MP. Similarly, trans-AVTG was in general more cytotoxic than 6-TG. Both prodrugs exhibited high growth-inhibitory activities in leukemic cells and melanoma cells. However, cis-AVTP was more effective against renal cancer cells than trans-AVTG, whereas trans-AVTG was more effective than cis-AVTP against ovarian cancer cells. Interestingly, analyses using the pattern-recognition algorithm COMPARE revealed that among all compounds in the database, the cytotoxic activity of both cis-AVTP and trans-AVTG correlated best with that of another thiopurine conjugate, NSC 348401 (6-[(7-nitro-2,1,3-benzoxadiazol-4-yl)thio]-9H-purin-2-amine). Collectively, the results show that cis-AVTP and trans-AVTG exhibit both distinct and similar cytotoxicities toward different histotypes. Further investigations into the mechanisms responsible for these differences are warranted.