Effects of the IMP-dehydrogenase inhibitor, Tiazofurin, in bcr-abl positive acute myelogenous leukemia. Part II. In vitro studies.

Inosine-5'-monophosphate-dehydrogenase (IMPDH) regulates the de novo synthesis of guanine ribonucleotides (GNT). IMPDH activity varies inversely with intracellular [GNT] and is linked to cellular proliferation. K562 leukemia cell growth was studied relative to IMPDH expression and activity following culture of the cells with Tiazofurin, an IMPDH inhibitor. Tiazofurin depressed IMPDH activity and [GTP] in K562 cells, and also increased IMPDH mRNA expression. Following exposure to Tiazofurin, K562 cell proliferation, entry into cycle, and sensitivity to cycle-active cytotoxic agents were increased. These findings indicate that the efficacy of standard chemotherapy in bcr-abl positive leukemias might be enhanced if combined sequentially with Tiazofurin.