TIAZOFURIN EFFECTS ON IMP-DEHYDROGENASE ACTIVITY AND EXPRESSION IN THE LEUKEMIA-CELLS OF PATIENTS WITH CML BLAST CRISIS

Tricot et al have reported that the nucleoside analog tiazofurin can i nduce hematologic remissions in patients with chronic myelogenous leuk emia in blast crisis (CML-BC). These reports prompted us to begin a de rivative, phase II trial of tiazofurin in CML-BC to determine if the p romising findings reported by these investigators could be reproduced. In our on-going trial patients receive tiazofurin by IV infusion (220 0-4400mg/m(2) over 1 hr) once every 24-48 hrs for up to 10 days. Each of 3 patients, treated to date on this trial, experienced substantial hematologic responses with normalization of WBC counts and complete or partial clearance of blasts from the blood within 4-11 days of treatm ent. These responses were relatively brief, in that leukemic blasts re accumulated in the marrow and blood of patients within 4 weeks followi ng treatment, but were re-induced with subsequent courses of treatment . Of interest, the rates of blast cell reaccumulation appeared to incr ease progressively following sequential courses of treatment. Tiazofur in, which inhibits IMP-dehydrogenase (IMPDH) and blocks guanine ribonu cleotide synthesis, has been shown to increase IMPDH mRNA expression i n various cell lines in vitro, as an apparently compensatory response to guanylate deprivation. Studies of IMPDH mRNA expression in the leuk emic blasts of CML-BC patients receiving tiazofurin treatment showed t hat this same phenomenon occurs in vivo. Since IMPDH activity is linke d to the proliferative activity of neoplastic cells, and amplification of IMPDH message expression induced by tiazofurin may lend to an incr eased sensitivity of the leukemic clone to cycle active agents.