Tiazofurin: biological effects and clinical uses.
Inosine 5'-phosphate dehydrogenase (IMPDH) activity is increased in all cancer cells. It is the rate-limiting enzyme of guanosine triphosphate (GTP) biosynthesis, and therefore, a sensitive target of chemotherapy. Tiazofurin selectively blocks IMPDH activity. Tiazofurin was found to have an antiproliferative effect on tumor cells in vitro and in the murine system. Based on these findings, Phase I trials were started elsewhere in patients with solid tumors, but were discontinued because of toxicity. In leukemic patients, we were able to demonstrate a good correlation between biochemical parameters (i.e., decline in IMPDH activity and GTP concentrations in blast cells) and clinical response. The most consistent responses to therapy were seen in patients with myeloid blast crisis of chronic myeloid leukemia. Severe toxicity was seen in the earlier patients in the study. However, better patient selection, limitation of treatment duration and earlier recognition and treatment of complications have now made it possible to administer tiazofurin without undue toxicity.
Tricot
G
G
Department of Medicine, Indiana University School of Medicine, Indianapolis.
Jayaram
H N
HN
Weber
G
G
Hoffman
R
R
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004341:Drug Evaluation; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy; D012254:Ribavirin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D012263:Ribonucleosides / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D012263:Ribonucleosides; D012254:Ribavirin; D007168:IMP Dehydrogenase; C033706:tiazofurin