title: Clinical and molecular impact of inhibition of IMP dehydrogenase activity by tiazofurin.
abstract: The impact of tiazofurin on inhibition of IMP dehydrogenase was discussed at the clinical and molecular levels. 1. Evidence was provided for the role of IMP dehydrogenase and guanylates in the expression of the neoplastic program in cancer cells with particular relevance to human leukemic cells. 2. The argument for expecting an impact of tiazofurin in human myelocytic cells was provided. 3. Similarity of the kinetics of human leukemic cell IMP dehydrogenase to the rat hepatoma enzyme was documented. 4. New evidence was provided for the role of salvage in chemotherapy and the function of hypoxanthine in inhibiting guanine salvage. 5. The action of tiazofurin and retinoic acid was reported in HL-60 leukemic cells. 6. The effect of tiazofurin and retinoic acid on proliferation and cytotoxicity was outlined for hepatoma 3924A cells. 7. The effect of guanine on induced differentiation by tiazofurin and retinoic acid was examined. 8. Biochemical basis was provided for the lack of development of resistance in patients treated with tiazofurin. 9. Presumptive evidence was provided that tiazofurin treatment induced differentiation of leukemic cells in the patients. 10. The molecular biology of tiazofurin-induced differentiation in K-562 cells was reviewed with the possible relevance to clinical treatment that tiazofurin might also act through down-regulation of ras oncogene.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis 46223.
authors.forename: G
authors.initials: G
authors.lastname: Weber
authors.forename: Y
authors.initials: Y
authors.lastname: Yamaji
authors.forename: E
authors.initials: E
authors.lastname: Olah
authors.forename: Y
authors.initials: Y
authors.lastname: Natsumeda
authors.forename: H N
authors.initials: HN
authors.lastname: Jayaram
authors.forename: E
authors.initials: E
authors.lastname: Lapis
authors.forename: W N
authors.initials: WN
authors.lastname: Zhen
authors.forename: N
authors.initials: N
authors.lastname: Prajda
authors.forename: R
authors.initials: R
authors.lastname: Hoffman
authors.forename: G J
authors.initials: GJ
authors.lastname: Tricot
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006151:Guanosine / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007658:Ketone Oxidoreductases / Q000037:antagonists & inhibitors*; D015473:Leukemia, Promyelocytic, Acute; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D051381:Rats; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology
chemical_list: D000964:Antimetabolites, Antineoplastic; D012263:Ribonucleosides; D006151:Guanosine; D012254:Ribavirin; D014212:Tretinoin; D007168:IMP Dehydrogenase; D007658:Ketone Oxidoreductases; C033706:tiazofurin