Role of differentiation induction in action of purine antimetabolites.
In cancer cells, particularly in leukaemic cells, guanylate biosynthesis is up-regulated as shown by the increased activities of IMP dehydrogenase, the rate-limiting enzyme of de novo GTP biosynthesis, and of the salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). In enzyme pattern-targeted chemotherapy, tiazofurin inhibits IMP dehydrogenase activity in cancer cells and allopurinol-induced high serum hypoxanthine levels inhibit HGPRT activity. A triad of responses was observed in the blast cells of patients treated with tiazofurin infusions: chemotherapy, induced differentiation, and down-regulation of c-Ki-ras and c-myc oncogenes. Tiazofurin was synergistic in cytotoxicity and in causing differentiation with ribavirin, retinoic acid, and gemcitabine [corrected]. Induced differentiation plays an important role in the overall impact of antipurine agents.
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
G
G
Weber
Y
Y
Hata
N
N
Prajda
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D009857:Oncogenes; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D012254:Ribavirin; C033706:tiazofurin; D000093542:Gemcitabine