Role of differentiation induction in action of purine antimetabolites

  title={Role of differentiation induction in action of purine antimetabolites},
  author={George Weber and Yukiko Hata and No{\'e}mi Prajda},
  journal={Pharmacy World and Science},
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 ofde 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… Expand


Induction of erythroid differentiation and modulation of gene expression by tiazofurin in K-562 leukemia cells.
Ganosine was effective in preventing the action of tiazofurin, thus providing evidence that the guanine nucleotides are critically involved in tiaz ofurin-initiated differentiation. Expand
Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient.
The decrease in IMP DH activity, GTP concentration, and expression of c-Ki-ras oncogene were early markers of the successful chemotherapeutic impact of tiazofurin in a patient with chronic granulocytic leukemia in blast crisis. Expand
Tiazofurin: biological effects and clinical uses.
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, and a good correlation between biochemical parameters and clinical response was demonstrated in leukemic patients. Expand
Synergistic action of tiazofurin and difluorodeoxycytidine on differentiation and cytotoxicity.
  • J. Ban, G. Weber
  • Biology, Medicine
  • Biochemical and biophysical research communications
  • 1992
Tiazofurin and DFDC are synergistically cytotoxic in hepatoma cells and additive in PANC-1 cells and should be helpful in treating leukemias and solid tumors in humans. Expand
Biochemically directed therapy of leukemia with tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity.
Tiazofurin was better tolerated in most patients than other antileukemic treatment modalities and provided a rational,Biochemically targeted, and biochemically monitored chemotherapy which should be of interest in the treatment of leukemias and as a paradigm in enzyme pattern-targeted chemotherapy. Expand
Alterations in glycoprotein synthesis and guanosine triphosphate levels associated with the differentiation of HL-60 leukemia cells produced by inhibitors of inosine 5'-phosphate dehydrogenase.
The exposure of HL-60 leukemia cells to inhibitors of IMP dehydrogenase caused a marked reduction in the incorporation of [3H]mannose into both cellular glycoproteins and their lipid-linked oligosaccharide precursors; these effects are presumably due to the pronounced decrease in intracellular levels of guanosine triphosphate produced by blockage of IMP dehydration. Expand
Synergistic cytotoxic effect of tiazofurin and ribavirin in hepatoma cells.
It is shown that the binding to IMP dehydrogenase of these drugs at two separate sites is translated into synergistic inhibition of de novo guanylate biosynthesis and synergistic toxicity in rat hepatoma 3924A cells. Expand
Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide).
This is the first report showing that a marked therapeutic response was achieved against rapidly growing hepatoma 3924A by treatment with a single anti-metabolite, and tiazofurin treatment resulted in significant anti-tumor activity in rats inoculated with hepatoma3924A. Expand
Studies on the mechanism of action of tiazofurin metabolism to an analog of NAD with potent IMP dehydrogenase-inhibitory activity.
Results suggested that the anabolite might be a dinucleotide with a phosphodiester linkage of the kind found in NAD, and attempts were made to synthesize such an analogue from the 5'-monophosphate of thiazole nucleoside and ATP-Mg2+, using a purified preparation of NAD pyrophosphorylase. Expand
IMP dehydrogenase and GTP as targets in human leukemia treatment.
  • G. Weber
  • Chemistry, Medicine
  • Advances in experimental medicine and biology
  • 1991
The significance of GTP in cancer biochemistry and chemotherapy was highlighted by the discovery that IMP dehydrogenase activity increased in a transformation- and progression-linked fashion in rat hepatomas of different growth rates. Expand