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Role of differentiation induction in action of purine antimetabolites

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Abstract

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 observed in the blast cells of patients treated with tiazofurin infusions: chemotherapy, induced differentiation, and down-regulation of c-Ki-ras andc-myc oncogenes. Tiazofurin was synergistic in cytotoxicity and in causing differentiation with ribavirin, retinoic acid, and difluorodeoxycytidine. Induced differentiation plays an important role in the overall impact of antipurine agents.

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References

  1. Weber G. Biochemical strategy of cancer cells and the design of chemotherapy: GHA Clowes Memorial Lecture. Cancer Res 1983;43:3466–92.

    PubMed  Google Scholar 

  2. Weber G. IMP dehydrogenase and GTP as targets in human leukaemia treatment. In: Harkness RA, editor. Purine and pyrimidine metabolism in man VII. Part B. New York: Plenum Press, 1991:287–92.

    Google Scholar 

  3. Tricot G, Jayaram HN, Weber G. Tiazofurin: biological effects and clinical uses. Int J Cell Cloning 1990;8:161–70.

    PubMed  Google Scholar 

  4. Lui MS, Faderan MA, Liepnieks JJ, Natsumeda Y, Olah E, Jayaram HN, et al. Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide). J Biol Chem 1984;259:5078–82.

    PubMed  Google Scholar 

  5. Cooney DA, Jayaram HN, Glazer RI, Kelley JA, Marquez G, Gebeyehu, et al. Studies on the mechanism of action of tiazofurin metabolism to an analog of NAD with potent IMP dehydrogenase-inhibiting activity. Adv Enzyme Regul 1983;21:271–303.

    PubMed  Google Scholar 

  6. Jayaram HN. Biochemical mechanisms of resistance to tiazofurin. Adv Enzyme Regul 1986;24:67–89.

    Google Scholar 

  7. Yamada Y, Natsumeda Y, Weber G. Action of the active metabolites of tiazofurin and ribavirin on purified IMP dehydrogenase. Biochemistry 1988;27:2193–6.

    PubMed  Google Scholar 

  8. Weber G, Jayaram HN, Lapis E, Natsumeda Y, Yamada Y, Yamaji Y, et al. Enzyme-pattern-targeted chemotherapy with tiazofurin and allopurinol in human leukaemia. Adv Enzyme Regul 1988;27:405–33.

    PubMed  Google Scholar 

  9. Weber G, Nagai M, Natsumeda Y, Eble JN, Jayaram HN, Paulik E, et al. Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient. Cancer Commun 1991;3:61–6.

    PubMed  Google Scholar 

  10. Olah E, Natsumeda Y, Ikegami T, Kote, Z, Horanyi M, Szelenyi J, et al. Induction of erythroid differentiation and modulation of gene expression by tiazofurin in K562 leukaemia cells. Proc Natl Acad Sci USA 1988;85:6533–7.

    PubMed  Google Scholar 

  11. Olah E, Kote Z, Natsumeda Y, Yamaji Y, Jarai G, Lapis E, et al. Down-regulation of c-myc and c-Ha-ras gene expression by tiazofurin in rat hepatoma cells. Cancer Biochem Biophys 1990;11:107–17.

    PubMed  Google Scholar 

  12. Tricot GJ, Jayaram HN, Lapis E, Natsumeda Y, Yamada Y, Nichols CR, et al. Biochemically directed therapy of leukaemia with tiazofurin, a selective blocker of inosine 5′-phosphate dehydrogenase activity. Cancer Res 1989;49:3696–701.

    PubMed  Google Scholar 

  13. Wright DG, A role for guanine ribonucleotides in the regulation of myeloid cell maturation. Blood 1987;69:334–7.

    PubMed  Google Scholar 

  14. Sokoloski JA, Blair OC, Sartorelli AC. Alterations in glycoprotein differentiation of HL-60 leukaemia cells produced by inhibitors of inosine 5′-phosphate dehydrogenase. Cancer Res 1986;46:2314–9.

    PubMed  Google Scholar 

  15. Natsumeda Y, Yamada Y, Yamaji Y, Weber G. Synergistic cytotoxic effect of tiazofurin and ribavirin in hepatoma cells. Biochem Biophys Res Commun 1988;153:321–7.

    PubMed  Google Scholar 

  16. Ban J, Weber G. Synergistic action of tiazofurin and difluorodeoxycytidine in differentiation and cytotoxicity. Biochem Biophys Res Commun 1992;184:551–9.

    PubMed  Google Scholar 

  17. Hata Y, Natsumeda Y, Weber G. Tiazofurin decreases Ras.GTP complex in K562 cells. Oncol Res. In press.

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Authors and Affiliations

  1. Laboratory for Experimental Oncology, Indiana University School of Medicine, 702 Barnhill Drive, 46202 5200, Indianapolis, IN, USA

    George Weber, Yuki Hata & Noemi Prajda

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  1. George Weber
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  2. Yuki Hata
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  3. Noemi Prajda
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Weber, G., Hata, Y. & Prajda, N. Role of differentiation induction in action of purine antimetabolites. Pharm World Sci 16, 77–83 (1994). https://doi.org/10.1007/BF01880659

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  • DOI: https://doi.org/10.1007/BF01880659

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