Skip to main content

Antimetabolites Reduce the Activities of Enzymes with Short Half-Lives in Addition to Inhibiting their Specific Targets

  • Chapter
Purine and Pyrimidine Metabolism in Man VIII

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 370))

Abstract

In evolution two pathways emerged for the biosynthesis of pyrimidine and purine nucleotides. The de novo biosynthetic pathway assembles nucleotides from small building blocks. By contrast, the salvage pathways provide mechanisms to recycle nucleosides and bases from the dead cells of tissues and from the blood stream1. In some lower organisms only one of these pathways operates2. However, in mammalians both de novo and salvage pathways function in all tissues. It has been recognized in the past 10 years that the activities of salvage enzymes in each of the biosynthetic segments of metabolism are markedly higher than those of the rate-limiting enzymes of de novo biosynthesis1.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. G. Weber, Biochemical strategy of cancer cells and the design of chemotherapy: G. H. A. Clowes Lecture, Cancer Res. 43: 3466 (1983).

    PubMed  CAS  Google Scholar 

  2. T. Aoki, Initial steps of de novo pyrimidine nucleotide biosynthesis in parasites and mammalian tissues: purification, regulation, adaptation, and evolution, Jpn. J. Parasitology 43: 1 (1994).

    Google Scholar 

  3. G. Weber, S. Ichikawa, M. Nagai, and Y. Natsumeda, Azidothymidine inhibition of thymidine kinase and synergistic cytotoxicity with methotrexate and 5-fluorouracil in rat hepatoma and human colon cancer cells, Cancer Commun. 2: 129 (1990).

    PubMed  CAS  Google Scholar 

  4. G. Weber, M. Nagai, N. Prajda, H. Nakamura, T. Szekeres, and E. Olah, AZT: a biochemical response modifier of methotrexate and 5-fluorouracil cytotoxicity in human ovarian and pancreatic carcinoma cells, Cancer Commun. 3: 127 (1991).

    PubMed  CAS  Google Scholar 

  5. M. Abonyi, N. Prajda, Y. Hata, H. Nakamura, and G. Weber, Methotrexate decreases thymidine kinase activity, Biochem. Biophys. Res. Commun. 187: 522 (1992).

    Article  PubMed  CAS  Google Scholar 

  6. G. Weber, and N. Prajda, Targeted and non-targeted actions of anti-cancer drugs, Advan. Enzyme Regul. 34: 71 (1994).

    Article  CAS  Google Scholar 

  7. N. Prajda, Y. Natsumeda, T. Ikegami, M.A. Reardon, S. Szondy, Y. Hashimoto, J. Emrani, and G. Weber, Enzymic programs of rat bone marrow and the impact of acivicin and tiazofurin, Biochem. Pharmacol. 37: 875 (1988).

    Article  PubMed  CAS  Google Scholar 

  8. M.J. Osborn, M. Freeman, and F.M. Huennekens, Inhibition of dihydrofolate reductase by aminopterin and amethopterin, Proc. Soc. Exptl. Biol. Med. 97: 429 (1958).

    Article  CAS  Google Scholar 

  9. K. Pillwein, H.N. Jayaram, and G. Weber, Effect of ischemia on nucleosides and bases in rat liver and hepatoma 3924A, Cancer Res. 47: 3092 (1987).

    PubMed  CAS  Google Scholar 

  10. C.J. Allegra, Antifolates, in: “Cancer Chemotherapy: Principles and Practice,” B.A. Chabner and J.M. Collins, eds., J.B. Lippincott Co., Philadelphia (1972).

    Google Scholar 

  11. M.S. Lui, M.A. Faderan, J.J. Liepnieks, Y. Natsumeda, E. Olah, H.N. Jayaram, and G. Weber, Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-ß-D-ribofuranosylthiazole-4-carboxamide), J. Biol. Chem. 259: 5078 (1984).

    PubMed  CAS  Google Scholar 

  12. G. Weber, IMP dehydrogenase and GTP as targets in human leukemia treatment, Advan. Exptl Med Biol 309B: 287 (1991).

    Article  CAS  Google Scholar 

  13. G. Tricot, H.N. Jayaram, G. Weber, and R. Hoffman, Tiazofurin: biological effects and clinical uses, Intl. J. Cell Cloning 8: 161 (1990).

    Article  CAS  Google Scholar 

  14. D. Wright, A role for guanine ribonucleotides in the regulation of myeloid cell maturation, Blood 69: 334 (1987).

    PubMed  CAS  Google Scholar 

  15. E. Olah, Y. Natsumeda, T. Ikegami, Z. Kote, M. Horanyi, J. Szelenyi, E. Paulik, T. Kremmer, S.R. Hollan, J. Sugar, and G. Weber, Induction of erythroid differentiation and modulation of gene expression by tiazofurin in K-562 cells produced by inhibitors of inosine 5’-phosphate dehydrogenase, Cancer Res. 46: 2314(1986).

    Google Scholar 

  16. G. Weber, M. Nagai, Y. Natsumeda, J.N. Eble, H.N. Jayaram, E. Paulik, W. Zhen, R. Hoffman, and G. Tricot, Tiazofurin down-regulates expression of c-Ki-ray oncogene in a leukemic patient, Cancer Commun. 3: 61 (1991).

    PubMed  CAS  Google Scholar 

  17. N. Prajda, Y. Hata, M. Abonyi, R.L. Singhal, and G. Weber, Sequential impact of tiazofurin and ribavirin on enzymic program of the bone marrow, Cancer Res. 53: 5982 (1993).

    PubMed  CAS  Google Scholar 

  18. R.L. Singhal, Y.A. Yeh, K.Y. Look, G.W. Sledge, Jr., and G. Weber, Coordinated increase in activities of the signal transduction enzymes PI kinase and PIP kinase in human cancer cells, Life Sci., accepted for publication (1994).

    Google Scholar 

  19. R.L. Singhal, N. Prajda, Y.A. Yeh, and G. Weber, 1-Phosphatidylinositol 4-phosphate 5-kinase (EC 2.7.1.68): A proliferation-and malignancy-linked signal transduction enzyme, Cancer Res. Nov. issue, 54: (1994).

    Google Scholar 

  20. M.T. Rizzo, and G. Weber, 1-Phosphatidylinositol 4-kinase (EC 2.7.1.67): An enzyme linked with proliferation and malignancy, Cancer Res. 54: 2611 (1994).

    PubMed  CAS  Google Scholar 

  21. G. Weber, and M.A. Reardon, Regulation of carbamoyl-phosphate synthase II, Advan. Enzyme Regal 25: 65 (1986).

    Article  CAS  Google Scholar 

  22. A.M. Billi, L. Cocco, A.M. Martelli, R.S. Gilmour, and G. Weber, Tiazofurin-induced changes in inositol lipid cycle in nuclei of Friend erythroleukemia cells, Biochem. Biophys. Res. Commun. 195: 8 (1993).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 1995 Springer Science+Business Media New York

About this chapter

Cite this chapter

Weber, G., Prajda, N., Singhal, R.L. (1995). Antimetabolites Reduce the Activities of Enzymes with Short Half-Lives in Addition to Inhibiting their Specific Targets. In: Sahota, A., Taylor, M.W. (eds) Purine and Pyrimidine Metabolism in Man VIII. Advances in Experimental Medicine and Biology, vol 370. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2584-4_33

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-2584-4_33

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6105-3

  • Online ISBN: 978-1-4615-2584-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics