Tumor Cell Responses to Inhibition of Thymidylate Synthase

  • Richard G. Moran
  • Khandan Keyomarsi
  • Ramesh Patel
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 244)


Whether inhibition of thymidylate synthase is lethal to a population of tumor cells depends upon three factors: 1) the dependence of the cells upon de novo synthesis of thymidine nucleotides; 2) the length of time enzyme is inhibited and the requirement for thymidine nucleotides during this period; and 3) the biochemical responses of the cells to the initial inhibition of enzyme, many of which interfere with maintenence of thymidylate synthase in an inhibited state. Following inhibition of thymidylate synthase, deoxyuridylate accumulates, as does the cellular content of thymidylate synthase. In addition, the initially formed enzyme-inhibitor complexes dissociate. These biochemical sequelae alter the effectiveness of the blockade of thymidylate synthase in a time-dependent, continuously-changing manner. Whether cell kill occurs depends on whether the dynamic balance of these factors allows a sufficiently low enzymatic activity to be maintained for a long enough period of time.

An analysis of this interaction of factors leads us to the conclusions that efficient tumor cell kill with fluoropyrimidines is best attained by combination with reduced folate cofactors and inhibitors of deoxypyrimidine biosynthesis. Each of these agents modifies the response of tumor cells with the result that the fluorodeoxyuridylate-induced inhibition of thymidylate synthase is maintained. This analysis also suggests that folate analogs inhibitory to thymidylate synthase are more compatible than pyrimidine analogs with inhibition of thymidylate synthase as an approach to cancer chemotherapy.


Ternary Complex L1210 Cell Folinic Acid Free Enzyme Clonogenic Assay 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Heidelberger, C., Danenberg, P.V., and Moran, R.G. (1983) Adv. Enzymol. 54, 57–119.Google Scholar
  2. 2.
    Keyomarsi, K. and Moran, R.G. (1988) J. Biol. Chem., submitted.Google Scholar
  3. 3.
    Myers, C.E., Young, R.C., and Chabner, B.A. (1975) J. Clin. Invest. 56, 1231–1238CrossRefGoogle Scholar
  4. 4.
    Moran, R.G., Spears, C.P., and Heidelberger, C. (1979) Proc. Natl. Acad. Sci., USA. 76, 1456–1460.CrossRefGoogle Scholar
  5. 5.
    Jackson, R.C. (1978) J. Biol. Chem. 253: 7440–7446.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Lorenson, M.Y., Maley, G.F., and Maley, F. (1967) J.Biol.Chem. 242: 3332–3344.PubMedGoogle Scholar
  7. 7.
    Moore, E.C. and Huribert, R.B. (1966) J.Biol. Chem. 241: 4802–4809.PubMedGoogle Scholar
  8. 8.
    Spears, C.P., Gustaysson, B.G., Mitchell, M.S., Spicer, D., Berne, M., Bernstein, L., and Danenberg, P.V. (1984) Cancer Res. 44: 4144–4150.Google Scholar
  9. 9.
    Jackman, A.L., Alison, D.A., Calvert, A.H., and Harrup, K.R. (1986) Cancer Res. 46: 2810–2815.PubMedGoogle Scholar
  10. 10.
    Lockshin, A., Moran, R.G., and Danenberg, P.V. (1979) Proc. Natl Acad. Sci., USA. 76, 750–754.CrossRefGoogle Scholar
  11. 11.
    Spears, C.P., Shahinian, A.H., Moran, R.G., and Heidelberger, C. (1982) Cancer Res. 42, 450–456.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Keyomarsi, K. and Moran, R.G. (1986) Cancer Res. 46, 5229–5235.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Goldman, I.D., (1974) Mol. Pharmacol. 10, 257–274PubMedGoogle Scholar
  14. 14.
    White, J.C., and Goldman, I.D. (1976) Mol. Pharmacol. 12, 711–719PubMedGoogle Scholar
  15. 15.
    Santi, D.V., McHenry, C.S., and Perriard, E.R. (1974) Biochemistry 13: 467–470CrossRefGoogle Scholar
  16. 16.
    Ullman, B., Melinda, L., Martin, D.W., and Santi, D.V (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 980–983CrossRefGoogle Scholar
  17. 17.
    Evans, R.M., Laskin, J.D., and Hakala, M.T. (1981) Cancer Res. 41, 3288–3295PubMedPubMedCentralGoogle Scholar
  18. 18.
    Evans, R.M., Laskin, J.D., and Hakala, M.T. (1980) Cancer Res. 40, 4113–4122PubMedGoogle Scholar
  19. 19.
    Cohen, L.S., and Studzinski, G.P. (1967) J. Cell Physiol. 69, 331–340CrossRefGoogle Scholar
  20. 20.
    Rueckert, R.R., and Mueller, G.C. (1960) Cancer Res. 20, 1584–1591PubMedGoogle Scholar
  21. 21.
    Maalge, O., and Hanawalt, P.C. (1961) J. Mol. Biol. 3, 144–155CrossRefGoogle Scholar
  22. 22.
    Lockshin, A., and Danenberg, P. V. (1981) Biochem. Pharmacol. 30, 247–257CrossRefGoogle Scholar
  23. 23.
    Galivan., J. H., Maley, G.F., and Maley, F. (1976) Biochemistry 15: 356–362.CrossRefGoogle Scholar
  24. 24.
    Moran, R.G., Danenberg, P.V., and Heidelberger, C. (1982) Biochem.Ph arm aco1. 31, 2929–2935.CrossRefGoogle Scholar
  25. 25.
    Unpublished observations.Google Scholar
  26. 26.
    Klubes, P., Cerna, I., and Meldon, M.A. (1982) Cancer Chemother. Pharmacol. 8: 17–21.CrossRefGoogle Scholar
  27. 27.
    Martin, D.S., Stolfi, R.L., Sawyer, R.C., Speigelman, S., and Young, C.W. (1983) Cancer Res. 43, 4653–4661PubMedGoogle Scholar
  28. 28.
    Jones, T.R., Calvert, A.H., Jackman,A.L., Brown, S.J., Jones, M., and Hanap, K.R. (1981) Eur. J. Cancer 17: 11–19.CrossRefGoogle Scholar
  29. 29.
    Jackson, R.C., Jackman, A.L., and Calvert, A.H. (1983) Biochem. Pharmacol. 32: 3783–3790.CrossRefGoogle Scholar
  30. 30.
    Pogolotti, A. L., Danenberg, P.V., Santi, D.V. (1986) J. Med. Chem. 29: 478–482.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Richard G. Moran
    • 3
  • Khandan Keyomarsi
    • 1
    • 2
  • Ramesh Patel
    • 1
    • 2
  1. 1.Departments of Pediatrics (RGM) and Biochemistry (RGM,KK)University of Southern CaliforniaUSA
  2. 2.Division of Hematology/OncologyChildren’s Hospital of Los Angeles (RGM,RP)Los AngelesUSA
  3. 3.Division of Hematology/OncologyChildren’s Hospital of Los AngelesLos AngelesUSA

Personalised recommendations