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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 131)

Abstract

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.

Keywords

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.

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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

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