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Distribution and Metabolism of Calcium Leucovorin in Normal and Tumor Tissue

  • Robert J. Mullin
  • Barry R. Keith
  • David S. Duch
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 131)

Abstract

Thymidylate synthase catalyzes the formation of thymidylate from deoxyuridine monophosphate in a reaction which employs the folate cofactor CH2-H4PteGlu both as methyl donor and reductant. The TS inhibitor FUra has been widely used clinically for the treatment of solid tumors, particularly colorectal carcinomas. Inhibition of TS by FUra occurs following its metabolism to FdUMP and formation of a ternary complex involving TS, FdUMP and CH2-H4PteGlu (1–3). An increased interest in the use of FUra stems from the observations in tissue culture (4, 5) and in extracts of human colon adenocarcinoma xenographs (6) that the antitumor effects of FUra can be potentiated by the administration of exogenous folates in the form of calcium leucovorin. The results of these studies indicated that the response of many tumors to FUra is limited by the intracellular concentration of CH2-H4PteGlu and that the metabolism of 5-CHO-H4PteGlu to CH2-H4PteGlu following cellular uptake expands this cofactor pool. With increased intracellular levels of CH2-H4PteGlu, the half-life of the ternary complex is increased, resulting in increased cytoxicity. In support of this model, enlargement of the CH2-H4PteGlu pool following administration of 5-CHO-H4PteGlu has been demonstrated in tissue culture (7).

Keywords

Sodium Ascorbate Plasma Folate Thymidylate Synthetase Total Folate Tetrahydrofolic Acid 
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

  • Robert J. Mullin
    • 1
  • Barry R. Keith
    • 1
  • David S. Duch
    • 1
  1. 1.Department of Medicinal Biochemistry, Wellcome Research LaboratoriesResearch Triangle ParkUSA

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