The Treatment of Metastatic Breast Cancer with 5-Fluorouracil and Leucovorin
The preclinical rationale for the use of 5-fluorouracil (5-FU) in combination with leucovorin has been well described in a number of articles . Briefly, the formation and stability of the ternary complex formed between an active metabolite of 5-FU (FdUMP), thymidylate synthase (TS), and the reduced folate 5-10-methylene tetrahydrofolate is highly dependent on the concentration and polyglutamated state of the folate [2,3]. The addition of exogenous folate has been shown to enhance ternary complex formation, and thereby enzyme inhibition, in in vitro and in vivo investigations [4,5]. Inhibition of TS results in thymidylate deficiency and presumably cytotoxicity due to a diminished ability of cells to replicate and repair DNA. In light of the encouraging experience using 5-FU with leucovorin for the treatment of metastatic colon cancer , we sought to test this combination for the therapy of metastatic breast cancer wherein 5-FU is known to be an active agent. The objectives of our study were twofold: 1) to assess the efficacy of 5-FU combined with leucovorin for the treatment of metastatic breast cancer, and 2) to determine the effect of leucovorin on the binding of FdUMP to TS in serial tumor samples obtained from patients undergoing therapy. This report represents a preliminary assessment of the efficacy and toxicity of the 5-FU and leucovorin combination and the biochemical studies relevant to the interaction of 5-FU with TS.
KeywordsMetastatic Breast Cancer Biochemical Evaluation Metastatic Colon Cancer Leucovorin Calcium Preclinical Rationale
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