Abstract
The antipyrimidine drug, 5-fluorouracil (5-FU), as its active metabolite, FdUMP, is a potent inhibitor of thymidylate synthase (TS), and this is generally considered to be its primary mechanism of action (Pratt et al., 1994). Drug combinations including 5-FU continue to be the primary treatment for metastatic colon carcinoma. This tumor is relatively refractory to DNA cross-linking agents, and because it usually expresses the multidrug resistance (MDR) phenotype is unresponsive to anthracyclines and vinca alkaloids. Although 5-FU is not subject to these limitations, it has other disadvantages: it requires intracellular activation to FdUMP, and when it inhibits TS, the resulting accumulation of deoxyuridylate (dUMP) tends to compete with the FdUMP for binding to TS. Because 5-FU has other biochemical effects, most notably incorporation into RNA, it is difficult to determine which of its therapeutic and toxic effects are a result of TS inhibition. In addition, 5-FU has rather unfavorable pharmacokinetics, with a terminal plasma half-life in humans of 10 to 20 minutes.
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Jackson, R.C. (1995). Inhibitors of Thymidylate Synthase and Glycinamide Ribonucleotide Transformylase. 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_39
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DOI: https://doi.org/10.1007/978-1-4615-2584-4_39
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