Abstract
To exert its antitumor effects, leucovorin must ultimately become activated by conversion to CH2FH4.* Elevation of this reduced folate cofactor stabilizes the inhibitory ternary complex formed between the FU active metabolite, FdUMP and thymidylate synthase, resulting in suppression of DNA synthesis or repair.1–4 It has been demonstrated both in animal models5 and in humans6 that administration of leucovorin results in intratumor elevation of CH2FH4 and the closely related reduced folate, FH4. However, precisely when and where the metabolic activity causing this elevation occurs remains in question. Further, while enzyme activities have been reported7–9 that could sustain the interconversions shown below, the precise metabolic pathways used have not been defined.
This work was supported by Grant No. CH461 from the American Cancer Society, Grant No. CA22754 from the National Cancer Institute, and Grant No. RR-01070 from the National Institutes of Health, Division of Research Services.
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Priest, D.G., Schmitz, J.C., Walle, T. (1993). Leucovorin as a Prodrug. In: Rustum, Y.M. (eds) Novel Approaches to Selective Treatments of Human Solid Tumors. Advances in Experimental Medicine and Biology, vol 339. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2488-5_4
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