Leucovorin as a Prodrug
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.
KeywordsFolinic Acid Thymidylate Synthetase Total Folate Advanced Colorectal Carcinoma Leucovorin Calcium
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