Inhibition of thymidylate synthase by the diastereoisomers of leucovorin

Cancer Chemotherapy and Pharmacology
P P Lee, R L Schilsky

Abstract

The clinical formulation of leucovorin (5-CHO-FH4) is a mixture of diastereoisomers with markedly different pharmacologic properties. Comparatively little information is available concerning the cellular pharmacology of reduced folate stereoisomers, due largely to the difficulty in preparing sufficient quantities of these compounds for in vitro use. Recent improvements in HPLC technology have now facilitated this process, enabling studies of folate stereochemistry on a larger scale. Using purified (6R) and (6S) leucovorin, we examined the effects of these compounds on the enzymatic activity of Lactobacillus casei thymidylate synthase (TS) in a cell-free system. The natural (6S), unnatural (6R), and racemic (6R,S) leucovorin preparations inhibited TS activity by 50% at concentrations of 0.11, 2.1, and 0.52 mM, respectively. Dixon plots demonstrated the inhibition to be competitive, with Ki values of 85 microM, 1.59 mM, and 385 microM for (6S), (6R), and (6R,S) leucovorin, respectively. In view of the high doses of leucovorin given clinically and the slow clearance of the unnatural isomer, our observations suggest that leucovorin may have important direct inhibitory effects on folate-requiring enzymes.

References

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Citations

Mar 1, 1994·British Journal of Clinical Pharmacology·R M MaderH Rainer
Sep 30, 2004·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Katalin BartyikEszter Karg
Apr 14, 2016·Biochimie·V T RamaekersE V Quadros
Jan 1, 1994·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·R RossoG Pancera

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