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Schedule-dependent Enhancement of the Cytotoxicity of Fluoropyrimidines to Human Carcinoma Cells in the Presence of Folinic Acid¹

Departments of Biochemistry, Pediatrics, and Molecular Pharmacology, and the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033

Previous studies from this laboratory indicated that the cytotoxic effects of the fluoropyrimidines on mouse leukemic cells are substantially augmented by folinic acid but that these effects are underestimated in growth inhibition experiments. These results have now been extended to two human tumor cell lines, the WiDr colorectal and T-24 bladder carcinoma cells. In both cell lines, the presence of folinic acid in the medium substantially enhanced the cytotoxicity of a 72-h exposure to either 5-fluorouracil (FUra) or 5-fluoro-2'-deoxyuridine. Folinic acid concentration-response curves for enhancement of the cytotoxicity of FUra to WiDr cells were broad but indicated that response was not maximal until at least 10 µM. Likewise, increased length of exposure to 10 µM folinic acid continuously enhanced the cytotoxicity of a 72-h treatment with FUra, but substantial enhancement was observed even after a 2-h exposure to folinate, and there was a diminished increment of cytotoxicity after 24-h exposure to folinic acid. Surprisingly, folinic acid augmentation of the cytotoxicity of a brief exposure to FUra (4 h) was minimal but enhancement of FUra cytotoxicity became much more pronounced with intervals of exposure to FUra of 24 h. If these results can be mimicked in vivo without undue host toxicity, our experiments suggest that a substantial improvement in the therapeutic activity of FUra plus folinate would result from prolonged exposure to both agents.

¹ This work was supported in part by USPHS Grant CA 36054 from the National Cancer Institute.

² Scholar of the Leukemia Society of America. Funds for this award were supplied by the Scott Helping Hand Fund. To whom requests for reprints should be addressed, at University of Southern California Cancer Center, 1303 N. Mission Road, Los Angeles, CA 90033.

Received 4/24/91. Accepted 6/25/91.

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