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Augmentation of the Therapeutic Activity of Lometrexol [(6-R)5,10-Dideazatetrahydrofolate] by Oral Folic Acid¹

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285 [T. A., J. F. W., C. S., J. R. B., G. B. G.]; Department of Radiology, Wishard Memorial Hospital, Indianapolis, Indiana 46202 [S. L.]; and Department of Pharmacology and Toxicology and the Massey Cancer Center, Medical College of Virginia, Richmond, Virginia 23298 [R. G. M.]

Recent clinical trials with lometrexol [(6R)-5,10-dideazatetrahydrofolate] have revealed a level of toxicity in humans that was not predicted on the basis of previous in vivo preclinical studies. Because standard laboratory animal diets contain high levels of folic acid relative to human folate intake, the toxicity and therapeutic activity of lometrexol was studied in mice under conditions of restricted dietary folate intake. Remarkably, the lethality of this drug increased by three orders of magnitude in mildly folate-deficient mice, mimicking the unexpected toxicity seen in humans. Lometrexol had limited therapeutic activity in folate-deficient mice bearing the C3H mammary adenocarcinoma, compared with the substantial therapeutic index for treatment of this tumor in animals on standard diet. When folic acid was administered p.o. to mice that were mildly folate deficient, antitumor activity was again observed at nontoxic doses of lometrexol, and the range of lometrexol doses that allowed safe therapeutic use of this drug increased at higher dietary folate intake. At a fixed dose of lometrexol, the antitumor effects in animals were dependent on the level of dietary folate and went through a distinct optimum. Excessively high folate intake reversed the antitumor effects of lometrexol. Optimization of the folic acid content in the diet and of the lometrexol dosage are predicted to have substantial impact on the clinical activity of this class of drugs.

¹ Supported in part by NIH Grant CA 27605 (to R. G. M.).

² To whom requests for reprints should be addressed, at Lilly Research Laboratories, Lilly Corporate Center, 307 East McCarty Street, Indianapolis, IN 46285-0540.

³ Deceased November 16, 1993.

Received 10/24/95. Accepted 3/14/96.

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