AUGMENTATION OF THE THERAPEUTIC ACTIVITY OF LOMETREXOL [(6-R)5,10-DIDEAZATETRAHYDROFOLATE] BY ORAL FOLIC-ACID

Recent clinical trials with lometrexol [(6R)-5,10-dideazatetrahydrofol ate] have revealed a level of toxicity in humans that was not predicte d on the basis of previous in vivo preclinical studies, Because standa rd laboratory animal diets contain high levels of folic acid relative to human folate intake, the toxicity and therapeutic activity of lomet rexol was studied in mice under conditions of restricted dietary folat e intake, Remarkably, the lethality of this drug increased by three or ders of magnitude in mildly folate-deficient mice, mimicking the unexp ected toxicity seen in humans, Lometrexol had limited therapeutic acti vity 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 a gain observed at nontoxic doses of lometrexol, and the range of lometr exol doses that allowed safe therapeutic use of this drug increased at higher dietary folate intake, At a fixed dose of lometrexol, the anti tumor effects in animals were dependent on the level of dietary folate and went through a distinct optimum, Excessively high folate intake r eversed the antitumor effects of lometrexol. Optimization of the folic acid content in the diet and of the lometrexol dosage are predicted t o have substantial impact on the clinical activity of this class of dr ugs.