Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514

We studied the effects of folic acid on modulating the toxicity and antitum or efficacy of LY231514. Using several human tumor cell lines adapted to gr owth in low folate medium, folic acid was shown to be 100- to 1000-fold les s active than folinic acid at protecting cells from LY231514-induced cytoto xicity. The lethality of LY231514 was compared in mice maintained on standa rd diet or low folate diet. The LD50 occurred at 60- and 250-fold lower dos es of LY231514 in DBA/2 and CD1 nu/nu mice, respectively, maintained on low folate diet compared to standard diet. The L5178Y/TK-/HX- murine lymphoma was much more sensitive to the antitumor action of LY231514 compared to wil d type L5178Y-S tumors. For mice on low folate diet, LY231514 at 0.3 and I mg/kg (qd x 10 i.p.) produced 100% inhibition of L5178Y/TK-/HX- lymphoma gr owth, and significant lethality occurred at greater than or equal to 3 mg/k g For mice on standard diet, LY231514 produced >95% inhibition of tumor gro wth at 30 to 300 mg/kg, but all mice died at 800 mg/kg. Folic acid suppleme ntation was demonstrated to preserve the antitumor activity of LY231514 whi le reducing toxicity. The combination of folic acid with LY231514 may provi de a mechanism for enhanced clinical antitumor selectivity.