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 antitumor efficacy of LY231514. Using several human tumor cell lines adapted to growth in low folate medium, folic acid was shown to be 100- to 1000-fold less active than folinic acid at protecting cells from LY231514-induced cytotoxicity. The lethality of LY231514 was compared in mice maintained on standard diet or low folate diet. The LD50 occurred at 60- and 250-fold lower doses 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 wild type L5178Y-S tumors. For mice on low folate diet, LY231514 at 0.3 and 1 mg/kg (qd x 10, i.p.) produced 100% inhibition of L5178Y/TK-/HX-lymphoma growth, and significant lethality occurred at > or = 3 mg/kg. For mice on standard diet, LY231514 produced > 95% inhibition of tumor growth at 30 to 300 mg/kg, but all mice died at 800 mg/kg. Folic acid supplementation was demonstrated to preserve the antitumor activity of LY231514 while reducing toxicity. The combination of folic acid with LY231514 may provide a mechanism for enhanced clinical antitumor selectivity.
Worzalla
J F
JF
Cancer Research Division, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285, USA.
Shih
C
C
Schultz
R M
RM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005494:Folic Acid Deficiency; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007928:Lethal Dose 50; D007940:Leukemia L5178 / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D000068437:Pemetrexed; D013940:Thymidylate Synthase / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid; D013940:Thymidylate Synthase