Preclinical and Clinical Evaluation of the Glycinamide Ribonucleotide Formyltransferase Inhibitors Lometrexol and LY309887

摘要: The importance of the purine de novo pathway in providing DNA precursors for cancer cell growth led to hypothesis that novel antifolate inhibitors glycinamide ribonucleotide formyltransferase (GARFT), first folate-dependent enzyme this pathway, might have utility treatment cancer. In 1987, clinical investigations were initiated with lometrexol (6R-dideazatetrahydrofolic acid, 6R-DDATHF), a “tight-binding” inhibitor GARFT potent antitumor activity number murine and human xenograft solid tumors. Unexpected observations delayed cumulative toxicity phase I trials prompted extensive preclinical dynamics folate status on efficacy other antifolates (1). addition, structure-activity studies identification second generation inhibitor, LY309887 (2´, 5´-thienyl-dideazatetrahydrofolic acid), which is more than has greater vivo (2). Biochemical pharmacological differences between respect potency inhibit GARFT, differential transport storage liver, polyglutamation suggest may manageable clinic lometrexol. A model seen been refined characterized provide understanding pharmacokinetics pharmacodynamics these events. concert recently published nutritional data humans sophisticated methods assessing modulating toxicities through vitamin supplementation, therapy be poised enter new success. report, we describe LY309887, unique biochemical properties against broad panel tumors, both as an tumor vivo. An overview results design trial will presented.