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

Abstract

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