Comparative Antitumor Activity and Intestinal Toxicity of 5′-Deoxy-5-fluorouridine and Its Prodrug Trimethoxybenzoyl-5′-deoxy-5-fluorocytidine

Abstract

N4-trimethoxybenzoyl-5''-deoxy-5-fluorocytidine (Ro 09-1390), a prodrug of the cytostatic 5''-deoxy-5-fluorouridine (5''DFUR), was synthesized with the aim of reducing of the dose-limiting toxicity of 5''-DFUR, which is diarrhea. In mice bearing Lewis lung carcinoma, 5''-DFUR given po produced a substantial amount of 5-fluorouracil (5-FU) in the intestinal tract as well as in tumors, were the enzyme pyrimidine nucleoside phosphorylase, essential for conversion of 5''-DFUR to 5-FU, is predominantly located. With the oral administration of Ro 09-1390 only a small amount of 5-FU was formed in the intestine; however, the administration of Ro 09-1390 and 5''-DFUR at the same dose produced similar amounts of 5-FU in tumor tissues. These differences in metabolism were reflected in their toxicity and antitumor efficacy. The administration of 5''-DFUR resulted in damage to the intestinal mucosal membrane and diarrhea in normal mice, whereas Ro 09-1390 was much less toxic to the intestinal tract. As regards antitumor activity, Ro 09-1390 and 5''-DFUR at equivalent doses inhibited the growth of Lewis lung carcinoma to similar extents. Since Ro 09-1390 was much less toxic to the intestinal tract than 5''-DFUR, mice bearing Lewis lung carcinoma could be given Ro 09-1390 daily over a longer period and at a higher dose, resulting in a longer survival time.