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

N(4)‐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, where 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.