Mechanism of induction of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2'-deoxyuridine.

作者：Janet A. Houghton, Peter John Houghton, Robert S. Wooten · 发表于：PubMed · 年份：1979 · 被引用次数：142 · 研究领域：Colorectal Cancer Treatments and Studies、Gastric Cancer Management and Outcomes、Cancer therapeutics and mechanisms

Abstract This study was designed to determine the mechanism by which three fluorinated pyrimidines induce gastrointestinal toxicity in the mouse. Two mechanisms were considered: ( a ) incorporation of the fluorinated analog into RNA; and ( b ) inhibition of the biosynthesis of thymidine 5′-monophosphate de novo through conversion of the administered agent to 5-fluoro-2′-deoxyuridine monophosphate (FdUMP). After a single administration, the 50% lethal dose levels for 5-fluorouridine (FUrd), 5-fluorouracil (FUra), and 5-fluoro-2′-deoxyuridine (FdUrd) were approximately 160, 260, and 1400 mg/kg (0.61, 2.0, and 5.7 mmol/kg), respectively. Dose levels of FdUrd that blocked the incorporation of [ 3 H]deoxyuridine into DNA did not inhibit the incorporation of either [ 3 H]deoxyguanosine or [ 3 H]thymidine ([ 3 H]dThd) into gastrointestinal tissues. The inhibition- versus -dose curves for the utilization of [ 3 H]deoxyguanosine and [ 3 H]dThd are similar after treatment with FdUrd. Utilization of [ 3 H]dThd is depressed by FUrd, FUra, and FdUrd in a dose-dependent manner in stomach, duodenum, ileum, and colorectal tissue; at equimolar doses, the order of inhibition is FUrd > FUra > FdUrd. Incorporation of [6- 3 H]FUrd, [6- 3 H]FUra, and [6- 3 H]FdUrd into RNA is dose related and at equimolar doses is greatest after FUrd and least after FdUrd. The relationship between the specific activities of RNA for each drug in any tissue changes with dose. A relationship between the incorporation...