Abstract
The mechanisms of apoptosis induction and mitotic inhibition in the intestinal epithelium were investigated in male BDF1 mice treated with a single oral dose of 5-fluorouracil (5-FU). We measured the concentrations of 5-FU in the plasma and intestinal tissues and followed the detailed incidental time courses of both apoptotic index (AI) and mitotic index (MI) in the five intestinal compartments. Although the plasma concentration of 5-FU decreased to a value lower than the minimal effective concentration (MEC) within 8 hr after administration, the intestinal tissue concentrations remained remarkably higher than the MEC until 48 hr. 5-FU induced an increases of AI and decrease of MI for more than 48 hr with time courses that differed among the intestinal compartments. We also determined the AI and MI after administration of two 5-FU derivatives, 5'-DFUR and Capecitabine. The derivatives were administered orally at the equivalent dose of 5-FU; nevertheless the observed changes of AI and MI were far less significant than those for 5-FU. This finding may reflect the number of enzymatic activation steps each compound undergoes and explain why the toxicities of the 5-FU derivatives in the intestinal epithelium are less than that of 5-FU itself. The present study suggests that the prolonged effect of 5-FU would be due to retention of 5-FU within the intestinal epithelium, and that the different time courses for AI and MI in each intestinal compartment would depend on the stage that the cell-cycle was in when 5-FU uptake occurred.
