INHIBITION BY URIDINE BUT NOT THYMIDINE OF P53-DEPENDENT INTESTINAL APOPTOSIS INITIATED BY 5-FLUOROURACIL - EVIDENCE FOR THE INVOLVEMENT OFRNA PERTURBATION

The epithelia from the crypts of the intestine are exquisitely sensiti ve to metabolic perturbation and undergo cell death with the classical morphology of apoptosis. Administration of 40 mg/kg 5-fluorouracil (5 -FU) to BDF-1 p53+/+ mice resulted in an increase in p53 protein at ce ll positions in the crypts that were also those subjected to an apopto tic cell death. In p53-/- mice apoptosis was almost completely absent, even after 24 hr, 5-FU is a pyrimidine antimetabolite cytotoxin with multiple mechanisms of action, including inhibition of thymidylate syn thase (TS), which gives rise to DNA damage, and incorporation into RNA . The inhibition of TS can be increased by coadministration of folinic acid and can be abrogated by administration of thymidine. The incorpo ration of 5-FU into RNA is inhibited by administration of uridine. p53 -Dependent cell death induced by 5-FU was only inhibited by administra tion of uridine, Uridine had no effect on the apoptosis initiated by 1 Gy of gamma-radiation. Although thymidine abrogated apoptosis induced by the pure TS inhibitor Tomudex, it had no effect on 5-FU-induced ap optosis, and coadministration of folinic acid did not increase apoptos is, The data show that 5-FU-induced cell death of intestinal epithelia l cells is p53-dependent and suggests that changes in RNA metabolism i nitiate events culminating in the expression of p53.