Abstracts
2000 Digestive Disease Week

# 2232 Pyrrolidinedithiocarbamate Enhances the p53 Independent Apoptosis Induced by 5-FU.
Simon P. Bach, Sarah T. O’Dwyer, Christopher S. Potten, Alastair Jm Watson, Liverpool, United Kingdom, Manchester, United Kingdom

Background: The antioxidant pyrrolidinedithiocarbamate (PDTC) modulates 5-fluorouracil (5-FU) activity in human colorectal cancer (CRC) xenografts via p53 independent pathways. PDTC also reduces intestinal toxicity of 5-FU by impairing acute p53 dependent apoptosis. The effect of PDTC/5-FU was studied in the intestinal crypts of a p53 -/- transgenic mice. Methods: 5-FU was administered in a dose of 40 or 200 mg/kg to p53 -/- transgenic mice alone or in conjunction with PDTC (250 mg/kg). Groups (n=5) were culled at regular timepoints up to 72 hours. Apoptosis and mitosis were identified by morphological analysis (validated by TUNEL)in 50 half crypt sections per mouse on a cell positional basis. For comparison p53 +/+ mice were treated with 5-FU 40mg/kg ± PDTC. Results: PDTC augments late apoptosis induced by 5-FU in p53 -/- small intestine.In addition early (p53 dependent)but not late (p53 independent) apoptosis was reduced in +/+ mice. No apoptosis occurred in the colonic crypts. Mitosis was also abolished following 5-FU therapy. Recovery occurred sooner with 40 compared to 400mg/kg 5-FU. The addition of PDTC had no effect on this parameter. Conclusion: PDTC promoted p53 independent apoptosis in -/- small intestinal but not colonic crypts and consistent with this finding, suppressed early but not late apoptosis in the +/+ small intestine. PDTC/5-FU can therefore augment existing p53 -/- apoptotic pathways.