M1947 Combinational Chemoprevention Using Low Dose Aspirin and Urso in Barrett's Mucosa

Abstract

INTRODUCTION: Combinational chemoprevention, whereby synergism can be achieved between two agents, represents an important development in the field of cancer prevention. Epidemiological studies on the development of esophageal adenocarcinoma suggest a positive association with reflux & a negative association with NSAIDs. We & others have reported the chemopreventive potential of NSAIDs. We also found that Urso, which can modify bile salt composition, possesses chemopreventive potential in-vitro. Our AIM was to examine the chemopreventive potential of low-dose Aspirin in combination with Urso. METHODS: Sprague-Dawley rats (n=100) were operated to induce gastroduodenal reflux into esophagus. 86 surviving rats were randomized to a diet containing 1% Urso (n=19), 0.3% Aspirin (n= 19), 1% Urso+0.15% Aspirin (n=19) or control diet (n=29) for 8 months. Rate of esophageal cancer, mucosal injury score & the rate of Barrett's esophagus was determined. Snapfrozen Barrett's tissue was analyzed for COX-2 expression & PGE2 levels. RESULTS: The combination treatment using Urso & low-dose Aspirin significantly reduced the rate of esophageal carcinoma (5/19=26%) compared to control (18/29=62% p<0.05). The use of combinational chemoprevention resulted in a relative cancer risk reduction of 58% (95% CI 45-69%) & number needed to treat was 3. The combinational treatment also reduced the PGE2 levels compared to control(132±24 vs 40±10pg/mg, p=0.002) . There was also a reduction in COX-2 expression in animals that received combinational treatment. Urso or Aspirin treatments alone were not associated with significant reduction in the risk of esophageal cancer. To our surprise, Urso alone increased the COX-2 expression, which may partly explain why Urso alone failed to decrease the risk of esophageal cancer, but was effective in reducing the cancer in combination with aspirin, which is a non-specific COX2 inhibitor. Additional mechanistic studies are underway. CONCLUSIONS: A combinational treatment with Urso & low-dose Aspirin appears to be a successful strategy to prevent the development of esophageal adenocarcinoma in animals. The cancer risk reduction with combinational therapy was associated with down-regulation of PGE2 synthesis pathway. Even though Urso is known to reduce the concentration of carcinogenic bile salts, the beneficial effects of this change were likely negated by increased PGE2 synthesis by Urso. One possible mechanism for the effectiveness of Urso & Aspirin combination was that the beneficial effects of Urso on bile salt modification were likely retained & its untoward effects were counteracted by Aspirin. A human study will be a reasonable approach.