Effects of aspirin on 1,2-dimethylhydrazine-induced colonic carcinogenesis.

The influence of aspirin (ASA) on 1,2-dimethylhydrazine (1,2-DMH)-induced colonic carcinogenesis was examined in weanling Sprague-Dawley rats. The incidence of adenocarcinomas in response to a single dose of 1,2-DMH was reduced 60% in rats receiving ASA for 1 week before and after the carcinogen. However, ASA had no effect on tumor incidence when initiated 4 weeks after a single dose of 1,2-DMH and continuing until the animals were killed at 36 weeks. The doses of ASA employed suppressed by 95% or more ex vivo colonic prostaglandin E2 (PGE2) production and reduced colonic mucosal cAMP levels in both rats exposed to 1,2-DMH and in age-matched controls. Proliferative activity of colonic mucosa as assessed from tritiated thymidine ([3H]dThd) incorporation into mucosal DNA was increased at 1 week but suppressed by 36 weeks after 1,2-DMH exposure. ASA significantly increased colonic mucosal DNA synthesis, suppressed colonic PGE2 production and reduced mucosal cAMP levels at both 1 and 36 weeks in rats given the 1,2-DMH vehicle. However, ASA failed to alter the enhanced mucosal DNA synthesis observed at 1 week or the suppressed DNA synthesis observed at 36 weeks after a single dose of 1,2-DMH, despite significant inhibition of colonic PGE2 production and reduction in mucosal cAMP levels by ASA. Treatment of rats for 1 week with ASA significantly inhibited basal and arachidonate stimulated decomposition of the 1,2-DMH intermediary metabolite methylazoxy-methanol, assessed ex vivo in colonic mucosal homogenates. Thus, while other mechanisms are not excluded, suppression of 1,2-DMH induced colonic carcinoma by concurrent administration of ASA may be linked in part to altered metabolic activation of this carcinogen via cyclooxygenase-dependent co-oxidation. By contrast, the previously reported suppression of the promotional phase of colonic carcinogenesis in rats by the delayed introduction of cyclooxygenase inhibitors may not be linked to inhibition of local colonic prostanoid production, since (i) inhibition of colonic prostanoid synthesis by ASA did not mimic this antipromotional effect, and (ii) the doses of non-steroidal anti-inflammatory drugs employed in some earlier studies may not significantly inhibit colonic prostanoid synthesis.