CYCLOOXYGENASE-INDEPENDENT CHEMOPREVENTION WITH AN ASPIRIN DERIVATIVEIN A RAT MODEL OF COLONIC ADENOCARCINOMA

Aspirin decreases the risk of colorectal cancer, reportedly through su ppression of cyclooxygenase (COX) activity. Using a rat model of colon ic adenocarcinoma, we compared the chemopreventative effects of aspiri n versus a nitric oxide-releasing derivative (NCX-4016) which does not inhibit COX. Beginning six weeks after intracolonic administration of trinitrobenzene sulfonic acid, the rats were given azoxymethane weekl y (15 mg/kg i.p.) for 4 weeks. Over the same 4-week period, the rats w ere treated daily with vehicle, aspirin (10 mg/kg) or NCX-4016 (equimo lar dose). Six weeks later, the number of aberrant crypt foci (an earl y preneoplastic lesion) were blindly counted by light microscopy. Effe cts of aspirin vs. NCX-4016 on COX-1 and COX-2 activity were compared, as was their analgesic activity Rats receiving vehicle developed a me an of 856 +/- 260 aberrant crypt foci in the colon. Aspirin reduced th e number of aberrant crypt foci by 64%, while NCX-4016 produced an 85% reduction. Aspirin, but not NCX-4016, markedly suppressed systemic CO X-1 and COX-2 activity, and colonic prostaglandin synthesis. Despite n ot inhibiting COX, NCX-4016 exhibited comparable analgesic activity to aspirin. These results demonstrate that NCX-4016, a nitric oxide-rele asing aspirin derivative, exhibited superior chemopreventative effects to aspirin in this model of colon cancer. This effect occurred indepe ndent of inhibition of COX-1 or COX-2. (C) 1998 Elsevier Science Inc.