Cyclooxygenase-independent chemoprevention with an aspirin derivative in a rat model of colonic adenocarcinoma.
Aspirin decreases the risk of colorectal cancer, reportedly through suppression of cyclooxygenase (COX) activity. Using a rat model of colonic adenocarcinoma, we compared the chemopreventative effects of aspirin 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 weekly (15 mg/kg i.p.) for 4 weeks. Over the same 4-week period, the rats were treated daily with vehicle, aspirin (10 mg/kg) or NCX-4016 (equimolar dose). Six weeks later, the number of aberrant crypt foci (an early preneoplastic lesion) were blindly counted by light microscopy. Effects of aspirin vs. NCX-4016 on COX-1 and COX-2 activity were compared, as was their analgesic activity. Rats receiving vehicle developed a mean of 856 +/- 260 aberrant crypt foci in the colon. Aspirin reduced the number of aberrant crypt foci by 64%, while NCX-4016 produced an 85% reduction. Aspirin, but not NCX-4016, markedly suppressed systemic COX-1 and COX-2 activity, and colonic prostaglandin synthesis. Despite not inhibiting COX, NCX-4016 exhibited comparable analgesic activity to aspirin. These results demonstrate that NCX-4016, a nitric oxide-releasing aspirin derivative, exhibited superior chemopreventative effects to aspirin in this model of colon cancer. This effect occurred independent of inhibition of COX-1 or COX-2.
Bak
A W
AW
Intestinal Disease Research Unit, University of Calgary, Alberta, Canada.
McKnight
W
W
Li
P
P
Del Soldato
P
P
Calignano
A
A
Cirino
G
G
Wallace
J L
JL
D000230:Adenocarcinoma / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001397:Azoxymethane; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D014302:Trinitrobenzenesulfonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat; C102148:nitroaspirin; D015232:Dinoprostone; D001397:Azoxymethane; D001241:Aspirin