Nitric Oxide-releasing Medications and Colorectal Cancer Risk: The Framingham Study

Background: The major sources of human exposure to nitric oxide (NO) are medicinal nitrovasodilators that release NO into the vasculature. Experimental NO- donating aspirin also releases NO in a similar manner, and is a potent in vitro inhibitor of colon cancer. Materials and Methods: The effects of nitrovasodilators on the risk of colorectal cancer was studied in the Framingham Heart and Offspring studies among 145 cases of colorectal cancer and 433 matched controls. Results: Eleven percent of controls reported currently using nitroglycerine or other long-lasting nitrates. In conditional logistic regression analysis, the odds ratio (OR) for colorectal cancer associated with nitrovasodilator use was 1.2 (95% confidence interval (CI) 0.6, 2.2). In subgroup analysis, the OR was 0.7 (95% CI 0.2, 2.2) in aspirin users and 1.6 (95% CI 0.8, 3.2) in subjects not taking aspirin. Conclusion: These data indicate that NO does not change the risk of colorectal cancer. Nitric oxide (NO) is a small biologically active molecule, whose production is determined by the expression of inducible nitric oxide synthase (iNOS or NOS2). The increase of NO biosynthesis in colonic tumor cells (1) is associated with cancer promotion and metastasis via increased oxidative DNA damage, cellular proliferation, angiogenesis and tumor growth (2). NOS2 activity is correlated with p53 mutations, and the generation of NO in "bursts" can reach local genotoxic concentrations. In addition, NOS2 inhibitors reduce the incidence of colon cancer incidence in laboratory rats, further indicating that NO promotes colon carcinogenesis (3). Paradoxically, NO can also inhibit colon carcinogenesis and induce apopotosis in tumor cells. Its effects appear to depend upon local conditions such as the level of expression of NOS2 and the differential sensitivity of tumor cells to NO-mediated actions (4). The major endogeneous sources of human exposure to nitric oxide are nitrovasodilators, which include nitroglycerine (glycerol trinitrate), amyl nitrite, isosorbide mono- and di- nitrate, erythrityl tetranitrate and sodium nitroprusside. These medications are taken sublingually, orally or subcutaneously to treat angina pectoris and other manifestations of coronary artery disease. Nitroglycerine has been used effectively for over 100 years, and the other organic medicinal nitrates have been available since the 1930s. All routes of administration release