Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung

Abstract

The existing epidemiologic literature was comprehensively reviewed to retrieve all epidemiologic studies (case control and cohort studies) that examined exposure to traditional over the counter nonsteroidal anti-inflammatory drugs (OTC NSAIDs) and the risk of cancers of the colon, breast, prostate and lung from 1980 forward. These malignancies account for more that half of all cancer deaths in the United States and the United Kingdom. Estimates of effects (relative risks or odds ratios) and 95% confidence intervals were abstracted from these reports for meta-analysis. Regular intake of OTC NSAIDs produced highly significant composite risk reductions of 43% for colon cancer, 25% for breast cancer, 28% for lung cancer, and 27% for prostate cancer. Furthermore, in a series of case control studies, daily use of a selective COX-2 inhibitor, either celecoxib or rofecoxib, significantly reduced the risk for each of these malignancies. The evidence is compelling that anti-inflammatory agents with selective or non-selective activity against cycloooxygenase- 2 (COX-2) have strong potential for the chemoprevention of cancers of the colon, breast, prostate and lung. Results confirming that COX-2 blockade is effective for cancer prevention have been tempered by observations that some selective COX-2 inhibitors pose a risk to the cardiovascular system. Nevertheless, meta-analysis of independent estimates from 72 studies provides no evidence that the selective COX-2 inhibitor, celecoxib, influences the relative risk of cardiovascular disease (composite relative risk = 0.98, 95% CI = 0.88-1.10). Molecular studies reveal that over-expression of COX-2 is a prominent feature of premalignant and malignant neoplasms. Evidence is accumulating that carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of COX-2 and the prostaglandin cascade in the "inflammogenesis of cancer".

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

“…11,53 As a result of documented cardiovascular side effects of COX-2 inhibitors, 25,26,54 alternative and safer therapies as single agent or in combination (as adjuvant) need to be tested in preclinical models. Based on our earlier data on the role of EP4 in multiple cellular events promoting breast cancer progression, our present preclinical data, and the fact that EP4 may have some redundancy for physiological functions shared with EP2, we suggest that EP4 may prove to be a safe target in the clinic for preventing and mitigating lymphatic metastasis of breast cancer in combination with other agents.…”

Alterations of Cyclooxygenase-2 Methylation Levels Before and After Intervention Trial to Prevent Gastric Cancer in a Chinese Population

“…Our current study revealed that COX-2 methylation was decreased in H. pylori-positive subjects after two-year lowdose (200 mg twice daily) intake of celecoxib. Although the mechanism of COX-2 methylation reduction by celecoxib still remains unclear, it may primarily involve the down-regulation of inflammatory reaction by direct COX-2 activity inhibition and the subsequent reduction of catalyzed prostaglandins or cytokines even in subjects with H. pylori remained in the gastric epithelial (36). A more significant decreasing trend of COX-2 methylation by celecoxib in chronic atrophic gastritis rather than in intestinal metaplasia might be resulted from the more significant prevalence of chronic inflammation in chronic atrophic gastritis than in intestinal metaplasia lesions.…”

Fatty Acids in Veterinary Medicine and Research

“…Many diseases involve inlammatory responses either as a reaction to disease or in the initiation of the disease process; although inlammation itself is not always detrimental, for instance, it is an important aspect of wound repair [11][12][13][14]. Elevated markers of inlammation are frequently detected in heart failure and cancers although this could be due to the response to disease, or the underlying cause of disease [15][16][17][18][19].…”