Cyclooxygenase-2: A Molecular Target For Chemoprevention Of Epithelial Tumors Of Skin And Colon

Abstract

Numerous epidemiological studies have found a reduced risk to develop colorectal cancer of persons with a regular intake of aspirin or other non-steroidal antiinflammatory drugs (NSAIDs). Clinical trials with NSAIDs in patients suffering from Familial Adenomatous Poliposis Coli (FAP) due to a germline mutation in the APC-tumor suppressor gene have clearly shown a regression of already existing colorectal adenomas`. Furthermore, animal models of colon and skin cancer have demonstrated a reduction in tumor multiplicity and incidence by a continuous application of NSAIDs, such as aspirin, sulindac³indomethacin⁴piroxicam⁵SC-58125⁶Celecoxib’, (and our own unpublished observation), and MF-tricyclic⁸. Experimental colon carcinogenesis was studied in the azoxymethane-treated rat and in Min mice, which carry a heterozygous germline deletion in the APC-gene and spontaneously develop adenomas throughout the intestinal tract. Squamous cell carcinogenesis has been studied predominantly in mouse skin. Here, tumorigenesis is initiated by a single mutation of the cellular Ha-ras gene, induced by exposure to a low dose of the carcinogen dimethyl-7,12-benz(a)anthracene. Initiated epidermal keratinocytes grow into macroscopically visible tumors only upon repeated treatment with tumor promoters such as the phorbolester TPA. Most of the papillomas regress, but some of them progress into carcinomas in the absence of any further treatment.