Rat colorectal tumours treated with a range of non-steroidal anti-inflammatory drugs show altered cyclooxygenase-2 and cyclooxygenase-1 splice variant mRNA expression levels

Non-steroidal anti-inflammatory drugs (NSAIDs) reduce tumour mass by increa sing the rate of tumour cell apoptosis and decreasing cell proliferation, T he classically recognized target for NSAID action are the two isoforms of t he cyclooxygenase (COX) gene, which is responsible for prostaglandin produc tion. In the rat, the COX-1 gene expresses an alternatively spliced mRNA CO X-1 splice variant (SV) which may, at best, code for a truncated COX-1 prot ein. Previously, we reported that COX-1SV mRNA is differentially expressed in the ageing stomach, In this study, carcinogen treated rats were treated for 23 weeks with celecoxib, sulindac or sulindac sulfone, while untreated rats received vehicle alone, For each animal, the number and volume of tumo ur per animal was recorded and histology was performed, Using competitive p olymerase chain reaction, we determined whether COX gene expression was alt ered in colorectal tumours and in regions of adjacent and distant macroscop ically normal intestine, from vehicle or NSAID treated rats. In addition, w e immunolocalized COX-1 and COX-2 in the same tumour and normal colonic tis sue, Tumours from animals treated with vehicle or celecoxib expressed signi ficantly elevated levels of COX-2 mRNA in comparison with the adjacent norm al mucosa, In contrast, tumours from sulindac and sulindac sulfone treated rats expressed significantly less COX-2 mRNA than tumours from vehicle trea ted rats. The expression of COX-1 mRNA remained unchanged in all tissues ex amined. However, COX-1SV mRNA levels were elevated in colorectal tumours an d reduced after NSAID treatment to the levels observed in normal colonic mu cosa, Our results indicate that the anti-neoplastic actions of NSAIDs may b e attributed to COX dependent and/or COX independent mechanisms of action, We also demonstrate the presence and differential expression of COX-1SV mRN A in colon tumours, COX-1SV mRNA represents 2% of the total COX-1 mRNA expr essed and its role in colon cancer remains to be established.