The potential of NSAIDs in the treatment of oesophagealcarcinoma

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, exert a complex spectrum of harmful and beneficial effects in the gastrointestinal (GI) tract. In the stomach, the deleterious effects of NSAIDs have been well documented and include ulceration, complicated by haemorrhage, perforation and intestinal stricture. NSAIDs have also been associated with colorectal damage and the exacerbation of inflammatory colorectal disease. At the other end of the spectrum, there is a growing conviction that the regular use of NSAIDs reduces the risk of sporadic colorectal carcinoma. In recognition of this potential, a double-blind trial of aspirin and resistant starch is being conducted in familial adenomatous polyposis patients, t The biphasic properties of NSA1Ds in the GI tract are under intensive review. In the stomach, the deleterious NSAID effects appear to be related to cyclo-oxygenase (COX) inhibition thereby reducing the synthesis of protective prostaglandin E2 (PGE2) production. As a secondary effect, NSAIDs can augment the synthesis of damaging leukotrienes (LTs) by 'shunting' the PG precursor arachidonic acid (AA) into lipoxygenase metabolism. Paradoxically, it is these biochemical effects that appear to protect against colorectal carcinoma since excessive PGE2 production appears to contribute to carcinogenesis. The carcinostimulant role of PGE2 is unclear, but it may regulate the balance between colorectal mucosal proliferation and apoptosis. To complicate matters further, recent biochemical advances have demonstrated the existence of 2 COX enzymes. COX-I regulates physiological PG synthesis while COX-2 can be induced by mitogens during pathophysiological reactions. These observations have farreaching therapeutic/commercial implications since the development of COX-2 selective NSAIDs would allow the treatment of PG-related disease without the risk of adverse GI reactions. This new generation of NSAIDs may be particularly useful in colorectal cancer prevention since carcinostimulant PGE2 appears to originate from COX-2. In the oesophagus, there are also reports of harmful and beneficial NSAID effects. These reports have been reconciled- and the emerging message is that PGE2 exerts deleterious effects in oesophageal pathologies. These include pro-inflammatory, dysmotility and carcinostimulant effects. It therefore follows that NSAIDs have preventative potential in patients at risk of oesophageal carcinoma. 3 This potential deserves serious consideration since the incidence of oesophageal carcinoma has increased dramatically in recent decades. In extension of prevention, this paper illustrates the potential of NSAIDs in the treatment of established oesophageal carcinoma.