COX-2 INHIBITORS IN OESOPHAGEAL CANCER

Cox-2 inhibitors in Oesophageal Cancer

Cox-2 inhibitors in Oesophageal Cancer

Introduction

Oesophageal cancer (OC) is one of the most lethal malignancies of the gastrointestinal (GI) tract due to the typically late stage at which oesophageal tumours are diagnosed, their poor response to therapy and metastatic ability. OC incorporates two distinct histological types, squamous cell carcinoma (SCC) and adenocarcinoma (AC), which has seen a sharp rise in incidence in Europe and the US over several decades. The most significant risk factor for AC is gastroesophageal reflux disease, where chronic inflammation can lead to intestinal metaplasia known as Barretts oesophagus and a 30-125-fold increase in the risk of developing AC . Despite management advances over the last two decades, the prognosis for invasive AC is poor, with 5-year survival rates remaining well below 20%. Given the toll of this disease, a primary focus has been placed on prevention. (Conio, 2003, p187)

Current evidence from epidemiological studies suggests that long-term non-steroidal anti-inflammatory drug (NSAID) intake may reduce the risk of developing several types of cancer, including GI malignancies. This evidence is particularly striking in the case of oesophageal cancer. A recent review of eight published epidemiologic investigations found that the reduction in relative risk of oesophageal cancer approaches 73% with daily intake of an NSAID . Similar studies have demonstrated a 40-60% decrease in the relative risk of colon cancer with continuous use of NSAIDs and , and other cancers such as stomach, breast, lung and ovarian also show risk reduction with NSAID intake . NSAIDs have been shown to inhibit tumourigenesis in rodent models of GI cancer. The NSAID indomethacin has been reported to have anti-tumour effects in animal models of oesophageal cancer and , and in rat models of Barretts oesophagus, selective and non-selective COX-2 inhibitors inhibited the development of adenocarcinoma induced by reflux and SSC induced by N-nitrosomethylbenzylamine .

NSAID's target the COX enzymes, which convert arachidonic acid (AA) to prostaglandins (PG) and other eicosanoids. COX-2, the inducible isoform, is undetectable in most normal tissues but is activated in response to pro-inflammatory cytokines and growth factors. Many studies have now reported COX-2 overexpression in tumours and its association with increased cell proliferation, metastasis and decreased apoptosis. Prostaglandins are believed to play a major role in these processes because of their effects on cell proliferation, apoptosis, angiogenesis and immune surveillance (Conio, 2003, p187). COX-2 upregulation has been reported in oesophageal SCC , and AC and . PGs have also been found to be overexpressed in oesophageal tumours as a consequence of enhanced COX-2 expression and . More-over, COX-2 expression levels have been found to be elevated in Barrett's oesophagus and have been reported to increase with the progression from metaplasia to dysplasia to adenocarcinoma . A recent report has also indicated that a single nucleotide polymorphism in the COX-2 promoter can elevate COX-2 expression and is associated with a greater risk of developing oesophageal cancer .

Evidence demonstrating the overexpression of COX-2 and PG, highlighted the potential of NSAIDs as chemopreventative agents, and ...