The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer

Inflammation has been implicated in the pathogenesis of many adult malignancies and is now recognised as the seventh “hallmark” of cancer. inflammatory response has been associated with a poorer response to chemotherapeutic agents and an increased risk of toxicity. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), potential chemotherapeutic drugs which may favourably manipulate the inflammatory response in CRC. emerging evidence of as much as a 40% reduction in mortality in patients undergoing curative treatment makes the concept of the use of NSAIDs as adjuvant treatment in high risk disease more compelling. present review examines the clinical evidence supporting the use of NSAIDs, statins and H2RAs in influencing the tumour microenvironment and host inflammatory response in CRC. Aspirin, NSAIDs and COX-2 inhibitors aspirin has also been found to confer a protective effect on the colorectum in patients with Lynch syndrome. 30% risk reduction with aspirin and non-aspirin NSAIDS and a potentially greater reduction with COX inhibitors. The effect is transcient over time, and greater benefit if the patient takes the pills greater than 10yrs, simularily cessation of regular use results in a return to normal population risk for subsequent CRC development. However given the extra side effect profile of adding NSAIDS into someones regime (gastic bleed), prophylactic agents in the general population is deferred until at least the optimal target population is identified. The mechanism of action of these drugs appears to increase in tumour cell apoptosis in association with a decrease in cell proliferation, angiogenesis and metastatic potential. Using COX inhibitors (aspirin) mediates (COX)-mediated synthesis of prostanoids, and in particular prostaglandin E2 (PGE2). PGE2 by COX-2, the inducible form of the enzyme has been shown to have several pro-tumour and immunosuppressant effects. Aspirin at doses that affect COX1 can also increase in platelet activation demonstrated in CRC patients, this might lead to decrease in haematogenous spread. Non Cox independent effects of NSAIDS are said to affect several molecular pathways, i.e. mTOR, PI3K, NF-KB as people with evidence of mutations in these pathways seem to do better with adminsteration of NSAIDS. Furthermore, NSAIDs have been shown to induce expression of MHC class II molecules on the surface of CRC cells, allowing an immune repsonce to occur against cancer cells and also a decrease in immunosuppressive regulatory T-lymphocytes (Treg). The level of inflammation can be measured in patients via blood tests for TNF receptor-2. Sub-analysis of a randomised trial of 5-fluorouracil and leucovorin with or without irinotecan in patients with stage III colon cancer examined the effect of aspirin and COXIBs on recurrence and survival.66 Even after controlling for treatment arm, NSAID use was associated with a 50% reduction in disease recurrence or death. ecreased synthesis of protective prostaglandins via inhibition of COX-2 has been shown to increase tumour radiosensitivity. Statins 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)- statins. results of meta-analyses suggest only a modest effect if any of statins on reducing the incidence of CRC in the general population. How do they decrease cancer? - Mevalonate, the end product of HMG-CoA reductase metabolism and its isoprenoid metabolites are required for the activation of the Ras superfamily of small GTPases by prenylation.78 In turn, these GTPases are crucial for downstream activity of several signal transduction pathways. Also they have a clear anti-inflammatory effect of statins (IL-6). Plus statin therapy has been shown to augment the activity of a number of chemotherapeutic agents, even in resistant cell lines. However most studies offer conflicting results, maybe due to there population variation in individuals and the dosing of statins used. Histamine H2 antagonists. Why? – H2RA- offer inhibition of histamine as a growth factor and inhibition of tumour-endothelial cell adhesion and motility. Furthermore, prolonged H2RA use has been shown to increase the systemic bioavailability of 5-fU. Histamine acts as an autocrine tumour growth factor and has been shown to increase CRC cell proliferation and growth + histamine has also been shown to increase expression of COX-2 and PGE2 as well as vascular endothelial growth factor in cell lines constitutively expressing COX-2. H2RAs may also reduce the metastatic potential of colorectal tumour cells by inhibition of E-selectin expression. H2RAs has been shown to restore circulating levels and activity of T-lymphocyte and NK cell subsets,116 potentially via augmentation of IL-2 and interferon activity in inflamation. Matsumoto and co-workers reported the survival analysis of a multicentre, randomised controlled trial of the effects of cimetidine on adjuvant 5-fluorouracil-induced appetite loss and oesophagitis.119 Interestingly, they found a significant increase in survival for both colonic and rectal cancers at almost 4 years. So far the role of these drugs have yet to be defined for the general population and for the ideal cancer patient in order to reap the most rewards without giving patients over treatment and extra morbidities that are related to long term use of inflammatory inhibitors. Further studies are needed ref