ABSTRACT
Title
The presence of two specific SNP may reduce mesalazine efficacy. Future prospects for the clinical management of IBD patients
Authors
V. Perrone1, E. Moroni2, P. Danelli2, C. Perrotta1, C. Carnovale1, R. Colognato1, G. Milani1, E. Clementi1,3, S. Radice1 and S. Antoniazzi1
1 Unit of Clinical Pharmacology, Dept. of Clinical Sciences, University Hospital “Luigi Sacco”; Univ. of Milan, 2 Unit of Surgery, Dept. of Clinical Sciences, Univ. Hospital “Luigi Sacco”,Univ. of Milan; 3 E. Medea Scientific Institute, Bosisio Parini, Lecco, Italy
1 Unit of Clinical Pharmacology, Dept. of Clinical Sciences, University Hospital “Luigi Sacco”; Univ. of Milan, 2 Unit of Surgery, Dept. of Clinical Sciences, Univ. Hospital “Luigi Sacco”,Univ. of Milan; 3 E. Medea Scientific Institute, Bosisio Parini, Lecco, Italy
Abstract
Colorectal cancer (CRC) is a serious complication of inflammatory bowel diseases (IBD) mainly Crohn’s disease (CD) and ulcerative colitis (UC). Mucosal inflammation is belived to be the driving force for neoplastic transformation, and risk is related to the duration, extent and severity of IBD. In these patients, the risk is directly related to the extent of the disease and the time course and severity of perianal involvement. Some studies largely disagree with these general conclusions, although it is true that these are only a few and are based on small sample sizes.
We report the case of two patients with longstanding Crohn’s disease and multiple complications that, after receiving treatment with mesalazine, werevdiagnosed with CRC that required radical surgery.
Mesalazine, a drug widely used as therapy in IBD, is structurally related to NSAIDs but it appears to be safer and free of serious adverse effects. Moreover, both the American and British National Gastroenterology Associations recommend the use of high doses of mesalazine for the first line treatment of mild ileal, ileocolonic or colonic CD. Indeed, the benefit of this drug in the primary prevention of dysplasia and CRC has been established and generally accepted despite the lack of double blind randomized studies. Mesalazine is useful in controlling active inflammation, maintaining remission and for chemioprevention. The mechanisms behind the antineoplastic effect of mesalazine are incompletely understood, but it is likely that they are mostly dependent on the ability of the drug to attenuate ongoing mucosal inflammation. Indeed, it is well known that mesalazine can modulate various inflammatory pathways (e.g. production of inflammatory cytokines, activity of inducible nitric oxide synthase, activation of nuclear factor-kB) that are relevant to CRC initiation and progression. There is also evidence that mesalazine inhibits the formation of reactive oxygen species (ROS) from polymorphonuclear leukocytes, which leads to a decrease or complete inhibition of DNA damage, a phenomenon that has been involved in colon carcinogenesis. More recently, it has also been shown that mesalazine can directly target CRC cells and interfere with biological pathways that control their growth and survival. COX-2 is a major target of CRC chemopreventive programs, as it is highly expressed in both sporadic and familial CRC, and activation of COX-2 is known to trigger and/or amplify biological pathways that sustain CRC growth. COX-2 is also over-expressed in IBD-related CRC tissue. Since mesalazine inhibits COX-2 in inflammatory cells, it is hypothesized that the antineoplastic effect of this drug is strictly dependent on the inhibition of COX-2 in CRC cells.
To our knowledge two COX-2SNPs, PTGS2103354G>A (rs 689469) and PTGS29850A/G (rs 4648298) are closely realted to increased the risk of developing CRC.
These evidence prompted us to evaluate whether mesalazine could be ineffective due to the presence of one of these SNPs in COX2. The absence in the patients of SNPs in enzymatic pathways dependent on mesalazine and related to the development of CRC such as PPARγ, c-myc, CDC25A, NF-kB- EGFR, SH-PTP2, further confirm this hypotheis.
This study is still in progress; the identification of these specific COX2 SNPs may be a marker for monitoring therapeutic effectiveness of mesalazine and for better patient of Crohn’s disease management.
We report the case of two patients with longstanding Crohn’s disease and multiple complications that, after receiving treatment with mesalazine, werevdiagnosed with CRC that required radical surgery.
Mesalazine, a drug widely used as therapy in IBD, is structurally related to NSAIDs but it appears to be safer and free of serious adverse effects. Moreover, both the American and British National Gastroenterology Associations recommend the use of high doses of mesalazine for the first line treatment of mild ileal, ileocolonic or colonic CD. Indeed, the benefit of this drug in the primary prevention of dysplasia and CRC has been established and generally accepted despite the lack of double blind randomized studies. Mesalazine is useful in controlling active inflammation, maintaining remission and for chemioprevention. The mechanisms behind the antineoplastic effect of mesalazine are incompletely understood, but it is likely that they are mostly dependent on the ability of the drug to attenuate ongoing mucosal inflammation. Indeed, it is well known that mesalazine can modulate various inflammatory pathways (e.g. production of inflammatory cytokines, activity of inducible nitric oxide synthase, activation of nuclear factor-kB) that are relevant to CRC initiation and progression. There is also evidence that mesalazine inhibits the formation of reactive oxygen species (ROS) from polymorphonuclear leukocytes, which leads to a decrease or complete inhibition of DNA damage, a phenomenon that has been involved in colon carcinogenesis. More recently, it has also been shown that mesalazine can directly target CRC cells and interfere with biological pathways that control their growth and survival. COX-2 is a major target of CRC chemopreventive programs, as it is highly expressed in both sporadic and familial CRC, and activation of COX-2 is known to trigger and/or amplify biological pathways that sustain CRC growth. COX-2 is also over-expressed in IBD-related CRC tissue. Since mesalazine inhibits COX-2 in inflammatory cells, it is hypothesized that the antineoplastic effect of this drug is strictly dependent on the inhibition of COX-2 in CRC cells.
To our knowledge two COX-2SNPs, PTGS2103354G>A (rs 689469) and PTGS29850A/G (rs 4648298) are closely realted to increased the risk of developing CRC.
These evidence prompted us to evaluate whether mesalazine could be ineffective due to the presence of one of these SNPs in COX2. The absence in the patients of SNPs in enzymatic pathways dependent on mesalazine and related to the development of CRC such as PPARγ, c-myc, CDC25A, NF-kB- EGFR, SH-PTP2, further confirm this hypotheis.
This study is still in progress; the identification of these specific COX2 SNPs may be a marker for monitoring therapeutic effectiveness of mesalazine and for better patient of Crohn’s disease management.