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1 Korean J Gastroenterol Vol. 63 No. 1, pissn eissn REVIEW ARTICLE 염증성장질환에서대장암의약물적예방 한승희, 이종훈 동아대학교의과대학내과학교실 Chemoprevention of Colorectal Cancer in Inflammatory Bowel Disease Sung-hee Han and Jonghun Lee Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea The risk of developing colorectal cancer is increased in patients with inflammatory bowel disease. Surveillance colonoscopy has not been shown to prolong survival and rates of interval cancer are reported to be high. Continuing colonic inflammation has been shown to be important in the development of colorectal cancer and therefore anti-inflammatory agents such as the 5-aminosalicylates and immunomodulators have been considered as potential chemopreventive agents. This review focuses on various chemopreventive agents that have been clearly shown to reduce the risk of colorectal adenoma and cancer in the patients with inflammatory bowel disease. (Korean J Gastroenterol 2014;63:3-10) Key Words: Chemoprevention; Inflammatory bowel diseases; Colorectal neoplasms 서론 염증성장질환은임상적으로크게궤양성대장염 (ulcerative colitis) 과크론병 (Crohn s disease) 으로분류되며, 이는만성적염증질환으로유전적감수성과장내세균의자극이원인인것으로알려져있다. 1 최근한국을포함한아시아에서발표된연구에의하면염증성장질환은 1980년대중반이래로급격하게증가하고있으며, 100,000명당궤양성대장염은 1968년에 0.34명이던것이 2008년 5.4명으로, 크론병은 0.05명에서 5.1 명으로크게늘었다. 2 염증성장질환은가족성용종증 (familial adenomatous polyposis) 및유전성비용종증대장암 (hereditary non-polyposis colorectal cancer) 과더불어대장암발생의 3대고위험군으로알려져있으며, 일반인구에비해 2배에서 11배까지대장암의발생위험이높다고보고된다. 3 유병기간이길어질수록대장암의발생률이높아진다고생각할때우리나라도염증성장질환의증가에따른대장암의증가가예 상되므로이의예방이중요해지고있다. 이를위해 American Gastroenterological Association (AGA) 와 British Society of Gastroenterology (BSG) 에서발표한바에따르면, AGA에서는병변의범위에따라 1년에서 3년, BSG에서는위험도를분류하여 1년에서 5년간격으로대장내시경의시행을권유하였고, 4,5 원발경화성담관염 (primary sclerosing cholangitis) 이동반된경우에는 AGA와 BSG에서동일하게 1년간격을권유하였다. 하지만대장내시경의전처치와대장내시경자체의거부감으로인해유병기간동안주기적인대장내시경검사가지속적으로시행되기힘들고, 중간암 (interval cancer) 은더욱늘고있는추세로보고되었다. 6 이러한대장내시경의한계로인해약제를사용한대장암의예방이더욱중요시되고있다. 이번종설에서는현재까지밝혀진염증성장질환에서대장암의약물적예방에대한이해를넓히는데도움이되고자한다. CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 이종훈, , 부산시서구대신공원로 32, 동아대학교의과대학내과학교실 Correspondence to: Jonghun Lee, Department of Internal Medicine, Dong-A University College of Medicine, 32 Daesingongwon-ro, Seo-gu, Busan , Korea. Tel: , Fax: , jh2002@dau.ac.kr Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 63 No. 1, January

2 4 한승희, 이종훈. 염증성장질환에서대장암의약물적예방 본론 유전적요인과관여하는유전자의변이가주된원인인산발성대장암 (sporadic colorectal cancer) 과는다르게, 염증성장질환과연계되어있는염증성대장암 (colitis-associated colon cancer) 은장상피층의만성염증에기인하며, 관련되는유전적기전또한다르다. 전체대장암의 65-85% 를차지하는산발성대장암이 adenoma-cancer 의경로를거친다면, 염증성대장암은 inflammation-dysplasia-cancer 의경로를거친다. 7,8 따라서염증조절을통한염증성대장암예방가능성이제기되었고, 이에대한최초의발표는 1994년스웨덴에서궤양성대장염환자들을대상으로이루어졌다. 9 이연구에서 sulphasalazine을사용한경우절반이상의염증성대장암이예방되는결과를보였고, 이후 5-aminosalicylate (5-ASA) 뿐아니라 corticosteroids, 면역조절제 (immunomodulator), folic acid, ursodeoxycholic acid (UDCA) 등의약물에대한연구들이추가적으로진행되었다 이에대해대규모의대조군및무작위연구가필요한실정이나, 염증성장질환치료의한계로인해현실적으로어려운점이많다. 본종설에서는상기약물들에대해현재까지발표된여러연구결과에대해정리하였다 Aminosalicylates (5-ASA) 5-ASA는염증성장질환에서염증을완화하여염증으로인한상피세포의과도한 turnover를억제하고생리적인자멸사의균형을유지하도록한다. 13 이는 Wnt/β-catenin 신호전달계를방해하여종양세포형성을억제하는 peroxisome proliferator activated receptor (ppar-γ) 를활성화시킴으로써이루어진다. 14 또한 5-ASA는항산화제로산화적손상과이로 인한장점막의 DNA변이를억제하며 microsatellite instability를감소시킨다. 7,15 이러한이유로현재까지 5-ASA의염증성대장암의예방에대한수많은연구들이이루어졌다 그중 2005년에이전의 9개의연구를메타분석한발표에서교차비는 0.51로 5-ASA는유의하게대장암을예방하는효과를보였다. 16 하지만최근의발표에서는이전에비해 5-ASA와대장암의관련성이약한경향을보일뿐만아니라, 2011년코호트연구에서는통계적으로유의하지않았으나 5 년이상 5-ASA를사용한남자에서대장암의발생확률이높음을보였다 년이후에발표된의미있는결과들을정리해놓은 Table 1을보면, 조사대상이병원인구인지혹은일반인구인지의여부에따라결과가달리보이는것을알수있다 일반인구를대상으로한 4개의발표를메타분석한 2012년도의연구에서 5-ASA는대장암의예방효과가없는것으로나타났다. 28 이의원인으로병원인구를대상으로하는경우가일반인구에서무작위추출하는경우보다대조군과비대조군을선택하는부분의선택오류발생가능성이높다는점과, 염증성장질환을치료하는과정중 5-ASA 이외의치료약물의이차적인이득을보았을가능성이있다는점을생각해볼수있다. 반대로대규모코호트연구의경우이질성 (heterogeneity) 으로인한제3의인자가개입할오류또한존재한다. 5-ASA는염증성장질환의치료및유지를목적으로사용되며의료진이환자에게권유하는데부담이크지않으므로 5-ASA 는여전히유용하며, 이에대해서는대규모코호트안에서 5-ASA 사용및질병의범위에따른하위그룹을나누어연구를진행하는것이필요하다. 2. Corticosteroids와면역조절제만성염증반응과정중에염증세포로부터분비되는과도 Table 1. Studies Evaluating the Role of 5-Aminosalicylates (5-ASA) in the Chemoprevention of Dysplasia/Cancer in Patients with Inflammatory Bowel Disease Case control and hospital based cohort studies Rubin Case control ASA >1.2 g 0.28 ( ) Siegel Case control 54 5-ASA >1 yr 0.30 ( ) 0.10 Velayos Case control ASA >1 yr 0.4 ( ) <0.05 Gupta Retrospective cohort ASA >4 mo 0.5 ( ) NS Ullman Retrospective cohort ASA (yes vs. no) 0.7 ( ) NS Tang Case control 48 5-ASA cumulative dose>4,500 g ( ) Population based cohort studies Jess Population based case control ASA >1.2 g/day 1.6 ( ) NS Terdiman Population based case control 1,536 5-ASA (yes or no) 0.97 ( ) NS Baars Population based case control ASA (yes or no) 0.73 ( ) NS Bernstein Population based cohort 8,744 5-ASA >1 yr 1.04 ( ) 0.87 Population based case control ASA >1 yr 1.02 ( ) 0.95 van Schaik Population based cohort 2,578 5-ASA >1.2 g/day for 6 mo 0.56 ( ) NS The Korean Journal of Gastroenterology

3 Han S and Lee J. Chemoprevention of Colorectal Cancer in Inflammatory Bowel Disease 5 한 cytokine, chemokine들은상피세포의사멸을억제하고과성장을유도하는중요한인자로역할을한다. 8 이러한과정중 DNA가닥의절단이나단염기의변이가빈번히이루어지고이를통해종양억제유전자의변이가유도된다. 7 이는염증반응을억제하는 corticosteroids와면역조절제가염증성대장암을예방할가능성을시사한다. Corticosteroid에대한연구결과는 Table 2와같이염증성대장암의예방에대하여대부분통계적유의성을가지지못하고, 일반인구를대상으로는오히려대장암의발생이증가하는것으로나타났다. 10,20,21,23,24,26,29-31 또한장기간사용할경우부작용이있어대장암의예방을위해권유하기는힘들다. 반면에 azathioprine, 6-mercaptopurine, methotrexate와같은면역조절제들은현재까지도연구되고있으며 Table 3과같이최근발표에따르면통계적으로유의하게염증성대장암의발생률을낮추는것을볼수있다. 10,11,20,21,23,24,26-28, 년네덜란드에서발표된연구에서 2,578명을대상으로전향적코호트연구를시행하였고 50 mg 이상의 azathioprine을적어도 6개월간유지하였을경우대장암의예방에유의한효과를나타냈다. 24 Thiopurine은용량의존적으로약효가서서히발현되 며, 35,36 최대발현까지는적어도 17주가량의기간이필요하다. 따라서상기연구의약물용량및사용기간의차이가결과의차이를보이는원인이라미루어짐작해볼수있다. 장기간사용시 lymphoma와 non-melanoma skin cancer 등의부작용또한알려져있으므로주의해야할것이다. 37,38 하지만그런부작용에도불구하고염증성장질환치료에면역조절제는중요하게사용되고있다. 3. Ursodeoxycholicacid (UDCA) 원발경화성담관염의 60-80% 에서염증성장질환이동반되며, 염증성대장암이발생할가능성은 5배가량증가한다. 39,40 원발경화성담관염에서는이차적으로담즙의분비가과도하게발생하게되고, 소장에서모두흡수되지못하여근위부대장의점막을자극하게된다. 이는원발경화성담관염과염증성장질환이동반된경우우측대장암이더흔하다는것과관련지어볼수있다. 29 UDCA는이러한과도한담즙의대장점막자극을억제하며따라서염증성대장암을예방하는역할을기대할수있다. 41 하지만현재까지 UDCA에대한연구들을살펴보면결과는다양하게나타나며일부에서는대장암을증가시키기 Table 2. Studies Evaluating the Role of Corticosteroids in the Chemoprevention of Dysplasia/Cancer in Inflammatory Bowel Disease Lashner Retrospective cohort 98 Any steroid use >6 mo 1.52 ( ) NS Shetty Case control 328 Any steroid use >6 mo 1.03 ( ) NS Eaden Case control 204 Regular steroid use vs. none 0.26 ( ) van Staa Population based case control 700 Any steroid use in the last 6 mo 1.83 ( ) <0.05 Velayos Case control 376 Steroid use >1 yr 0.4 ( ) <0.05 Siegel Case control 54 Any steroid use vs. none 0.56 ( ) 0.42 Gupta Retrospective cohort 418 Steroid use >4 mo 0.6 ( ) NS Terdiman Population based case control 1,536 Steroid use in the last 1 yr 1.43 ( ) <0.05 Tang Case control 48 Ever used steroids vs. none 1.0 ( ) 1.00 Table 3. Studies Evaluating the Role of Immunomodulators in Prevention of Dysplasia/Colorectal Cancer in Patients with Inflammatory Bowel Disease Connell Case control 266 Azathioprine ever use vs. none 0.38 ( ) 0.54 Lashner Retrospective cohort 98 Azathioprine use >6 mo 1.12 ( ) NS Fraser Retrospective cohort 1,349 Azathioprine (yes vs. no) 0.8 ( ) NS Rutter Case control 204 Azathioprine >1 yr 0.22 ( ) 0.17 van Staa Population based case control 700 Thiopurine use in the last 6 mo 0.85 ( ) NS Matula Retrospective cohort study 315 Thiopurine use >3 mo 1.06 ( ) NS Velayos Case control 376 Thiopurine use >1 yr 3.0 ( ) NS Siegel Case control 54 Any immunomodulator ever vs. none 0.57 ( ) 0.51 Gupta Retrospective cohort 418 Thiopurine >4 mo 0.8 ( ) NS Terdiman Population based case control 1,536 Immunomodulator use in the last 1 yr 1.35 ( ) NS Tang Case control 48 6MP ever use vs. none 0.38 ( ) 0.45 Baars Population based case control 566 Thiopurine use ever vs. none 0.36 ( ) <0.05 van Schaik Population based cohort (registry) 2,578 Azathioprine >50 mg for 6 mo 0.10 ( ) <0.05 Vol. 63 No. 1, January 2014

4 6 한승희, 이종훈. 염증성장질환에서대장암의약물적예방 Table 4. Studies on the Chemopreventive Effect of Folic Acid Supplementation on Dysplasia or Colon Cancer Risk in Patients with Inflammatory Bowel Disease Studies with folic acid supplementation as primary interest Lashner Case control 99 Folic acid (yes vs. no) 0.38 ( ) NS Lashner Retrospective 98 Folic acid 0.4 mg >6 mo 0.76 ( ) NS Cohort study Folic acid 1 mg >6 mo 0.54 ( ) NS Studies where folic acid supplementation was a secondary interest Shetty Case control 328 Folic acid (use >6 mo) 0.47 ( ) NS Rutter Case control 204 Folic acid (yes vs. no) 0.4 ( ) 0.4 Velayos Case control 336 Folic acid (use noted on 2 of office visits) 0.9 ( ) NS Siegel Case control 54 Folic acid (yes vs. no) 0.80 ( ) 1.00 Gupta Retrospective cohort 418 Folic acid (use >4 mo) 1.3 ( ) NS Tang Case control 48 Folic acid (1 mg/day) 0.11 ( ) Baars Population based case control 566 Folic acid (yes vs. no) 0.93 ( ) NS van Schaik Population based cohort study 2,578 Folic acid (yes vs. no) 2.11 ( ) NS Song Case control 5,442 Folic acid (yes vs. no) 도한다. 41, 년메타분석을통해 UDCA의용량에따라 25 mg/kg/day 미만의 low-to-medium군과 25 mg/kg/day이상의 high군으로나누어보았을때 low-to-medium군에서는 UDCA가염증성대장암을예방하는역할을하지만 high군에서는반대의역할을하는것으로나타났다. 43 상기메타분석에서 low-to- medium군은 2001년부터 2012년까지 5개의논문이포함되었고이중 1개를제외하고적게는 0.97배에서많게는 0.3배까지염증성대장암의발생을억제하는효과를보였다 High군에는 2011년에발표된논문이포함되었고오히려염증성대장암이 3.72배증가하는경향을띠었다. 41 고용량군에서혈중 UDCA의농도는증가하며이는장내세균에의해 lithocholic acid와 chenodeoxycholic acid로대사되는데, Chenodeoxycholic acid는 lithocholic acid로전환되고이는산화적스트레스및유전자손상을야기한다. 49 원발경화성담관염의경우권장되는 UDCA 용량은적게는 17 mg/kg/day 에서많게는 23 mg/kg/day이다. 50 따라서원발경화성담관염과염증성장질환이동반된경우는대장암의예방을위해서 25 mg/kg/day 미만의용량으로 UDCA의사용을권유할수있으며, 원발경화성담관염이없는염증성장질환의경우는앞으로연구가필요한부분이라하겠다. 4. Folic acid Folic acid의부족은산발성대장암의원인중하나다. 51 Folic acid는유전자의합성및보수와세포사멸의조절에있어중요역할을하며, folic acid의부족은 nuclear factor-kppa B (NF-κB) 기전에교차반응을일으켜 sonic hedgehog (Shh) 신호를활성화시켜대장암의침습성을높인다. 52 이러한 folic acid의부족은염증성장질환의경우위장관의영양분흡수부족, sulfasalazine과의경쟁적흡수등으로인해 더흔할것으로생각된다. 53 하지만염증성장질환의환자들에게 folic acid를보충함으로써염증성대장암을예방하는효과는기대에미치지못하고있고, 최근에발표된일반인구를대상으로 folic acid와위약을비교한메타분석한결과에따르면 folic acid는대장암뿐아니라어떠한부위의암에도예방효과가없었다. 54,55 Folic acid의염증성대장암의예방효과는 Table 4에서보듯이대부분의연구들이통계적유의성을가지지못하였으며, 가진다하더라도대상환자군의수가적어의미를부여하기는어려웠다. 10,12,20,21,23,24,27-29,33,51 이러한이유로현재 folic acid는염증성대장암을예방하기위해추천하는것에큰이점이없다. 5. Non-steroidal anti-inflammatory drugs (NSAID), aspirin and statins 만성염증반응이특징인염증성장질환의경우염증세포가생성하는과량의 cytokine은 NF-κB의활성을유도함으로써장상피세포의 cycloocygenase-2 (COX-2) 를과발현되게하고, 그결과과량의프로스타글란딘을생성하며상피세포의성장을유도한다. 56 NSAID, aspirin은 COX-2의기전에서프로스타글린딘의생성을억제하여염증성대장암의예방을기대할수있다. 57 Table 5와같이대부분의연구에서 NSAID와 aspirin은염증성대장암을예방하는데통계적유의성을가지지못하였으나, 비교적감소하는양상을보였다. 21,24,26,27,30,31,58-61 또한 2006년 376명을대상으로문진을한연구에서는 NSAID 와 aspirin이유의하게예방효과를보였다. 21 대장암의위험성이높지않은경우 NSAID 및 aspirin을예방목적으로사용하기에는출혈등의부작용이우려되는것이사실이나, 고위험군에서는 75 mg에서 160 mg의저용량을하루한번사용하는것만으로도의미를가진다고보는견해도있다 Statin The Korean Journal of Gastroenterology

5 Han S and Lee J. Chemoprevention of Colorectal Cancer in Inflammatory Bowel Disease 7 Table 5. Studies Evaluating the Role of NSAIDs, Aspirin and Statins in Prevention of Dysplasia/Colorectal Cancer in Patients with Inflammatory Bowel Disease NSAIDS Bansal Retrospective cohort 11,446 Having an NSAID related diagnosis 0.84 ( ) NS van Staa Population based case control 700 Any NSAID use in the last 6 mo 0.80 ( ) NS Velayos Case control 376 NSAID use noted on 2 office visits 0.1 ( ) <0.05 Terdiman Population based case control 1,536 NSAID use in the last 1 yr 0.97 ( ) NS Tang Case control 48 Ever used NSAID vs. none 0.29 ( ) 0.36 Baars Population based case control 376 Ever used NSAID vs. none 1.96 ( ) NS Samadder Population based case control 60 NSAID use once weekly for at least 3 yr 0.47 ( ) NS Broughton Case control 23 NSAID use (yes vs. no) 0.54 ( ) 0.19 Aspirin Eaden Case control 204 Aspirin use (yes vs. no) 0.80 ( ) 0.74 van Staa Population based case control 700 Aspirin use in the last 6 mo (prescribed only) 1.52 ( ) NS Velayos Case control 376 Aspirin use noted on 2 office visits 0.3 ( ) <0.05 (self-reported) Broughton Case control 58 Aspirin use (yes vs. no) 0.36 ( ) <0.01 Statin Poynter Case control 55 Statin use for at least 5 yr 0.06 ( ) <0.05 Samadder Case control 60 Statin use for at least 5 yr 0.07 ( ) <0.05 Broughton Case control 233 Statin <40 mg/day 0.51 ( ) 0.14 Statin 40 mg/day 0.19 ( ) <0.01 Duration <2 yr 0.66 ( ) 0.47 Duration 2-5 yr 0.38 ( ) 0.05 Duration >5 yr 0.18 ( ) <0.01 은 3-hydroxy-3-methyglutaryl-coenzyme A reductase (HMG-CoAR) 의억제제로, 종양세포의성장과전이및신생혈관생성을억제하고세포면역을증강하며종양억제 cytokine을활성화시킨다고알려져있다. 65,66 최근일반환자들을대상으로한 42개의연구를메타분석한결과 statin은유의하게대장암을예방하는효과를보였다. 이는코호트연구, 대조군연구, 무작위연구에서모두같이나타났으며, 특히지용성 statin을사용한경우와 aspirin을병용한경우그효과는더욱컸다. 60,67 또한 2012년발표된대조군연구에서는 statin의용량이많을수록, 기간이길수록큰영향력을보였으나, 60 statin에대한연구가항상같은결과를보이지는않았다. 68 그원인으로 HMG-CoAR의유전적다양성과 KRAS 변이가제시되고있으며, 69,70 향후이에대한연구가더필요하다. 결론 염증성장질환환자들을대상으로염증성대장암을예방하기위한연구들이지속적으로진행되고있음에도불구하고, 명백한예방효과를가지는것은원발경화성담관염이같이있는경우의 UDCA 뿐이다. 또한 5-ASA와면역조절제는이점이많으나모든연구들이같은결과를보이지않는다. 하지만이들약제는염증성장질환의치료및유지에사용되는동시에, 염증성대장암의예방효과를가질수있다는점에서의미 있는약제들이다. Corticosteroids는이점보다는부작용이많다는점에서, folic acid는통계적유의성을보이지못한다는점에서의미를부여하기힘들어보인다. NSAID와 statin에대해서는아직더많은연구가이루어져야하지만, 최근 statin의암예방효과에대한긍정적연구가보고되고있다. 60,67 최근에는신생혈관의억제및장내세균을이용한염증성대장암예방뿐아니라 cocoa polyphenols부터 matrix metalloproteinase까지다양한부분에서연구가이루어지고있다 앞으로는지금까지의연구들과는다른대규모의무작위전향연구가이루어져염증성대장암의예방이가능해지기를기대한다. REFERENCES 1. Danese S, Fiocchi C. Etiopathogenesis of inflammatory bowel diseases. World J Gastroenterol 2006;12: Prideaux L, Kamm MA, De Cruz PP, Chan FK, Ng SC. Inflammatory bowel disease in Asia: a systematic review. J Gastroenterol Hepatol 2012;27: O'Connor PM, Lapointe TK, Beck PL, Buret AG. Mechanisms by which inflammation may increase intestinal cancer risk in inflammatory bowel disease. Inflamm Bowel Dis 2010;16: Farraye FA, Odze RD, Eaden J, et al; AGA Institute Medical Position Panel on Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease. AGA medical position Vol. 63 No. 1, January 2014

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