Z Gastroenterol 2000; 38(12): 963-970
DOI: 10.1055/s-2000-10027
Übersichten
© Karl Demeter Verlag im Georg Thieme Verlag Stuttgart · New York

Aminosalizylate und Aspirin bei Kolonkarzinomen: vom Entzündungshemmer zum Tumorprophylaktikum?

H. Allgayer1 , T. Tillmann2 , A. Hombach2 , W. Kruis2 , C. Pohl2
  • Abteilung Krebsnachsorge, Rehaklinik „Ob der Tauber” der LVA Württemberg, Akademisches Lehrkrankenhaus der Universität Heidelberg
  • , Innere Abteilung, Evangelisches Krankenhaus Köln-Kalk, Akademisches Lehrkrankenhaus der Universität Köln
Further Information

Publication History

22.11.1999

24.3.2000

Publication Date:
31 December 2000 (online)

Zusammenfassung

Ziel dieser Arbeit ist es, einen Überblick zu geben über Antitumoreigenschaften von Medikamenten, die ursprünglich als Entzündungshemmer eingesetzt ­wurden, wie Aminosalizylate, Aspirin oder andere nichtsteroidale Antiphlogistika. Ausgehend von experimentellen und epidemiologischen Untersuchungen, die prophylaktische und/oder Tumorregressions/-suppressionseigenschaften belegen, werden spezifische antineoplastische Wirkungsweisen dargelegt wie die Hemmung Zyklooxygenase (COX)-abhängiger und -unabhängiger Schritte einschließlich der Rolle von Transkriptionsfaktoren wie NFkB in der Regulation des Zellzyklus. Darüber hinaus spielen weitere tumorhemmende Eigenschaften dieser Medikamente möglicherweise eine wichtige Rolle, wie die Induktion der Apoptose von Karzinomzellen und/oder Hemmung potenziell tumorrelevanter oxidativer DNA-Schäden. Basierend auf diesen Daten, wird die mögliche klinische Relevanz erörtert.

Aminosalicylates and aspirin for colonic cancer: From anti-inflammatory to antineoplastic drugs?

The aim of this article is to review potential antineoplastic properties of anti-inflammatory compounds commonly used in various inflammatory diseases such as aminosalicylates, aspirin and other nonsteroidal drugs. Starting from experimental and epidemiologic evidence showing prophylaxis and/or tumor ­regression/suppression, specific antineoplastic actions especially the inhibition of cyclooxygenase-(COX)dependent and COX-independent steps including the role of transscription factor (NFkB) in the cell cycle regulation are reviewed. In addition other mechanisms by which these drugs may exert antitumor effects, also may be important such as induction of apoptosis of cancer cells and/or inhibition of potentially carcinogenic oxidative DNA damage. Based on this knowledge potential clinical implications are discussed.

Literatur

  • 1 Boring C C, Squires T S, Tong T. Cancer Statistics 1994.  Cancer J Clin. 1994;  44 7-26
  • 2 Winawer S J, Zauber A G, Ho M N. et al . Prevention of colorectal cancer by colonoscopic polypectomy: The National Polyp Study Workgroup.  N Engl J Med. 1993;  329 1977-1981
  • 3 Krebs in Deutschland, Häufigkeiten und Trends Arbeitsgemeinschaft Bevölkerungsbezogener Krebsregister in Deutschland. Saarbrücken; 1997
  • 4 Thun M J. NSAID use and decreased risk of gastrointestinal cancers.  Gastroenterol Clin North Am. 1996;  25 333-34
  • 5 Shiff S J, Rigas B. Nonsteroidal anti-inflammatory drugs and colorectal cancer: Evolving concepts of their chemopreventive actions.  Gastroenterology. 1997;  113 1992-1998
  • 6 Klampfer L, Cammenga J, Wisniewski H, Nimer S D. Sodium salicylate activates caspases and induces apoptosis of myeloid cell lines.  Blood. 1999;  93 2386-2394
  • 7 Reinacker-Schick A, Seidensticker F, Petrasch S, Philippou S, Schmiegel W. Mesalazine induces apoptosis and decreases proliferation in normal epithelial cells in patients with sporadic colorectal polyps.  Gastroenterology. 1998;  114 A 666
  • 8 Reiser M, Schmiegel W. Doppelblinde, multizentrische, placebokontrollierte Studie zur Prävention kolorektaler Polypen durch 5-Aminosalizylsäure nach Polypektomie (German 5-ASA-Polyp-Prevention Study) (GAPPS) (SAG-6).  Z Gastroenterol. 1999;  12 XXIII
  • 9 Bedi A, Pasricha P J, Akhtar A J. et al . Inhibition of apoptosis during development of colorectal cancer.  Cancer Res. 1995;  55 1811-1816
  • 10 Giardello F M, Offerhaus G JA, Du B ois RN. Role of nonsteroidal drugs in colon cancer prevention.  Eur J Cancer. 1995;  31A 1071-1076
  • 11 Alexandrov K, Rojas M, Kadlubar F F, Lang N P, Bartsch H. Evidence of anti (a) pyrene diolepoxide-DNA adduct formation in human colonic mucosa.  Carcinogenesis. 1996;  17 2081-2083
  • 12 Bartsch H. Etheno-DNA base adducts as tools in human cancer etiology and chemoprevention.  Eur J Cancer Prevention. 1997;  6 529-534
  • 13 Pollard M, Luckert P H. Indomethacin treatment of rats with dimethylhydrazine-induced intestinal tumors.  Cancer Treat Rep. 1980;  64 1323-1327
  • 14 Moorghen M, Ince P, Finney K J. et al . A protective effect of sulindac against chemically-induced primary colonic tumors in mice.  J Pathol. 1988;  156 341-347
  • 15 Norisarou T, Satoh M, Nano M, Takahashi T. Inhibition of initiation and promotion by N-methyl-nitroso urea-induced colon carcinogenesis in rats by non steroid anti-inflammatory drug indomethacin.  Carcinogenesis. 1982;  4 1225-1227
  • 16 Pollard M, Ludkert P H, Schmid M A. The suppressive effect of piroxicam on autochtonous intestinal tumors in the rat.  Cancer Lett. 1983;  21 57-61
  • 17 Reddy B S, Rao C V, Rivenson A, Kelloff G. Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats.  Carcinogenesis. 1993;  14 1493-1497
  • 18 Reddy B S, Maruyama H, Kelloff G. Dose-related inhibition of colon carcinogenesis by dietary piroxicam, a nonsteroidal anti-inflammatory drug during different stages of rat colon tumor development.  Cancer Res. 1987;  47 5340-5346
  • 19 Jacoby R F, Marshall D J, Newton M A. et al . Chemoprevention of spontaneous intestinal adenomas in the APC Min mouse model by the non steroidal anti-inflammatory drug piroxicam.  Cancer Res. 1996;  56 710-714
  • 20 Boolbol S K, Dannenberg A J, Chadburn A. et al . Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis.  Cancer Res. 1996;  56 2556-2560
  • 21 Beazer-Barclay Y, Levy D B, Moser A R. et al . Sulindac suppresses tumorigenesis in the Min mouse.  Carcinogenesis. 1996;  17 1757-1760
  • 22 Powell S M, Ziliz N, Beaser-Barklay Y. et al . APC mutations occur early during colorectal tumorigenesis.  Nature. 1992;  359 235-237
  • 23 Kinzler K W, Vogelstein B. Lessons from hereditary colorectal cancer.  Cell. 1996;  87 159-170
  • 24 Waddell W R, Loughry R W. Sulindac for polyposis of the colon.   J Surg Oncol. 1983;  24 83-87
  • 25 Barnes C J, Lee M. Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin.  Gastroenterology. 1998;  114 873-877
  • 26 MacGregor D J, Kom Y S, Siddiki B B. et al . Induction of colon cancer cell apoptosis in vitro and inhibition of intestinal tumor formation in Min/+ mice by balsalazide and metabolites.  Gastroenterology. 1996;  110 A553
  • 27 Ritland S R, Leigthon I A, Hirsch R E. et al . Evaluation of 5-aminosalicylic acid (5-ASA) for cancer prevention: Lack of efficacy against nascent adenomatous polyps in the APC (Min) mouse.  Clin Cancer Res. 1999;  5 855-863
  • 28 Ekbom A, Helmick C, Zack M, Adami H O. Ulcerative colitis and colorectal cancer.  N Engl J Med. 1990;  323 1228-1233
  • 29 Isomäki H A, Hakulinen T, Joutsenlahti U. Excess risk of lymphomas, leukemia and yeloma in patients with rheumatoid arthritis.  J Chron Dis. 1978;  31 691-696
  • 30 Rosenberg L, Palmer J R, Zauber A G. et al . A hypothesis: Non-steroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer.  J Natl Cancer Inst. 1991;  83 355-358
  • 31 Peleg I I, Maibach H T, Brown S H, Wilcox C M. Aspirin and nonstoidal anti-inflammatory drug use and the risk of subsequent colorectal cancer.  Arch Intem Med. 1994;  154 394-399
  • 32 Schreinemachers D M, Eversen R B. Aspirin use and lung, colon and breast cancer incidence in a prospective study.  Epidemiology. 1994;  5 138-146
  • 33 Thun M J, Namboodiri M M, Calle E E, Flanders W D, Heath C W. Aspirin use and reduced risk of fatal cancer.  N Engl J Med. 1991;  325 1593-1596
  • 34 Thun M J, Calle E E, Namboodiri M M. et al . Risk factors for fatal colonic cancer in a large prospective study.  J Natl Cancer Inst. 1992;  84 1491-1500
  • 35 Thun M J, Namboodiri M M, Calle E E, Flanders D W, Heath C W. Aspirin use and risk of fatal cancer.  Cancer Res. 1993;  53 1322-1327
  • 36 Paganini H ill A, Chao A, Ross K K, Henderson B E. Aspirin use and chronic diseases: A cohort study of the elderly.  BMJ. 1989;  299 1247-1250
  • 37 Paganini Hill A. Aspirin and colorectal cancer: The Leisure World Cohort revisited.  Prev. Medicine. 1995;  24 113-115
  • 38 Gann P H, Manson J E, Glynn J. et al . Low dose aspirin and incidence of colorectal tumors in a randomized trial.  J Natl Cancer Inst. 1993;  85 1220-1224
  • 39 Stürmer T, Glynn R J, Lee I M. et al . Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians Health Study.  Ann Intern Med. 1998;  128 713-720
  • 40 Smalley W, Rav W A, Daugherty J. Use of nonsteroidal antiinflammatory drugs and incidence of colorectal cancer: a population-based study.  Arch. Int Med. 1999;  159 161-164
  • 41 Giardello F M, Hamilton S R, Brush A J. et al . Treatment of colonic and rectal adenomatosis polyposis.  N Engl J Med. 1993;  328 1313-1316
  • 42 Nugent K P, Farmer K, Spiegelman A D, Williams C B, Phillips R K. Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis.  Br J Sury. 1993;  80 1618-1619
  • 43 Keller J J, Ofterhaus G JA, Polak M. et al . Rectal epithelial apoptosis in familial adenomatous polyposis patients treated with sulindac.  Gut. 1999;  45 822-828
  • 44 Bachwich D R, Lichtenstein G R, Traber P G. Cancer in inflammatory bowel disease.  Gastroenterol Clin North Am. 1994;  78 1399-1412
  • 45 Kornfeld D. Sulfasalazine use as a preventive factor for colorectal cancer in ulcerative colitis patients - a review.  Inflamm Bowel Dis. 1996;  2 276-278
  • 46 Pinczowski D, Ekbom A, Baron J, Yuen J, Adami H O. Risk factors for colorectal cancer in patients with ulcerative colitis: A case-control study.  Gastroenterology. 1994;  107 117-120
  • 47 Thompson C B. Apoptosis in the pathogenesis and treatment of disease.  Science. 1995;  267 1456-1462
  • 48 Shiff S J, Qiao L, Tsai L -L, Rigas B. Sulindac-sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells.   J Clin Invest. 1995;  96 491-503
  • 49 Shiff S j, Koutsos M J, Qiao L, Rigas B. Nonsteroidal anti-inflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: Effects on cell cycle and apoptosis.  Exp Cell Res. 1996;  222 179-188
  • 50 Goldberg Y, Nassif I I, Pittas A. et al . The antiproliferative effect of sulindac and sulindac sulfide on HT-29 colon cancer cells: Alterations in tumor suppressor and cell cycle regulatory proteins.  Oncogene. 1996;  12 893-901
  • 51 Qiao L, Hanif R, Sphicas E, Shiff S J, Rigas B. Effect of aspirin on induction of apoptosis in HT-29 human colon adenocarcinoma cells.  Biochem Pharmacol. 1998;  55 53-64
  • 52 Qiao L, Shiff S J, Rigas B. Sulindac sulfide inhibits the prolifera­tion of colon cancer cells: diminished expression of the proliferation markers PCNA and Ki-67.  Cancer Lett. 1997;  115 229-234
  • 53 Williams C W, Du B ois RN. Prostaglandin endoperoxide synthetase: Why two isoforms?.  Am J Physiol. 1996;  270 G 393-G400
  • 54 Bayer B M, Beaven M A. Evidence that indomethacine reversibly inhibits cell growth in the G1 phase of the cell cycle.  Biochem Pharmacol. 1997;  28 441-443
  • 55 Eberhart C E, Dubois R N. Eicosanoids and the gastrointestinal tract.  Gastroenterology. 1995;  109 285-301
  • 56 Marnett L J. Aspirin and the potential role of prostaglandins in colon cancer.  Cancer Res. 1992;  52 5575-5589
  • 57 Kargman S, O’Neil G, Vickers P. et al . Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer.  Cancer Res. 1995;  55 2556-2559
  • 58 Tsujii M, Kawano S, DuBois R N. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2.  Cell. 1995;  83 493-501
  • 59 Oshima M, Dichuk J E, Kargman S L. et al . Suppression of intestinal polyposis in APC(716 knockout mice by inhibition of cyclooxygenase-2 (COX-2).  Cell. 1996;  87 803-809
  • 60 Singh J, Hamid R, Reddy B S. Dietary fat and colon cancer. Modulation of cyclooxygenase-2 by types and amount of dietary fat during the postinitiation stage of colon carcinogenesis.  Cancer Res. 1997;  57 3465-3470
  • 61 Singer I I, Kawka D W, Schloemann S. et al . Cyclooxygenase-2 is induced in colonic epithelial cells in inflammatory bowel disease.  Gastroenterology. 1998;  115 297-306
  • 62 Hanif R, Pittas A, Feng Y. et al . Effect of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway.  Biochem Pharmacol. 1996;  52 237-245
  • 63 Piazza G A, Albert D S, Hixon L J. et al . Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels.  Cancer Res. 1997;  75 2909-2915
  • 64 Elder D JE, Hague A, Hicks D J, Paraskeva C. Differential growth inhibition by the aspirin metabolite salicylate in human colorectal tumor cell lines: Enhanced apoptosis in carcinoma and in vitro-transformed adenoma relative to adenoma cell lines.  Cancer Res. 1996;  56 2273-2276
  • 65 Kopp E, Ghosh S. Inhibition of NFkB by sodium salicylate and aspirin.  Science. 1994;  265 956-959
  • 66 Kaiser G C, Yan F, Polk D B. Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor kB activation in mouse colonocytes.  Gastroenterology. 1999;  116 602-609
  • 67 Hinz M, Krappmann D, Eichten A. et al . NF-kB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition.  Mol Cell Biol. 1999;  19 2690-2698
  • 68 Yin M -J, Yamamoto Y, Gaynor R B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IkB kinase-ß.  Nature. 1998;  396 77-80
  • 69 Schwenger P, Bellosta P, Vietor I. et al . Sodium salicylate induces apoptosis via p38 mitogen-activated protein kinase but inhibits tumor necrosis factor-induced c-Jun N-terminal kinase/stress-activated protein kinase activation.  Proc Natl Acad Sci USA. 1997;  94 2869-2873
  • 70 Chan T A, Morin P J, Vogelstein B, Kinzler K W. Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis.  Proc Natl Acad Sci USA. 1998;  95 681-686
  • 71 Hall P A, Coates P J, Ansari B, Hopwood D. Regulation of cell number in the mammalian gastrointestinal tract: The importance of apoptosis.  J Cell Sci. 1994;  107 3569-3577
  • 72 Bedi A, Pasricha P J, Akhtar A J, Barber J P. et al . Inhibition of apoptosis during development of colorectal cancer.  Cancer Res. 1995;  55 1811-1816
  • 73 Wang C -Y, Mayo M W, Korneluk R G, Goeddel D V, Baldwin A S. NF-kB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.  Science. 1998;  281 1680-1683
  • 74 Piazza G A, Rahm A LK, Krutzsch M. et al . Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis.  Cancer Res. 1995;  55 3110-3116
  • 75 Sheng H, Shao J, Morrow J D, Beauchamp R D, DuBois R N. Modulation of apoptosis and bcl-2 expression by prostaglandin E2 in human colon cancer cells.  Cancer Res. 1998;  58 362-366
  • 76 Tillmann T, Hombach A, Diehl V. et al . Inhibition der Expression von bcl-2 als möglicher Wirkungsmechanismus der chemoprotektiven Wirkung von Salizylsäure gegen Kolonkarzinome.   Z Gastroenterol. 1998;  36 A706
  • 77 Sinicrope F A, Ruan S B, Cleary K R. et al . bcl-2 and p53 oncoprotein expression during colorectal carcinogenesis.  Cancer Res. 1995;  55 237-241
  • 78 Baretton G D, Diebold J, Chrstiforis G. et al . Apoptosis and immunohistochemical bcl-2 expression in colorectal adenomes and carcinomas.  Cancer. 1996;  77 255-264
  • 79 Winde G, Schmid K W, Brandt B, Müller O, Osswald H. Clinical and genomic influence of sulindac on rectal mucosa in familial adenomatous polyposis.  Dis Colon Rectum. 1997;  40 1156-1169
  • 80 Wu G D. A nuclear receptor to prevent colon cancer.  N Engl J Med. 2000;  342 651-653
  • 81 Allgayer H, Stenson W F. A comparison of effects of sulfasalazine and its metabolites on the metabolism of endogenous vs. exogenous arachidonic acid.  Immunopharmacology. 1988;  15 39-46
  • 82 Dittmann K H, Mayer C X, Rodemann H P, Perides P E, Denzlinger C. MK 886, a leukotriene biosynthesis inhibitor, induces antiproliferative effects and apotposis in HL-60 cells.  Leukemia Research. 1998;  52 49-53
  • 83 Loft S, Poulsen H E. Cancer risk and oxidative DNA damage in man.  J Mol Med. 1996;  74 297-312
  • 84 Cheng K C, Cahill D S, Kasai H, Nishimura S, Loeb L A. 8-Hydroxyguanine, an abundant form of oxidative DNA damage causes G-T and A-C substitutions.  J Biol Chem. 1992;  267 166-172
  • 85 Schmutte C, Yang A S, Beart R W, Jones P A. Base excision repair of U:G mismatches at mutational hotspot in the p53 gene is more efficient than base excision repair of T:G mismatches in extracts of human colon tumors.  Cancer Res. 1995;  55 3742-3746
  • 86 Malins D C, Haimanot R. Major alterations in the nucleotide structure of DNA in cancer of the female breast.  Cancer Res. 1991;  51 5430-5432
  • 87 Farinati F, Cardin R, Rugge M. et al . Oxidative DNA damage accumulation in gastric carcinogenesis.  Gut. 1998;  42 351-356
  • 88 Pool-Zobel B L, Collins A K, Rechkammer G. Levels of endogenous DNA damage and oxidized DNA bases in colon cells derived from biopsies 50 non colon cancer patients.  Proc Annu Meet Am Ass Cancer Res. 1997;  38 A300
  • 89 Lih-Brody L, Powell S R, Collier K P. et al . Increased oxidative stress and decreased antioxidative defenses in mucosa of inflammatory bowel disease.  Dig Dis Sci. 1996;  41 2078-2086
  • 90 Allgayer H, Höfer P, Schmidt M. et al . Superoxide, hydroxyl and fatty acid radical scavenging by aminosalicylates. Direct evaluation with electron spin resonance spectroscopy.  Biochem Pharmacol. 1992;  43 259-262
  • 91 Allgayer H, Such P, Klotz P, Fischer C, Kruis W. Formation and inhibition of deoxyribose radicals: Potential disease mechanisms and modes of action of aminosalicylates in inflammatory bowel disease.  Magn Reson Med. 1995;  6 237-239
  • 92 Allgayer H, Kolb M, Stuber V, Kruis W. Modulation of base hydroxylation by bile acids and salicylates in a model of human colonic mucosal DNA: Putative implications in colonic cancer.  Dig Dis Sci. 1999;  44 761-767
  • 93 Rainford K D. The effects of aspirin and other non-steroid antiinflammatory analgesic drugs an gastrointestinal mucus glycoprotein biosynthesis in vivo: Relationship to ulcerogenic actions.  Biochem Pharmacol. 1978;  27 877-885
  • 94 Lauritsen K, Hansen J, Ryde M, Rask-Madsen J. Colonic azodisalicylate metabolism determined by in vivo dialysis in healthy volunteers and patients with ulcerative colitis.  Gastroenterology. 1984;  86 1496-1500
  • 95 Nair J, Vaca E, Velic J. et al . High dietary omega 6-polyursatte­n­ated fatty acids drastically increase the formation of etheno-DNA base adducts in white blood cells of female subjects.  Cancer Epidemiol Biomarkers Prev. 1997;  6 597-601
  • 96 Gupta R A, DuBois R N. Aspirin, NSAIDs and colon cancer prevention: Mechanisms?.  Gastroenterology. 1998;  114 1095-1109
  • 97 Kontsos M J, Shift S J, Rigas B. Can non-steroidal anti-inflammatory drugs be recommended to prevent colon cancer in high risk elderly patients?.  Drugs Aging. 1995;  6 421-425
  • 98 Greenberg E R, Baron J A. Aspirin and other non steroid anti-inflammatory drugs as cancer-preventive agents.  IAR Sci Publ. 1996;  139 91-96
  • 99 Langman M, Boyle P. Chemoprevention of colorectal cancer.  Gut. 1998;  43 585-588
  • 100 Walker A M, Snzeke P, Bianchi L A. et al . 5-Aminosalicylates, sulfasalazine, steroid use and complications in patients with ulcerative colitis.  Am J Gastroenterol. 1997;  92 816-820
  • 101 Steinbach G, Lynch P M, Phillips RK S. et al . The effect of celecobix, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.  N Engl J Med. 2000;  342 1946-1952

Anschrift für die Verfasser:

Prof. Dr. H Allgayer

Rehaklinik Ob der Tauber der LVA Württemberg

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