counteract PMN-induced stress rather than to accumulate mutations, which may finally lead to cancer. Acknowledgements: We would like to thank Professor Ted R Hupp (University of Edinburgh, UK) for the kind gift of the HCT116p532/2 and HCT116p212/2 cells; Drs Rick Boland, Minoru Koi and Ajay Goel (Baylor University Medical Center, Dallas) for the HCT116+chr3, Lovo+chr2, Lovo(DT40.2)-4-1 and HEC59+chr2 cells; Dr Fran¸coise Praz for the HCT116-mlh1-2 cells; and Drs Martin Willheim and Guenther Hofbauer for cell sorting (Core Unit Zellsortierung, Medical University of Vienna). In addition, we are grateful to Dr Paul Grundtner, Dr Rayko Evstatiev, Dr Stefanie Kulnigg, Dr Agu Chukwuma and Mag. Sabine Gruber (MUW, Vienna) for useful discussions and Cornelia Lichtenberger and Manuela Nemeth for technical support. Funding: This study was supported by the Austrian Science Fund (FWF grant P18270). Competing interests: None. REFERENCES 1. Itzkowitz SH, Yio X. Inflammation and cancer, IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 2004;287:G7–17. 2. Grisham MB, Granger DN. Neutrophil-mediated mucosal injury. Role of reactive oxygen metabolites. Dig Dis Sci 1988;33:6S–15S. 3. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448:427–34. 4. Hofseth LJ, Khan MA, Ambrose M, et al. The adaptive imbalance in base excision– repair enzymes generates microsatellite instability in chronic inflammation. J Clin Invest 2003;112:1887–94. 5. Imlay JA, Chin SM, Linn S. Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science 1988;240:640–2. 6. Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 2004;44:239–67. 7. Jackson AL, Chen R, Loeb LA. Induction of microsatellite instability by oxidative DNA damage. Proc Natl Acad Sci U S A 1998;95:12468–73. 8. Gasche C, Chang CL, Rhees J, et al. Oxidative stress increases frameshift mutations in human colorectal cancer cells. Cancer Res 2001;61:7444–8. 9. Britigan BE, Serody JS, Cohen MS. The role of lactoferrin as an anti-inflammatory molecule. Adv Exp Med Biol 1994;357:143–56. 10. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539–45. 11. Quinn MT, Gauss KA. Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. J Leukoc Biol 2004;76:760–81. 12. Glaab WE, Hill RB, Skopek TR. Suppression of spontaneous and hydrogen peroxide- induced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells. Carcinogenesis 2001;22:1709–13. 13. Kolodner RD, Marsischky GT. Eukaryotic DNA mismatch repair. Curr Opin Genet Dev 1999;9:89–96. 14. Peinado MA, Malkhosyan S, Velazquez A, et al. Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. Proc Natl Acad Sci U S A 1992;89:10065–9. 15. Ionov Y, Peinado MA, Malkhosyan S, et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993;363:558–61. 16. Johnson RE, Kovvali GK, Guzder SN, et al. Evidence for involvement of yeast proliferating cell nuclear antigen in DNA mismatch repair. J Biol Chem 1996;271:27987–90. 17. Marti TM, Kunz C, Fleck O. DNA mismatch repair and mutation avoidance pathways. J Cell Physiol 2002;191:28–41. 18. Rotman G, Shiloh Y. Ataxia–telangiectasia: is ATM a sensor of oxidative damage and stress? Bioessays 1997;19:911–7. 19. Walworth N, Davey S, Beach D. Fission yeast chk1 protein kinase links the rad checkpoint pathway to cdc2. Nature 1993;363:368–71. 20. Matsuoka S, Huang M, Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 1998;282:1893–7. 21. Helt CE, Cliby WA, Keng PC, et al. Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein exhibit selective target specificities in response to different forms of DNA damage. J Biol Chem 2005;280:1186–92. 22. Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003;421:499–506. 23. Zhao H, Piwnica-Worms H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol 2001;21:4129–39. 24. el-Deiry WS. Regulation of p53 downstream genes. Semin Cancer Biol 1998;8:345–57. 25. el-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993;75:817–25. 26. Koi M, Umar A, Chauhan DP, et al. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N9-nitro-N- nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res 1994;54:4308–12. Gut 2008;57:780–787. doi:10.1136/gut.2007.141556 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. C o l o r e c t a l c a n c e r Carethers JM, Hawn MT, Chauhan DP, et al. Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N9-nitro-N- nitrosoguanidine. J Clin Invest 1996;98:199–206. Chang DK, Goel A, Ricciardiello L, et al. Effect of H(2)O(2) on cell cycle and survival in DNA mismatch repair-deficient and -proficient cell lines. Cancer Lett 2003;195:243–51. Gasche C, Chang CL, Natarajan L, et al. Identification of frame-shift intermediate mutant cells. Proc Natl Acad Sci U S A 2003;100:1914–9. Bunz F, Dutriaux A, Lengauer C, et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 1998;282:1497–501. Watanabe Y, Haugen-Strano A, Umar A, et al. Complementation of an hMSH2 defect in human colorectal carcinoma cells by human chromosome 2 transfer. Mol Carcinogenesis 2000;29:37–49. Umar A, Koi M, Risinger JI, et al. Correction of hypermutability, N-methyl-N9-nitro-N- nitrosoguanidine resistance, and defective DNA mismatch repair by introducing chromosome 2 into human tumor cells with mutations in MSH2 and MSH6. Cancer Res 1997;57:3949–55. Jacob S, Aguado M, Fallik D, et al. The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells. Cancer Res 2001;61:6555–62. Collins SJ, Ruscetti FW, Gallagher RE, et al. Normal functional characteristics of cultured human promyelocytic leukemia cells (HL-60) after induction of differentiation by dimethylsulfoxide. J Exp Med 1979;149:969–74. Adamson AW, Beardsley DI, Kim WJ, et al. Methylator-induced, mismatch repair- dependent G2 arrest is activated through Chk1 and Chk2. Mol Biol Cell 2005;16:1513–26. Luciani MG, Campregher C, Fortune JM, et al. 5-ASA affects cell cycle progression in colorectal cells by reversibly activating a replication checkpoint. Gastroenterology 2007;132:221–35. Muller-Peddinghaus R. In vitro determination of phagocyte activity by luminol- and lucigenin-amplified chemiluminescence. Int J Immunopharmacol 1984;6:455–66. Yu PW, Czuprynski CJ. Regulation of luminol-dependent chemiluminescence and degranulation by bovine neutrophils stimulated with opsonized zymosan. Vet Immunol Immunopathol 1996;50:29–42. Barzilai A, Yamamoto K. DNA damage responses to oxidative stress. DNA Repair (Amst) 2004;3:1109–15. Chang CL, Marra G, Chauhan DP, et al. Oxidative stress inactivates the human DNA mismatch repair system. Am J Physiol Cell Physiol 2002;283:C148–54. Simelyte E, Boyle DL, Firestein GS. DNA mismatch repair enzyme expression in synovial tissue. Ann Rheum Dis 2004;63:1695–9. Shackelford RE, Innes CL, Sieber SO, et al. The ataxia telangiectasia gene product is required for oxidative stress-induced G1 and G2 checkpoint function in human fibroblasts. J Biol Chem 2001;276:21951–9. Dulic V, Stein GH, Far DF, et al. Nuclear accumulation of p21Cip1 at the onset of mitosis: a role at the G2/M-phase transition. Mol Cell Biol 1998;18:546–57. Yamane K, Taylor K, Kinsella TJ. Mismatch repair-mediated G2/M arrest by 6- thioguanine involves the ATR-Chk1 pathway. Biochem Biophys Res Commun 2004;318:297–302. Seril DN, Liao J, Yang GY, et al. Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 2003;24:353–62. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, et al. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 2004;73:39–85. Chen P, Gatei M, O’Connell MJ, et al. Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia–telangiectasia cells. Oncogene 1999;18:249–56. Siliciano JD, Canman CE, Taya Y, et al. DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev 1997;11:3471–81. Taylor WR, Stark GR. Regulation of the G2/M transition by p53. Oncogene 2001;20:1803–15. Foote CS, Goyne TE, Lehrer RI. Assessment of chlorination by human neutrophils. Nature 1983;301:715–6. Brestel EP. Co-oxidation of luminol by hypochlorite and hydrogen peroxide implications for neutrophil chemiluminescence. Biochem Biophys Res Commun 1985;126:482–8. Franchitto A, Pichierri P, Piergentili R, et al. The mammalian mismatch repair protein MSH2 is required for correct MRE11 and RAD51 relocalization and for efficient cell cycle arrest induced by ionizing radiation in G2 phase. Oncogene 2003;22:2110–20. Mirzoeva OK, Kawaguchi T, Pieper RO. The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity. Mol Cancer Ther 2006;5:2757–66. Waga S, Stillman B. The DNA replication fork in eukaryotic cells. Annu Rev Biochem 1998;67:721–51. Yin J, Harpaz N, Tong Y, et al. p53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology 1993;104:1633–9. Brentnall TA, Crispin DA, Rabinovitch PS, et al. Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology 1994;107:369–78. Goel A, Mittal A, Nemeth A, et al. In vivo effects of mesalazine (5-ASA) or E. coli Nissle 1917 on microsatellite instability in ulcerative colitis (UC). Gut 2006;55:A134. 787