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The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon
  1. Dessislava Mladenova1,
  2. Joseph J Daniel1,
  3. Jane E Dahlstrom2,
  4. Elaine Bean2,
  5. Ruta Gupta2,
  6. Russell Pickford3,
  7. Nicola Currey1,
  8. Elizabeth A Musgrove1,4,
  9. Maija R J Kohonen-Corish1,4
  1. 1Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. 2ACT Pathology, The Canberra Hospital and Australian National University Medical School, Canberra, ACT, Australia
  3. 3Bioanalytical Mass Spectrometry Facility, University of NSW Analytical Centre, NSW, Australia
  4. 4St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW, Australia
  1. Correspondence to Dr Maija Kohonen-Corish, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst Sydney NSW 2010, Australia; m.corish{at}garvan.org.au

Abstract

Background and aims The non-steroidal anti-inflammatory drug sulindac is an effective chemopreventive agent in sporadic colorectal cancer but its potential benefit in mismatch repair deficient cancers remains to be defined. We wanted to determine whether genetic defects that are relevant for colorectal cancer, such as Msh2 or p53 deficiency, would influence the efficiency of sulindac chemoprevention or increase the side effects.

Methods Msh2 or p53 deficient and wild-type mice received feed containing 160–320 ppm sulindac for up to 25 weeks with or without a concurrent treatment with the carcinogen azoxymethane. Colon tissue was analysed by histopathology and molecular biology methods.

Results We show that sulindac prevented azoxymethane-induced distal colon tumours in all mice. In the proximal colon, however, sulindac induced new inflammatory lesions on the mucosal folds, which further developed into adenocarcinoma in up to 18–25% of the p53 or Msh2 deficient mice but rarely in wild-type mice. This region in the proximal colon was characterised by a distinct profile of pro- and anti-inflammatory factors, which were modulated by the sulindac diet, including upregulation of hypoxia inducible factor 1α and macrophage inflammatory protein 2.

Conclusions These data show that the sulindac diet promotes carcinogenesis in the mouse proximal colon possibly through chronic inflammation. Sulindac has both beneficial and harmful effects in vivo, which are associated with different microenvironments within the colon of experimental mice. Deficiency for the Msh2 or p53 tumour suppressor genes increases the harmful side effects of long-term sulindac treatment in the mouse colon.

  • Msh2, p53 or HIF1α
  • deficient mice
  • NSAID sulindac
  • chemoprevention
  • inflammation and colorectal cancer
  • MIP-2
  • carcinogenesis
  • chemoprevention
  • colorectal cancer
  • non-steroidal anti-inflammatory drugs

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Footnotes

  • D M and JJ D contributed equally to this study.

  • Funding RT Hall Trust and the Australian Cancer Research Foundation. Subsidised access was provided to the Bioanalytical Mass Spectrometry Facility within the Analytical Centre of the UNSW. MKC and EM are Cancer Institute NSW Career Development Fellows and MKC is a recipient of the Cancer Institute NSW Program Grant SCRIPT for Colorectal Cancer. DM was supported by the Cancer Institute NSW Research Scholar Award and the Australian Postgraduate Award, JJD by the National Health and Medical Research Council Dora Lush Biomedical Scholarship.

  • Competing interests None declared.

  • Ethics approval All animal experiments were approved by the Garvan/St Vincent's Animal Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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