The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon.
OBJECTIVE
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.
Mladenova
Dessislava
D
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst Sydney NSW 2010, Australia. m.corish@garvan.org.au
Daniel
Joseph J
JJ
Dahlstrom
Jane E
JE
Bean
Elaine
E
Gupta
Ruta
R
Pickford
Russell
R
Currey
Nicola
N
Musgrove
Elizabeth A
EA
Kohonen-Corish
Maija R J
MR
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000172:deficiency; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D013467:Sulindac / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D002273:Carcinogens; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D016159:Tumor Suppressor Protein p53; D013467:Sulindac; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D001397:Azoxymethane