Sulindac enhances cell proliferation in DMH-treated mouse colonic mucosa.
In a previous study we reported that the NSAID sulindac had a marked inhibitory effect on the development of colonic tumours in mice treated with the carcinogen 1,2-dimethylhydrazine (DMH). In this study we examined the effects of sulindac in respect of cell-kinetic changes in mouse colonic mucosa as determined by flash labelling with the thymidine analogue bromodeoxyuridine (BrdUrd) at varying intervals during the process of colonic carcinogenesis. We also investigated the possibility that these changes may be modulated by misoprostol a prostaglandin E1 analogue. Four groups of 36 mice each were treated for 18 weeks with the following drug/s respectively: (1) DMH; (2) DMH and sulindac; (3) DMH, sulindac and misoprostol; and (4) DMH and misoprostol. Three animals from each group were killed each week between the sixth week and the eighteenth week after the start of the experiment. A 1-h flash label technique was employed and paraffin sections of colonic mucosa were examined. For each animal a total of 50 perfect axially cut crypts were chosen and the following parameters determined: crypt length, labelling index and labelling index distribution: the data were analysed using the computer program GLIM. For each of the four groups, crypt lengths increased significantly with the duration of treatment with no significant difference between the groups. In sulindac-treated animals the labelling index for all positions increased with duration of treatment whereas for animals not treated with sulindac there was no significant difference in labelling index with respect to duration of treatment. The administration of misoprostol did not appear to significantly alter the effects of sulindac. It is postulated that the observed increase in cell proliferation could be a compensatory phenomenon occurring secondary to loss of crypt epithelial cells by apoptosis induced by sulindac. Also the finding of an increase in labelling index mediated by a chemopreventive agent indirectly questions the rationale behind the therapeutic manipulation of crypt cell proliferation in order to reduce the risk of colon cancer.
Moorghen
M
M
Department of Pathology and Microbiology, University of Bristol, UK. M.Moorghen@bristol.ac.uk
Orde
M
M
Finney
K J
KJ
Appleton
D R
DR
Watson
A J
AJ
D019813:1,2-Dimethylhydrazine / Q000633:toxicity*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003106:Colon; D005260:Female; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016595:Misoprostol / Q000494:pharmacology; D008940:Mitotic Index; D013467:Sulindac / Q000494:pharmacology*; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002273:Carcinogens; D016595:Misoprostol; D013467:Sulindac; D019813:1,2-Dimethylhydrazine