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. 2001 May;48(5):660–666. doi: 10.1136/gut.48.5.660

Non-steroidal anti-inflammatory drugs with activity against either cyclooxygenase 1 or cyclooxygenase 2 inhibit colorectal cancer in a DMH rodent model by inducing apoptosis and inhibiting cell proliferation

W Brown 1, S Skinner 1, C Malcontenti-Wilso 1, D Vogiagis 1, P O'Brien 1
PMCID: PMC1728280  PMID: 11302965

Abstract

BACKGROUND—Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer by 40-60% but the mechanism by which this occurs is uncertain. Selective cyclooxygenase 2 inhibitors are potentially ideal chemopreventive agents as they are less toxic than standard NSAIDs. No study has compared the efficacy of these drugs at clinically relevant doses in a tumour model.
AIMS—To assess the efficacy of a range of NSAIDs with varying activity against the two cyclooxygenase isoforms in a rodent colorectal carcinogen model at anti-inflammatory doses and to explore the effect of NSAIDs on the rate of tumour apoptosis and proliferation.
METHODS—Colorectal tumours were induced in six week old Sprague-Dawley rats with five weekly doses of 1,2 dimethylhydrazine. Test agents were: indomethacin 2 mg/kg/day, meloxicam 0.6 mg/kg/day, celecoxib 6 mg/kg/day, and sulindac sulphone 40 mg/kg/day. Sulindac was tested at its chemoprotective dose of 20 mg/kg/day. After 23 weeks the number and volume of tumours per animal were recorded. Histology was performed. Tumour apoptosis was quantified on haematoxylin-eosin sections. Tumour proliferation was quantified using an immunohistochemical stain for bromodexoyuridine incorporation.
RESULTS—Test agents effectively reduced the number and volume of tumours developing in the treatment period. In all groups there was an increase in the rate of tumour apoptosis and a reduced rate of proliferation.
CONCLUSIONS—These data suggest that the chemopreventive effect of NSAIDs is independent of their cyclooxygenase inhibitory profile. One potential mechanism for their action may be through induction of apoptosis and inhibition of proliferation.


Keywords: non-steroidal anti-inflammatory drugs; chemoprevention; colorectal cancer; apoptosis; bromodexoyuridine

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Figure 1  .

Figure 1  

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Photomicrograph of rodent colorectal tumour (×1000 magnification; oil emersion). Apoptotic tumour cells were recognised by their shrunken size, loss of contact with surrounding tissue (at times forming the classically described halo), and nuclear condensation. Arrows indicate examples of apoptotic tumour cells.

Figure 2  .

Figure 2  

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Mean (SEM) number of tumours developing per animal over 23 weeks was significantly reduced compared with control animals in all treatment groups. *p<0.05.

Figure 3  .

Figure 3  

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Mean (SEM) volume of tumour (tumour load) developing per animal over 23 weeks was significantly reduced compared with control animals in all treatment groups. *p<0.05.

Figure 4  .

Figure 4  

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Mean (SEM) rate of apoptosis per tumour in all treatments was increased compared with the mean rate of apoptosis per tumour in control animals. Within treatment groups there was no significant difference in the mean rates of apoptosis according to their histology.

Figure 5  .

Figure 5  

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Mean (SEM) rate of cells in the S phase (proliferation index) per tumour in all treatments was decreased compared with the mean proliferation index per tumour in control animals. Within treatment groups, there was no significant difference in the mean proliferation index according to their histology.

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