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Gut. Dec 2000; 47(6): 812–819.
PMCID: PMC1728141
Sulindac and a cyclooxygenase-2 inhibitor, etodolac, increase APC mRNA in the colon of rats treated with azoxymethane
Y Kishimoto, N Takata, T Jinnai, T Morisawa, G Shiota, H Kawasaki, and J Hasegawa
Department of Clinical Pharmacology, Faculty of Medicine, Tottori University, 86 Nishicho, Yonago 683-8503, Japan. ykishimo/at/grape.med.tottori-u.ac.jp
BACKGROUND—Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to protect against the development of colon cancer. However, the mechanism(s) by which NSAIDs exert their effects is not clear.
AIMS—The aim of this study was to examine the effects of NSAIDs on mRNA expression of tumour suppressor adenomatous polyposis coli (APC) gene in rat colon mucosa.
METHODS—Starting at six weeks of age, three groups of rats (groups 1, 2, and 3) were treated with azoxymethane (AOM), a colon specific carcinogen, and another three groups (groups 4, 5, and 6) were not given AOM. Groups 2 and 3 were given 10 mg/kg of sulindac or etodolac, respectively, three times weekly during the experiment. Groups 4 and 5 were also given sulindac or etodolac, respectively, in the same manner as in groups 2 and 3. Group 6 (untreated control) was not given any agent (AOM or NSAIDs). At 10 weeks of age, preneoplastic lesions (aberrant crypt foci (ACF)) induced by AOM in the colon were counted, and the level of expression of APC mRNA in the colonic mucosa was estimated by the reverse transcription-competitive polymerase chain reaction method and northern blot analysis.
RESULTS—Mean occurrence of ACF in rats in groups 2 and 3 was reduced to approximately 50% of that in group 1. The level of APC mRNA expression in group 1 (AOM alone) was lower than that in group 6 (untreated control) (p<0.05); however, levels of APC mRNA expression in groups 2, 3, 4, and 5, to which NSAIDs had been administered, were significantly increased compared with levels in groups 1 and 6 (p<0.01).
CONCLUSIONS—Both sulindac and etodolac reduced the occurrence of ACF and induced an increase in APC mRNA in rat colon mucosa.


Keywords: adenomatous polyposis coli; cyclooxygenase; non-steroidal anti-inflammatory drugs; aberrant crypt foci; colon; azoxymethane
Figure 1
Figure 1  
Experimental protocol. Azoxymethane (AOM) was given as 15 mg/kg by subcutaneous injection, saline as 0.3 ml subcutaneously, sulindac as 10 mg/kg in 5% gum arabic aqueous solution three times a week by oral savage, and etodolac (more ...)
Figure 2
Figure 2  
Analysis of cyclooxygenase (COX)-2, COX-1, adenomatous polyposis coli (APC), and β-actin mRNA expression. mRNA extracted from rat colonic tissue was reverse transcribed and amplified in the presence of different amounts of mimic DNA (lanes, from (more ...)
Figure 3
Figure 3  
Northern blot analysis of cyclooxygenase (COX)-1 and adenomatous polyposis coli (APC) mRNAs from each group (groups 1, 2, 3, 4, 5, and 6). β-Actin expression was used as an internal control.
Figure 4
Figure 4  
Levels of COX-2 mRNA expression measured by RT-competitive PCR. Data are shown as box plots: the box covers all values (including minimum and maximum values). The broken line indicates the limit of detection for COX-2 mRNA expression by RT-PCR. Levels (more ...)
Figure 5
Figure 5  
Levels of COX-1 expression measured by RT-competitive PCR. Data are shown as box plots: the box covers all values (including minimum and maximum values), and the central continuous line in each box represents the mean. Levels of COX-1 expression in each (more ...)
Figure 6
Figure 6  
Levels of adenomatous polyposis coli (APC) expression measured by RT-competitive PCR. Data are shown as box plots: the box covers all values (including minimum and maximum values), and the central continuous line in each box represents the mean. Levels (more ...)
Figure 7
Figure 7  
COX-1 and APC mRNA expression measured by northern blot analysis. mRNA levels were measured by northern blot analysis as described in materials and methods. Values are expressed as the ratio (%) to the average of those of group 6 (no treatment). (more ...)
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