Therapeutic utility of aspirin in the ApcMin/+ murine model of colon carcinogenesis

Abstract

Background: In recent years it has become evident that nonsteroidal anti-inflammatory drugs, in particular aspirin represent a potential class of cancer chemotherapeutic agents. Despite the wealth of knowledge gained from epidemiological, clinical and animal studies, the effectiveness of aspirin to treat established gastrointestinal cancer has not been determined. The present study examines the ability of aspirin to treat established polyposis in Min/+ mice.

Methods: Min/+ mice with established polyposis were treated orally once daily from 12-16 weeks of age with either drug vehicle or aspirin (25 mg/kg). Upon completion of treatment, the number, location and size of intestinal tumours was determined. Additional variables examined were the number of apoptotic cells within tumours and COX activity.

Results: Administration of aspirin for 4 weeks to Min/+ mice produce no effect on tumour number compared to vehicle-treated Min/+ mice (65 +/- 8 vs. 63 +/- 9, respectively). In addition, aspirin had no effect on tumour size or location. However, aspirin treatment produced a greater than 2-fold (p<0.05) increase in the number of apoptotic positive cells within tumours and significantly decreased hepatic PGE2 content.

Conclusions: Aspirin was found to have no effect on tumour number and size when administered to Min/+ mice with established polyposis. The findings in the present study call in to question the utility of aspirin as a stand-alone treatment for established GI cancer. However, aspirin's ability to significantly promote apoptosis may render it suitable for use in combinatorial chemotherapy.

Figure 1

Size distribution of adenomas in the small (panel A) and large (panel B) intestines of Min/+ mice treated once daily with aspirin over a period of four weeks. Adenoma sizes were determined from captured images and categorised based on diameter (mm). Data are presented as the percent of total polyps.

Figure 2

Effect of aspirin on cyclooxygenase (COX) activity in Min/+ mice. COX activity was determined by measuring the ability of hepatic tissue to synthesise prostaglandin E₂ (PGE₂) ex vivo. Hepatic tissue was obtained 3 hours following the final dose of either vehicle (n = 13) or aspirin (25 mg/kg p.o., n = 11). A separate group of wild type mice (n = 6) were treated with vehicle once daily for 4 weeks to establish normal capacity of liver tissue to synthesise PGE₂. Data are expressed as the mean ± SEM. ^* p < 0.05 versus wild type. δ p < 0.05 versus vehicle-treated Min/+ mice. Statistical analysis conducted using a one-way analysis of variance with a Bonferroni post test.

Figure 3

Assessment of apoptosis in small intestinal adenomas of vehicle- and aspirin-treated Min/+ mice. Apoptosis was detected in situ via the TUNEL principle. An average of 4 adenomas were counted per animal. Data are depicted as the number of apoptotic cells per adenoma area (mm²). ^* p = 0.05 versus vehicle-treated Min/+ mice.