Article

Regional response leading to tumorigenesis after sulindac in small and large intestine of mice with Apc mutations.

Strang Cancer Research Laboratory at The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Carcinogenesis (Impact Factor: 5.33). 04/2003; 24(3):605-11.
Source: PubMed

ABSTRACT

Sulindac and other NSAIDs have been widely studied as potential chemopreventive agents for colon cancer. Short-term studies have shown adenomatous polyps to regress in patients with familial adenomatous polyposis (FAP). In this study the effect of sulindac on cancer as an endpoint was evaluated in ApcMin mice, a preclinical model of FAP with an Apc mutation in codon 850 that leads to gastrointestinal adenomas and carcinomas. Three groups of mice were studied all of which were fed AIN-76A diet: one group was fed AIN-76A diet alone, a second group received sulindac 200 p.p.m. premixed in the diet and a third group received sulindac 180 p.p.m. added in drinking water. ApcMin mice were killed 9 weeks after feeding was initiated. Mice receiving sulindac developed fewer tumors in the intestine overall; the major decrease in tumor development after sulindac was seen in the small intestine regardless of route of administration. In the large intestine, however, sulindac significantly increased the incidence, multiplicity and volume of tumors in the colon of ApcMin mice, a regional response to sulindac differing from previous reports. Quantitative measurements of apoptosis, Bax and Bcl-xL protein expression in the ApcMin mice revealed the ratio of Bax/Bcl-xL expression and apoptosis increased in the small intestine but decreased in the cecum, consistent with the regional tumorigenesis observed after sulindac. These findings thus suggest involvement of Bax and apoptosis in tumors developing after sulindac treatment in this mouse model.

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Available from: Raju Kucherlapati
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    • "For example, mice receiving sulindac developed fewer tumours in the overall intestine and the major decrease in tumour development after sulindac treatment was seen in the small intestine. However, sulindac significantly increased the incidence, multiplicity and volume of tumours in the colon of Min/+ mice [69] . So, there is a region-specific response to sulindac . "
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    • "Nevertheless, the anti-emetic and anti-pruretic actions in the present report suggest that Zangrado is not only effective but possesses characteristics that offer advantages over current therapeutic options. The Apc Min/+ murine model of colon cancer [23] was chosen for evaluation because nausea and emesis are significant factors in the management of cancer, chemotherapy and palliative medicine in general [10]. In these states it is important that any therapy does not exacerbate the cancerous state while alleviating the symptoms, hence the evaluation in the Min/+ model of familial adenomatous polyposis. "
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    • "For example, treatment of HT-29 cells with sulindac results in loss of resistance to apoptosis, which is associated with an apoptotic effect of PLA 2 [53,66]. But sulindac does not produce the same effect in small and large intestine of mice with APC mutation [67], because there is a difference in apoptotic response and Bax/Bcl-xL expression between small and large intestine. Our study is the first to show that sulindac can correct defective AARGC in small intestine of APC Min/+ mice. "
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