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


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.


Available from: Raju Kucherlapati
  • Source
    • "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 . "
    [Show abstract] [Hide abstract] ABSTRACT: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a prominent heterocyclic aromatic amine (HAA) found in meat and fish cooked at moderate to high temperature. It is considered as a potent dietary factor promoting colon carcinogenesis. However, the role of intestinal cells in PhIP bioactivation has not been fully explained, particularly when cells are pre-malignant. Loss of function of the adenomatous polyposis coli (APC) gene product is an early and frequent event in human colorectal carcinogenesis. Normal (Apc(+/+)) and pre-malignant (Apc(Min/+), where Min=multiple intestinal neoplasia) colonic epithelial cells of mice can be used to study promotion of carcinogenesis, but these cells have not been characterized for bio-activation of HAA. We investigated the metabolism of (14)C-PhIP in these two murine cell lines. Cells induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) metabolized PhIP into 4'-OH-PhIP as the main metabolite in PhiP detoxification. Besides, 5-OH-PhIP was identified, revealing the formation of intermediary reactive metabolites, since it results from a degradation of conjugates of N-acetoxy-PhIP. Apc(Min/+) cells produce significantly higher amounts of these metabolites. Demethylated metabolites are also observed, indicating that the colon contains a significant CYP1 family dependent metabolic activity. A minor hydroxy-glucuronide-PhIP metabolite is observed in Apc(Min/+) cells, the glucuronidation being known as an important step in the detoxification pathway. Quantitative real-time reverse transcription polymerase chain reaction experiments demonstrate that induction by TCDD has prevailing effects in gene expression of CYP1A1, CYP1A2 and CYP1B1 in Apc(Min/+) cells. In these cells, N-acetyltransferase-2 is also expressed at higher levels. So, the more important potency to metabolically bio-activate PhIP, as measured in Apc(Min/+) cells, can be linked to a higher probability to generate new in situ mutations.
    Full-text · Article · Jun 2008 · Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
  • Source
    • "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. "
    [Show abstract] [Hide abstract] ABSTRACT: We examined the therapeutic potential of a proprietary Croton palanostigma extract (Zangrado(R)) in the management of emesis and itch. Emesis was induced in ferrets with morphine-6-glucuronide (0.05 mg/kg sc) in the presence of Zangrado (3 mg/kg, ip) and the cannabinoid receptor 1 antagonist, AM 251 (5 mg/kg, ip). Topical Zangrado (1%) was assessed for anti-pruretic actions in the 5-HT-induced scratching model in rats and evaluated in capsaicin-induced gastric hyperemia as measured by laser doppler flow. In the ApcMinmouse model of precancerous adenomatosis polyposis, mice received Zangrado (100 mug/ml in drinking water) from the age of 6 - 16 weeks for effects on polyp number. In RAW 264.7 cells Zangrado was examined for effects on lipopolysaccharide-induced nitrite production. Zangrado was a highly effective anti-emetic, reducing morphine-induced vomiting and retching by 77%. These benefits were not associated with sedation or hypothermia and were not reversed by cannabinoid receptor antagonism. Itch responses were blocked in both the morphine and 5-HT models. Zangrado did not exacerbate the ApcMincondition rather health was improved. Capsaicin-induced hyperemia was blocked by Zangrado, which also attenuated the production of nitric oxide by activated macrophages. Zangrado is an effective anti-emetic and anti-itch therapy that is devoid of common side-effects, cannabinoid-independent and broadly suppresses sensory afferent nerve activation. This complementary medicine represents a promising new approach to the management of nausea, itch and irritable bowel syndrome.
    Full-text · Article · Feb 2008 · Journal of Translational Medicine
  • Source
    • "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. "
    [Show abstract] [Hide abstract] ABSTRACT: The effect of APC loss on azoxymethane (AOM)-induced apoptosis and cell proliferation, as well as their regulation by sulindac was examined in colon and small intestine in APC(Min/+) mice. APC(Min/+) mice showed increased epithelial proliferation in all regions, with significant impairment of apoptosis in small intestine, but not in colon. Sulindac administration restored defective apoptosis to normal. As the apoptotic defect occurred at the major site of intestinal tumor formation in APC(Min/+) mice and as it was restored to normal by a proven chemopreventive agent, this defect in apoptosis might be a key biological consequence of APC dysfunction contributing to tumor formation.
    Full-text · Article · May 2007 · Cancer Letters
Show more