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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    • "The ApcMin/+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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    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.
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    ABSTRACT: Colorectal cancer is among the major cancers and one of the leading causes of cancer-related deaths in Western societies. Its occurrence is strongly affected by environmental factors such as diet. Thus, for preventative strategies it is vitally important to understand the mechanisms that stimulate adenoma growth and development towards accelerated malignancy or, in contrast, attenuate them to remain in quiescence for periods as long as decades. The main objective of this study was to investigate whether diet is able to modulate β-catenin signalling related to the promotion or prevention of intestinal tumourigenesis in an animal model of colon cancer, the Min/+ mouse. 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On the other hand, adenomas staying quiescent for a long period of time are most probably found in the cloudberry or white currant diet groups. The levels of membranous E-cadherin and β-catenin increased as the adenomas in the inulin diet group grew, which could be a result of the overall increase in the protein levels of the cell. Therefore, the increasing levels of membranous β-catenin in Min/+ mice adenomas would be undesirable, due to the simultaneous increase in oncogenic nuclear β-catenin. We propose that the decreased amount of membranous β-catenin in benign adenomas of berry groups also means a decrease in the nuclear pool of β-catenin. Tumour promotion, but not the tumour prevention, influenced β-catenin signalling already in the normal appearing mucosa. Inulin-induced tumour promotion was related to β-catenin signalling in Min/+ mice, and in WT mice changes were also visible. 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Ravinnon siis tiedetään vaikuttavan paksusuolisyövän kehitykseen, mutta tarkkaa selitystä tälle ei vielä osata antaa. Syövän ehkäisemiseksi olisi tärkeä löytää ravinnon suolistossa aiheuttamia muutoksia, jotka joko altistavat tai suojaavat syövältä. Olisi myös tärkeä ymmärtää syömämme ruoan vaikutus siihen, miksi jotkut kasvaimet muuttuvat nopeasti syöväksi, kun taas toiset kasvaimet pysyvät vuosikausia hyvänlaatuisina muuttumatta syöväksi. Syövän kehitys on monimutkainen prosessi, jossa solujen normaali kehitys muuttuu mm. siksi, että solut tulkitsevat ulkopuoleltaan tulevaa informaatiota väärin omien viestiketjujensa häiriintyessä. Solujen sisäisiä signalointireittejä tiedetään olevan huomattava määrä ja yksi selkeästi paksusuolisyövän kehitykseen liitetty on β-kateniini -signalointi. Marjo Misikankaan väitöskirjatutkimuksen tarkoituksena oli selvittää kokeellisella paksusuolisyöpämallilla voidaanko ravinnolla muuttaa suoliston solujen β-kateniini -signalointia. 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