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| Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis |
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| Author(s): Boolbol SK, Dannenberg AJ, Chadburn A, Martucci C, Guo XJ, Ramonetti JT, AbreuGoris M, Newmark HL, Lipkin ML, DeCosse JJ, Bertagnolli MM |
| Source: CANCER RESEARCH Volume: 56 Issue: 11 Pages: 2556-2560 Published: JUN 1 1996 |
| Times Cited: 431 References: 32 |
| Abstract: Inducible cyclooxygenase (Cox-2), also known as prostaglandin H synthase 2 (PGH-2) is a key enzyme in the formation of prostaglandins and thromboxanes, Cox-2 is the product of an immediate-early gene that is expressed in response to growth factors, tumor promoters, or cytokines. Overexpression of Cox-2 is associated with both human colon cancers and suppression of apoptosis in cultured epithelial cells, an activity that is reversed by the nonsteroidal anti-inflammatory drug, sulindac sulfide, To address the relationship between Cox-2, apoptosis, and tumor development in vivo, we studied C57BL/6J-Min/+(Min) mice, a strain containing a fully penetrant dominant mutation in the Ape gene, leading to the development of gastrointestinal adenomas by 110 days of age, Min mice were fed AIN-76A chow diet and given sulindac (0.5 +/- 0.1 mg/day) in drinking water, Control Min mice and homozygous C57BL/6J-+/+ normal littermates lacking the Ape mutation (+/+) were fed AIN-76A diet and given tap water to drink, At 110 days of age, all mice were sacrificed, and their intestinal tracts were examined, Control Min mice had 11.9 +/- 7.8 tumors per mouse compared to 0.1 +/- 0.1 tumors for sulindactreated Min mice, As expected, +/+ littermates had no macroscopic tumors. Examination of histologically normal-appearing small bowel from Min animals revealed increased amounts of Cox-2 and prostaglandin E(2) compared to +/+ littermates, Using two different in situ techniques, terminal transferase-mediated dUTP nick end labeling and a direct immunoperoxidase method, Min animals also demonstrated a 27-47% decrease in enterocyte apoptosis compared to +/+ animals, Treatment with sulindac not only inhibited tumor formation but decreased small bowel Cox-2 and prostaglandin E, to baseline and restored normal levels of apoptosis, These data suggest that overexpression of Cox-2 is associated with tumorigenesis in the gastrointestinal epithelium, and that both are inhibited by sulindac administration.
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| Document Type: Article |
| Language: English |
Addresses:
1. CORNELL UNIV, NEW YORK HOSP, MED CTR, NEW YORK, NY 10021 USA
2. STRANG CANC PREVENT CTR, NEW YORK, NY 10021 USA |
| Publisher: AMER ASSOC CANCER RESEARCH, PUBLIC LEDGER BLDG, SUITE 816, 150 S. INDEPENDENCE MALL W., PHILADELPHIA, PA 19106 |
| Subject Category: Oncology |
| IDS Number: UN250 |
| ISSN: 0008-5472 |
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