Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis

• Published in: Cancer research (Chicago, Ill.) Ill.), 1996-06, Vol.56 (11), p.2556-2560
• Main Authors: BOOLBOL, S. K, DANNENBERG, A. J, BERTAGNOLLI, M. M, CHADBURN, A, MARTUCCI, C, GUO, X. J, RAMONETTI, J. T, ABREU-GORIS, M, NEWMARK, H. L, LIPKIN, M. L, DECOSSE, J. J
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli - drug therapy; Animals; Antineoplastic agents; Apoptosis; Base Sequence; Biological and medical sciences; Chemotherapy; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - therapeutic use; Cytokines - genetics; DNA Primers - chemistry; Epithelial Cells; Female; Gene Expression; Intestinal Mucosa - cytology; Isoenzymes - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - metabolism; RNA, Messenger - genetics; Sulindac - therapeutic use
• ISSN: 0008-5472

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 epithelia] 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 Apc 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 Apc 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 sulindac-treated 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(2) 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.