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Titolo:
Chemoprevention of intestinal polyposis in the Apc(Delta 716) mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor
Autore:
Oshima, M; Murai, N; Kargman, S; Arguello, M; Luk, P; Kwong, E; Taketo, MM; Evans, JF;
Indirizzi:
Merck & Co Inc, Dept Pharmacol, W Point, PA 19486 USA Merck & Co Inc W Point PA USA 19486 Dept Pharmacol, W Point, PA 19486 USA Banyu Pharmaceut Co Ltd Merck, Tsukuba Res Inst, Tsukuba, Ibaraki 3002611,Japan Banyu Pharmaceut Co Ltd Merck Tsukuba Ibaraki Japan 3002611 3002611,Japan Merck Frosst Canada Inc, Merck Frosst Ctr Therapeut Res, Pointe Claire, PQH9R 4P8, Canada Merck Frosst Canada Inc Pointe Claire PQ Canada H9R 4P8 PQH9R 4P8, Canada Univ Tokyo, Grad Sch Pharmaceut Sci, Lab Biomed Genet, Tokyo 1130033, Japan Univ Tokyo Tokyo Japan 1130033 i, Lab Biomed Genet, Tokyo 1130033, Japan
Titolo Testata:
CANCER RESEARCH
fascicolo: 4, volume: 61, anno: 2001,
pagine: 1733 - 1740
SICI:
0008-5472(20010215)61:4<1733:COIPIT>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
FAMILIAL ADENOMATOUS POLYPOSIS; PROSTAGLANDIN G/H SYNTHASE-1; COLON-CANCER CELLS; ANTIINFLAMMATORY DRUGS; COLORECTAL ADENOMAS; KNOCKOUT MICE; MIN MOUSE; EXPRESSION; SULINDAC; EFFICACY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Evans, JF Merck & Co Inc, Dept Pharmacol, WP26A-3000,770 Sunneytown Pike, W Point, PA 19486 USA Merck & Co Inc WP26A-3000,770 Sunneytown Pike W PointPA USA 19486
Citazione:
M. Oshima et al., "Chemoprevention of intestinal polyposis in the Apc(Delta 716) mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor", CANCER RES, 61(4), 2001, pp. 1733-1740

Abstract

Mutations in the human adenomatous polyposis (APC) gene are causative for familial adenomatous polyposis (FAP), a rare condition in which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer, The APC gene is a tumor suppressor that has been termed the "gatekeeper gene" for colon cancer. In addition to the 100% mutation rate in FAP patients, the APC gene is mutated in >80% of sporadic colon and intestinal cancers. The Ape gene in mice has been mutated either by chemical carcinogenesis, resulting in the Min mouse Apc(Delta 850), or by heterologous recombination, resulting in the Apc(Delta 716) or Apc(Delta 1368) mice (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). Although homozygote Apc(-/-) mice are embryonically lethal, the heterozygotes are viable but develop numerous intestinal polyps with loss of Ape heterozygosity within thepolyps (M. Oshima et al., Proc. Natl. Acad, Sci. USA, 92: 4482-4486, 1995). The proinflammatory, prooncogenic protein cyclooxygenase (COX)-2 has beenshown to be markedly induced in the Apc(Delta 716) polyps at an early stage of polyp development (M. Oshima et al., Cell, 87: 803-809, 1996). We demonstrate here that treatment with the specific COX-2 inhibitor rofecoxib results in a dose-dependent reduction in the number and size of intestinal andcolonic polyps in the Apc(Delta 716) mouse. The plasma concentration of rofecoxib that resulted in a 55% inhibition of polyp number and an 80% inhibition of polyps >1 mm in size is comparable with the human clinical steady-state concentration of 25 mg rofecoxib (Vioxx) taken once daily (A. Porras et al., Clin. Pharm. Ther., 67: 137, 2000). Polyps from both untreated and rofecoxib- or sulindac-treated Apc(Delta 716) mice expressed COX-1 and -2, whereas normal epithelium from all mice expressed COX-1 but minimal amounts of COX-2. Polyps from either rofecoxib- or sulindac-treated mice had lower rates of DNA replication, expressed less proangiogenic vascular endothelial-derived growth factor and more membrane-hound beta -catenin, but showed unchanged nuclear localization of this transcription factor. This study showing the inhibition of polyposis in the Apc(Delta 716) mouse suggests that the specific COX-2 inhibitor rofecoxib (Vioxx) has potential as a chemopreventive agent in human intestinal and colon cancer.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 11/07/20 alle ore 14:37:56