PMID:11245490

Citation	Oshima, M, Murai, N, Kargman, S, Arguello, M, Luk, P, Kwong, E, Taketo, MM and Evans, JF (2001) Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res. 61:1733-40
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 Apc gene in mice has been mutated either by chemical carcinogenesis, resulting in the Min mouse Apcdelta850, or by heterologous recombination, resulting in the Apcdelta716 or Apedelta1368 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 Apc heterozygosity within the polyps (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). The proinflammatory, prooncogenic protein cyclooxygenase (COX)-2 has been shown to be markedly induced in the Apcdelta716 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 and colonic polyps in the Apcdelta716 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 Apcdelta716 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-bound beta-catenin, but showed unchanged nuclear localization of this transcription factor. This study showing the inhibition of polyposis in the Apcdelta716 mouse suggests that the specific COX-2 inhibitor rofecoxib (Vioxx) has potential as a chemopreventive agent in human intestinal and colon cancer.
Links	PubMed
Keywords	Animals; Anticarcinogenic Agents/pharmacokinetics; Anticarcinogenic Agents/pharmacology; Cell Nucleus/metabolism; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors/pharmacokinetics; Cyclooxygenase Inhibitors/pharmacology; Cytoskeletal Proteins/metabolism; DNA Replication/drug effects; Dose-Response Relationship, Drug; Female; Genes, APC/genetics; Intestinal Neoplasms/enzymology; Intestinal Neoplasms/genetics; Intestinal Neoplasms/prevention & control; Intestinal Polyps/enzymology; Intestinal Polyps/genetics; Intestinal Polyps/prevention & control; Isoenzymes/antagonists & inhibitors; Isoenzymes/biosynthesis; Lactones/pharmacokinetics; Lactones/pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin-Endoperoxide Synthases/biosynthesis; Sulfones; Sulindac/analogs & derivatives; Sulindac/pharmacokinetics; Sulindac/pharmacology; Trans-Activators; beta Catenin
edit table

Annotations

Gene product	Qualifier	GO ID	GO term name	Evidence Code	with/from	Aspect	Notes	Status
edit table

References

See Help:References for how to manage references in GONUTS.