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.