Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction

R. A. Wagenaar-Miller, G. Hanley, R. .Shattuck-Brandt, R. N. DuBois, R. L. Bell, L. M. Matrisian, D. W. Morgan

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2) are expressed in both sporadic and familial adenomatous colonic polyps and tumours and have been independently shown to play causal roles in intestinal tumour formation in mouse models of colon cancer. The apparent roles of these enzymes in intestinal tumorigenesis led us to examine, in the Min mouse model of colon cancer, if selective COX-2 and MMP inhibitors provide additive or synergistic therapeutic benefits in intestinal turnout prevention. The broad-spectrum MMP inhibitor (A-177430; MMPI) and the selective COX-2 inhibitor (A-285969; COX-21) both showed dose-dependent inhibition of the number of adenomas in Min mice. Using suboptimal doses, the MMPI reduced turnout multiplicity by 32%, the COX-21 by 48% and, both agents in combination resulted in a 67% decrease compared to control demonstrating a cooperative effect on intestinal tumorigenesis. Apoptosis, proliferation, and angiogenesis were assayed in tumors from each treatment group. These agents in combination allowed for a lowered dosage to be administered to achieve significant biological effects. Clinically, this could potentially reduce side effects associated with currently used MMP and COX-2 inhibitors. Together, these compounds could represent an easily tolerated chemopreventive approach.

Original languageEnglish (US)
Pages (from-to)1445-1452
Number of pages8
JournalBritish Journal of Cancer
Volume88
Issue number9
DOIs
StatePublished - May 6 2003
Externally publishedYes

Keywords

  • Colon cancer
  • Cyclooxygenase-2
  • Matrix metalloproteinase
  • Multiple intestinal neoplasia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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