Reference SummaryWagenaar-Miller RA, Br J Cancer 2003 May 6;88(9):1445-52

Title

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

Authors

Wagenaar-Miller RA; Hanley G; Shattuck-Brandt R; DuBois RN; Bell RL; Matrisian LM; Morgan DW

Journal

Br J Cancer

Volume

Issue

Year

2003

Pages

1445-52

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 tumour prevention. The broad-spectrum MMP inhibitor (A-177430; MMPI) and the selective COX-2 inhibitor (A-285969; COX-2I) both showed dose-dependent inhibition of the number of adenomas in Min mice. Using suboptimal doses, the MMPI reduced tumour multiplicity by 32%, the COX-2I 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.British Journal of Cancer (2003) 88, 1445-1452. doi:10.1038/sj.bjc.6600867 www.bjcancer.com

Links

J:83488 – MGI References
12778076 – National Library of Medicine/PubMed

Strain Notes

Strain	Note
C57BL/6J-Apc^Min/+	Mice were originally obtained from The Jackson Laboratory.

Models
Strain	Model Name	Treatment Agent(s)	Organ Affected	Frequency
C57BL/6J-Apc^Min/+	Intestine adenoma		Intestine	observed
C57BL/6J-Apc^Min/+	Intestine adenoma	A-177430, MMP inhibitor	Intestine	observed
C57BL/6J-Apc^Min/+	Intestine adenoma	A-285969, Cox-2 inhibitor	Intestine	observed
C57BL/6J-Apc^Min/+	Intestine adenoma	sulindac	Intestine	observed
C57BL/6J-Apc^Min/+	Intestine adenoma	A-177430, MMP inhibitor A-285969, Cox-2 inhibitor	Intestine	observed