TY - JOUR
T1 - Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction
AU - Wagenaar-Miller, R. A.
AU - Hanley, G.
AU - .Shattuck-Brandt, R.
AU - DuBois, R. N.
AU - Bell, R. L.
AU - Matrisian, L. M.
AU - Morgan, D. W.
N1 - Funding Information:
We thank Dr Barbara Fingleton for her assistance with microscopy and for her thoughtful comments regarding the manuscript. We also thank Dr Ambra Pozzi for providing the cultured endothelial cells and for her assistance with the in vitro apoptosis assay. Finally, we thank the staff of the Vanderbilt University Animal Care Facility for their excellent care of the mice. Supported by NIH T32 CA 09385 (RAW-M), ROI CA60867, and P30 CA68485.
PY - 2003/5/6
Y1 - 2003/5/6
N2 - 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.
AB - 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.
KW - Colon cancer
KW - Cyclooxygenase-2
KW - Matrix metalloproteinase
KW - Multiple intestinal neoplasia
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U2 - 10.1038/sj.bjc.6600867
DO - 10.1038/sj.bjc.6600867
M3 - Article
C2 - 12778076
AN - SCOPUS:0038751784
SN - 0007-0920
VL - 88
SP - 1445
EP - 1452
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 9
ER -