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 journalArticle

30 Citations (Scopus)

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

Fingerprint

Matrix Metalloproteinase 2
Cyclooxygenase 2
Adenoma
MMPI
Matrix Metalloproteinase Inhibitors
Cyclooxygenase 2 Inhibitors
Colonic Neoplasms
Carcinogenesis
Colonic Polyps
Adenomatous Polyps
Neoplasms
Apoptosis
Enzymes
Inhibition (Psychology)
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wagenaar-Miller, R. A., Hanley, G., .Shattuck-Brandt, R., DuBois, R. N., Bell, R. L., Matrisian, L. M., & Morgan, D. W. (2003). Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction. British Journal of Cancer, 88(9), 1445-1452. https://doi.org/10.1038/sj.bjc.6600867

Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction. / Wagenaar-Miller, R. A.; Hanley, G.; .Shattuck-Brandt, R.; DuBois, R. N.; Bell, R. L.; Matrisian, L. M.; Morgan, D. W.

In: British Journal of Cancer, Vol. 88, No. 9, 06.05.2003, p. 1445-1452.

Research output: Contribution to journalArticle

Wagenaar-Miller, RA, Hanley, G, .Shattuck-Brandt, R, DuBois, RN, Bell, RL, Matrisian, LM & Morgan, DW 2003, 'Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction', British Journal of Cancer, vol. 88, no. 9, pp. 1445-1452. https://doi.org/10.1038/sj.bjc.6600867
Wagenaar-Miller RA, Hanley G, .Shattuck-Brandt R, DuBois RN, Bell RL, Matrisian LM et al. Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction. British Journal of Cancer. 2003 May 6;88(9):1445-1452. https://doi.org/10.1038/sj.bjc.6600867
Wagenaar-Miller, R. A. ; Hanley, G. ; .Shattuck-Brandt, R. ; DuBois, R. N. ; Bell, R. L. ; Matrisian, L. M. ; Morgan, D. W. / Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction. In: British Journal of Cancer. 2003 ; Vol. 88, No. 9. pp. 1445-1452.
@article{e6486a29a0e845d197301eaa703c0af2,
title = "Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction",
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.",
keywords = "Colon cancer, Cyclooxygenase-2, Matrix metalloproteinase, Multiple intestinal neoplasia",
author = "Wagenaar-Miller, {R. A.} and G. Hanley and R. .Shattuck-Brandt and DuBois, {R. N.} and Bell, {R. L.} and Matrisian, {L. M.} and Morgan, {D. W.}",
year = "2003",
month = "5",
day = "6",
doi = "10.1038/sj.bjc.6600867",
language = "English (US)",
volume = "88",
pages = "1445--1452",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "9",

}

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.

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

UR - http://www.scopus.com/inward/record.url?scp=0038751784&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038751784&partnerID=8YFLogxK

U2 - 10.1038/sj.bjc.6600867

DO - 10.1038/sj.bjc.6600867

M3 - Article

C2 - 12778076

AN - SCOPUS:0038751784

VL - 88

SP - 1445

EP - 1452

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 9

ER -