Development of matrix metalloproteinase inhibitors in cancer therapy

Manuel Hidalgo, S. Gail Eckhardt

Research output: Contribution to journalArticle

Abstract

The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.

Original languageEnglish (US)
Pages (from-to)178-193
Number of pages16
JournalJournal of the National Cancer Institute
Volume93
Issue number3
StatePublished - Feb 7 2001
Externally publishedYes

Fingerprint

Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases
Peptidomimetics
Tetracyclines
Neoplasms
Zinc
Catalytic Domain
Therapeutics
Clinical Trials
Neoplasm Metastasis
Phase III Clinical Trials
Clinical Trials, Phase I
Medical Oncology
Diphosphonates
Cytostatic Agents
Growth
Tetracycline
Pharmaceutical Preparations
Biological Availability
Extracellular Matrix

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Development of matrix metalloproteinase inhibitors in cancer therapy. / Hidalgo, Manuel; Eckhardt, S. Gail.

In: Journal of the National Cancer Institute, Vol. 93, No. 3, 07.02.2001, p. 178-193.

Research output: Contribution to journalArticle

Hidalgo, Manuel ; Eckhardt, S. Gail. / Development of matrix metalloproteinase inhibitors in cancer therapy. In: Journal of the National Cancer Institute. 2001 ; Vol. 93, No. 3. pp. 178-193.
@article{938f765951de471a945da9bf946f68c6,
title = "Development of matrix metalloproteinase inhibitors in cancer therapy",
abstract = "The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.",
author = "Manuel Hidalgo and Eckhardt, {S. Gail}",
year = "2001",
month = "2",
day = "7",
language = "English (US)",
volume = "93",
pages = "178--193",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - Development of matrix metalloproteinase inhibitors in cancer therapy

AU - Hidalgo, Manuel

AU - Eckhardt, S. Gail

PY - 2001/2/7

Y1 - 2001/2/7

N2 - The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.

AB - The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.

UR - http://www.scopus.com/inward/record.url?scp=0035819527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035819527&partnerID=8YFLogxK

M3 - Article

VL - 93

SP - 178

EP - 193

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 3

ER -