Matrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations

For at least 30 years, matrix metalloproteinases (MMPs) have been heralded as promising targets for cancer therapy on the basis of their massive up-regulation in malignant tissues and their unique ability to degrade all components of the extracellular matrix. Preclinical studies testing the efficacy of MMP suppression in tumor models were so compelling that synthetic metalloproteinase inhibitors (MPIs) were rapidly developed and routed into human clinical trials. The results of these trials have been disappointing. Here we review the studies that brought MPIs into clinical testing and discuss the design and outcome of the trials in light of new information about the cellular source, substrates, and mode of action of MMPs at different stages of tumor progression. The important lessons learned from the MPI experience may be of great value for future studies of MPIs and for cancer drug development in general.

[1]  R. Schultz,et al.  Inhibition by human recombinant tissue inhibitor of metalloproteinases of human amnion invasion and lung colonization by murine B16-F10 melanoma cells. , 1988, Cancer research.

[2]  Y. Iwamoto,et al.  Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. , 1988, Cancer research.

[3]  Y. DeClerck,et al.  Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. , 1990, Journal of the National Cancer Institute.

[4]  Y. DeClerck,et al.  Effect of tissue inhibitor of the matrix metalloproteinases-2 expression on the growth and spontaneous metastasis of a human melanoma cell line. , 1994, Cancer research.

[5]  Y. DeClerck,et al.  Protease inhibitors: role and potential therapeutic use in human cancer. , 1994 .

[6]  R. Khokha,et al.  Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravasation but reduces tumor growth. , 1994, Cancer research.

[7]  R. Khokha.  Suppression of the tumorigenic and metastatic abilities of murine B16-F10 melanoma cells in vivo by the overexpression of the tissue inhibitor of the metalloproteinases-1. , 1994, Journal of the National Cancer Institute.

[8]  G. Sledge,et al.  Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. , 1995, Journal of the National Cancer Institute.

[9]  R. Khokha,et al.  Inhibition of SV40 T antigen-induced hepatocellular carcinoma in TIMP-1 transgenic mice. , 1996, Oncogene.

[10]  W. Stetler-Stevenson.  Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix. , 1996, The American journal of pathology.

[11]  M. Gore,et al.  Tumour marker levels during marimastat therapy , 1996, The Lancet.

[12]  A. Millar,et al.  Tumour marker levels during marimastat therapy , 1996, The Lancet.

[13]  B. Hogan,et al.  Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[14]  L. Matrisian,et al.  Differing effects of endogenous and synthetic inhibitors of metalloproteinases on intestinal tumorigenesis , 1998, International journal of cancer.

[15]  J. Foidart,et al.  In Vivo Evidence That the Stromelysin-3 Metalloproteinase Contributes in a Paracrine Manner to Epithelial Cell Malignancy , 1998, The Journal of cell biology.

[16]  J. Nemunaitis,et al.  Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  L. Matrisian,et al.  The matrix metalloproteinase matrilysin influences early-stage mammary tumorigenesis. , 1998, Cancer research.

[18]  Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen , 1999, British Journal of Cancer.

[19]  Latest FDA approvals for dentistry. , 1999, General dentistry.

[20]  D. Pinkel,et al.  The Stromal Proteinase MMP3/Stromelysin-1 Promotes Mammary Carcinogenesis , 1999, Cell.

[21]  W. Stetler-Stevenson,et al.  Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. , 1999, The Journal of clinical investigation.

[22]  E. Casper,et al.  Marimastat in patients with advanced pancreatic cancer: a dose-finding study. , 1999, American journal of clinical oncology.

[23]  R. Khokha,et al.  Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  A. Gearing,et al.  Design and therapeutic application of matrix metalloproteinase inhibitors. , 1999, Chemical reviews.

[25]  D. Hanahan,et al.  Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. , 1999, Science.

[26]  H. Yoshiji,et al.  The Effects of Sustained Elevated Levels of Circulating Tissue Inhibitor of Metalloproteinases‐1 on the Development of Breast Cancer in Mice , 1999, Annals of the New York Academy of Sciences.

[27]  J. Woessner,et al.  Matrix metalloproteinases and TIMPs , 2000 .

[28]  R. Glasspool,et al.  Clinical imaging of cancer metastasis. , 2000, European journal of cancer.

[29]  B. Druker,et al.  Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. , 2000, The Journal of clinical investigation.

[30]  Shigeyoshi Itohara,et al.  Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis , 2000, Nature Cell Biology.

[31]  L. Matrisian,et al.  Matrix metalloproteinases: multifunctional contributors to tumor progression. , 2000, Molecular medicine today.

[32]  Scott E. Fraser,et al.  In vivo visualization of gene expression using magnetic resonance imaging , 2000, Nature Biotechnology.

[33]  A. Pozzi,et al.  Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[34]  D. Hanahan,et al.  MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis , 2000, Cell.

[35]  G. Bergers,et al.  Matrix metalloproteinases as emerging targets in anticancer therapy: status and prospects , 2000 .

[36]  B. Fingleton,et al.  Matrix metalloproteinases: biologic activity and clinical implications. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  P. Brown.  Ongoing trials with matrix metalloproteinase inhibitors , 2000, Expert opinion on investigational drugs.

[38]  M. Hidalgo,et al.  Development of matrix metalloproteinase inhibitors in cancer therapy. , 2001, Journal of the National Cancer Institute.

[39]  A. Rosemurgy,et al.  Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  A. Krüger,et al.  Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis. , 2001, Cancer research.

[41]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[42]  L. Matrisian,et al.  Matrix metalloproteinases: they're not just for matrix anymore! , 2001, Current opinion in cell biology.

[43]  Ralph Weissleder,et al.  In vivo molecular target assessment of matrix metalloproteinase inhibition , 2001, Nature Medicine.

[44]  A. Pozzi,et al.  Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis , 2002, Oncogene.

[45]  D. Scadden,et al.  Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: a phase I AIDS malignancy consortium study. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.