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Matrix metalloproteinase inhibitors

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Abstract

Matrix metalloproteinases (MMPs) are a family of zincdependent proteinases that are associated with the tumorigenic process. MMPs degrade the extracellular matrix, promoting tumor invasion and metastasis. They also regulate host defense mechanisms and normal cell function; blocking all MMPs may not lead to a positive therapeutic outcome. Most clinical trials of MMP inhibitors (MMPIs) have yielded disappointing results, perhaps due to inappropriate study design or tumor staging, or to lack of selectivity. Positive results have been seen in gastric cancer with marimastat and in Kaposi’s sarcoma with metastat. This review summarizes the current status of MMPIs.

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References and Recommended Reading

  1. Fini ME, Cook JR, Mohan R, et al.: Regulation of matrix metalloproteinase gene expression. In Matrix Metalloproteinases. Edited by Parks WC, Mecham RP. San Diego: Academic Press; 1998:299–356.

    Chapter  Google Scholar 

  2. Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases. Structure, function, and biochemistry. Circ Res 2003, 92:827–839. Excellent review on the structure, substrate specificity, and activation of MMPs as well as TIMPs.

    Article  CAS  PubMed  Google Scholar 

  3. Bissell MJ, Radisky D: Putting tumors in context. Nat Rev Cancer 2001, 1:46–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sternlicht MD, Lochter A, Sympson CJ, et al.: The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 1999, 98:137–146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. D’Armiento J, DiColandrea T, Dalal SS, et al.: Collagenase expression in transgenic mouse skin causes hyperkeratosis and acanthosis and increases susceptibility to tumorigenesis. Mol Cell Biol 1995, 15:5732–5739.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bannikov GA, Karelina TV, Collier IE, et al.: Substrate binding of gelatinase B induces its enzymatic activity in the presence of intact propeptide. J Biol Chem 2002, 277:16022–16027.

    Article  CAS  PubMed  Google Scholar 

  7. Knäuper V, Will H, López-Otin C, et al.: Cellular mechanisms for human procollagenase-3 (MMP-13) activation. J Biol Chem 1996, 271:17124–17131.

    Article  PubMed  Google Scholar 

  8. Brew K, Dinakarpandian D, Nagase H: Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 2000, 1477:267–283.

    Article  CAS  PubMed  Google Scholar 

  9. Jiang Y, Goldberg ID, Shi YE: Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 2002, 21:2245–2252.

    Article  CAS  PubMed  Google Scholar 

  10. Park M-J, Kim M-S, Park I-C, et al.: PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. Cancer Res 2002, 62:6318–6322.

    CAS  PubMed  Google Scholar 

  11. Koul D, Parthasarathy R, Shen R, et al.: Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene 2001, 20:6669–6678.

    Article  CAS  PubMed  Google Scholar 

  12. Johansson N, Ala-aho R, Uitto V-J, et al.: Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen activated protein kinase. J Cell Sci 2000, 113:227–235.

    CAS  PubMed  Google Scholar 

  13. Lakka SS, Jasti SL, Gondi C, et al.: Downregulation of MMP-9 in ERK-mutated stable transfectants. Oncogene 2002, 21:5601–5608.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang Y, Thant AA, Machida K, et al.: Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90. Cancer Res 2002, 62:3962–3965.

    CAS  PubMed  Google Scholar 

  15. Hua J, Muschel RJ: Inhibition of matrix metalloproteinase-9 expression by a ribozyme blocks metastasis in a rat sarcoma model system. Cancer Res 1996, 56:5279–5284.

    CAS  PubMed  Google Scholar 

  16. Kondraganti S, Mohanam S, Chintala SK, et al.: Selective suppression of matrix metalloproteinase-9 in human glioblastoma cells by antisense gene transfer impairs glioblastoma cell invasion. Cancer Res 2000, 60:6851–6855.

    CAS  PubMed  Google Scholar 

  17. Lund LR, Rómer J, Bugge TH, et al.: Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO J 1999, 18:4645–4656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Betz M, Huxley P, Davies SJ, Mushtaq et al.: 1.8-A crystal structure of the catalytic domain of human neutrophil collagenase (matrix metalloproteinase-8) complexed with a peptidomimetic hydroxamate primed-side inhibitor with distinct selectivity profile. Eur J Biochem 1997, 247:356–363.

    Article  CAS  PubMed  Google Scholar 

  19. Wojtowicz-Praja S, Low J, Marshall J, et al.: Phase 1 trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer. Invest New Drugs 1996, 14:193–202.

    Google Scholar 

  20. Macaulay VM, O’Byrne KJ, Saunders MP, et al.: Phase 1 study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions. Clin Cancer Res 1999, 5:513–520.

    CAS  PubMed  Google Scholar 

  21. Beattie GJ, Smyth JF: Phase 1 study of intraperitoneal metalloproteinase inhibitor BB94 in patients with malignant ascites. Clin Cancer Res 1998, 4:1899–1902.

    CAS  PubMed  Google Scholar 

  22. Nemunaitis J, Poole C, Primrose J, 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. Clin Cancer Res 1998, 4:1101–1109.

    CAS  PubMed  Google Scholar 

  23. Bramhall SR, Rosemurgy A, Brown PD, et al.: Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001, 19:3447–3455.

    Article  CAS  PubMed  Google Scholar 

  24. Bramhall SR, Hallissey MT, Whiting J, et al.: Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer 2002, 86:1864–1870. This landmark randomized, double-blind, placebo-controlled study of an MMPI in patients with advanced gastric cancer showed a modest survival difference between the two groups.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Coussens LM, Fingleton B, Matrisian LM: Matrix Metalloproteinase inhibitors and cancer: trials and tribulations [review]. Science 2002, 295:2387–2392. This article explains new concepts of MMP action and explores reasons for MMP failures.

    Article  CAS  PubMed  Google Scholar 

  26. Rowinsky EK, Humphrey R, Hammond LA, M et al.: Phase 1 and pharmacologic study of the specific matrix metalloproteinase inhibitor Bay 12-9566 on a protracted oral daily dosing schedule in patients with solid malignancies. J Clin Oncol 2000, 18:178–186.

    Article  CAS  PubMed  Google Scholar 

  27. Goel R, Hirte H, Major P, et al.: Clinical pharmacology of the metalloproteinase (MMP) and angiogenesis inhibitor Bayer 12-9566 in cancer patients [abstract]. Proc ASCO 1999, 18:160a.

    Google Scholar 

  28. Erlichman C, Adjei A, Alberts S, et al.: Phase 1 study of BAY 12-9566: a matrix metalloproteinase inhibitor (MMPI) [abstract]. Proc ASCO 1998, 17:217a.

    Google Scholar 

  29. Grochow L, O’Reilly S, Humphrey R, et al.: Phase 1 and pharmacokinetic study of the matrix metalloproteinase inhibitor (MMPI), BAY 12-9566 [abstract]. Proc ASCO 1998, 17:213a.

    Google Scholar 

  30. Tolcher A, Rowinsky EK, Rizzo J, et al.: A phase 1 and pharmacokinetic study of the oral matrix metalloproteinase inhibitor Bay 12-9566 in combination with paclitaxel and carboplatin [abstract]. Proc ASCO 1999, 18:160.

    Google Scholar 

  31. Moore M, Hamm J, Eisenberg P, et al.: A comparison between gemcitabine (GEM) and the matrix metalloproteinase (MMP) inhibitor BAY12-9566 (9566) in patients (PTS) with advanced pancreatic cancer [abstract]. Proc ASCO 2000, 19:240a.

    Google Scholar 

  32. Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM: Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 2000, 18:1135–1149.

    Article  CAS  PubMed  Google Scholar 

  33. Hande K, Wilding G, Ripple et al.: Phase 1 study of AG3340, a matrix metalloprotease (MMP) inhibitor, in patient having advance cancer [abstract]. Ann Oncol 1998, 9:74.

    Article  Google Scholar 

  34. Wilding G, Small E, Ripple G, et al.: Phase 1 study of AG3340, a matrix metalloprotease inhibitor, in combination with mitoxantrone/prednisone in patients having advanced prostate cancer [abstract]. Ann Oncol 1998, 9:74.

    Article  Google Scholar 

  35. D’Olimpio J, Hande K, Collier M, et al.: Phase 1 study of the matrix metalloprotease inhibitor AG3340 in combination with paclitaxel and carboplatin for the treatment of patients with advanced solid tumors [abstract]. Proc ASCO 1999, 18:160.

    Google Scholar 

  36. Poulaki V: BMS-275291 Bristol-Myers Squibb. Curr Opin Investig Drugs 2002, 3:500–504.

    CAS  PubMed  Google Scholar 

  37. Levitt NC, Eskens F, Proper DJ, et al.: A phase one pharmacokinetic study of CGS27023A, a matrix metalloproteinase inhibitor [abstract]. Proc ASCO 1998, 17:213.

    Google Scholar 

  38. Mant TGK, Bradford DBA, Amin DM, et al.: A phase 1, doubleblind, randomized, placebo-controlled study to investigate the safety, tolerability, and pharmacokinetic profile of S-3304, a matrix metalloproteinase inhibitor, when given in multiple doses with high doses for 4 weeks to healthy volunteers [abstract]. Eur J Cancer 2002, 38:S81.

    Google Scholar 

  39. Yoshioka T, Watanabe F, Tsuzuki H, et al.: In vitro pharmacological profiles and in vivo anti-angiogenesis activity of S-3304, a novel matrix metalloproteinase inhibitor [abstract]. Eur J Cancer 2002, 38:S81.

    Google Scholar 

  40. Creaven PJ, Sullivan DM, Eckhardt G, et al.: A phase I study of S-3304 a matrix metalloproteinases inhibitor in patients with solid tumors [abstract]. Eur J Cancer 2002, 38:S77.

    Google Scholar 

  41. Dupont E, Brazeau P, Juneau C: Extracts of shark cartilage having an antiangiogenic activity and an effect on tumor progression: process of making thereof. United States Patent #5 1995, 618:925.

    Google Scholar 

  42. Gringas D, Renaud A, Mousseau N, et al.: Matrix proteinase inhibition by AE-941, a multifunctional antiangiogenic compound. Anticancer Res 2001, 21:145–156.

    Google Scholar 

  43. Batist G, Patenaude F, Champage P, et al.: Neovastat (AE-941) in refractory renal cell carcinoma patients: report of a phase II trial with two dose levels. Ann Oncol 2002, 13:1259–1263.

    Article  CAS  PubMed  Google Scholar 

  44. Gordon MS, Battiato LA, Jones D, et al.: A phase 1 trial of doxycycline (Doxy) in patients with caner [abstract]. Proc ASCO 1997, 16:226.

    Google Scholar 

  45. Rudek MA, Figg WD, Dyer V, et al.: Phase 1 clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J Clin Oncol 2001, 19:584–592.

    Article  CAS  PubMed  Google Scholar 

  46. Cianfrocca M, Cooley TP, Lee JY, et al.: Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi’s sarcoma: a phase I AIDS malignancy consortium study. J Clin Oncol 2002, 20(1):153–159.

    CAS  PubMed  Google Scholar 

  47. Clinical Trials: Linking Patients to Medical Research. http://www.clinicaltrials.gov/ct. Accessed June 23, 2003.

  48. Stearns ME, Wang M: Alendronate blocks metalloproteinase secretion and bone collagen I release by PC-3 ML cells in SCID mice. Clin Exp Metastasis 1998, 16:693–702.

    Article  CAS  PubMed  Google Scholar 

  49. Liotta LA, Tryggvason K, Garbisa S, et al.: Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 1980, 284:67–68.

    Article  CAS  PubMed  Google Scholar 

  50. López-Otín C, Overall C: Protease degradomics: a new challenge for proteomics. Nat Rev Mol Cell Biol 2002, 3:509–519. This review explains the concept of degradomics, a study of proteases and protease-substrate repertories.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, 14263, Buffalo, NY, USA

    Nithya Ramnath MD & Patrick J. Creaven MD, PhD

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  1. Nithya Ramnath MD
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  2. Patrick J. Creaven MD, PhD
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Ramnath, N., Creaven, P.J. Matrix metalloproteinase inhibitors. Curr Oncol Rep 6, 96–102 (2004). https://doi.org/10.1007/s11912-004-0020-7

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  • DOI: https://doi.org/10.1007/s11912-004-0020-7

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