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.

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

“…Our results should be paralleled with the recently halted clinical development of some synthetic MMPIs due to the occurrence of severe side effects, including inflammatory polyarthritis, in cancer patients treated with such molecules [24,69]. In this context, it is worth noting that elevated MMP-9 levels were consistently reported in arthritic patients [70].…”

“…Hence, restoration of this balance by adding exogenous inhibitors was contemplated for anti-cancer therapy. Indeed, both physiological (TIMPs) and nonphysiological MMP inhibitors (MMPIs) efficiently inhibited tumor invasion and metastasis in several in vitro and in vivo models [21][22][23][24]. However, due to their relatively large size and their short half-life in vivo, TIMPs were not considered suitable for therapeutic applications.…”

“…Among these MMPIs, hydroxamic acid based compounds were demonstrated as potent inhibitors of both tumor growth and invasion [21][22][23]. Several synthetic MMPIs are currently in phase II/III clinical trials in a number of solid tumors [20,24].…”

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

“…Prinomastat inhibits tumour growth and angiogenesis in several xenograft models. 115 In a phase II study in patients with progressive breast cancer, no objective disease responses were observed. 127 Two phase III trials with prinomastat were discontinued after preliminary results failed to meet primary efficacy objectives in advanced hormone refractory prostate cancer 128,129 and in stage IV NSCLC patients.…”

“…114 However, phase I and II clinical trials with intraperitoneally administered batimastat have not shown any marked responses and there is no further development of batimastat for cancer therapy at the moment. 115 Marimastat (BB-2516) is an orally bioavailable low-molecularweight MMPI. Marimastat is a broad-spectrum MMPI, which inhibits the activity of MMP-1, -2, -3, -7, -9 and -12.…”