Given that MMPs play important role in tumor invasion and metastasis, inhibition of MMPs activity has been the focus of much anticancer research and clinical trials. Pharmaceutical industries have invested considerable effort over the past decade to develop safe and effective MMP inhibitors for use in cancer patient. Three classes of synthetic MMP inhibitors have been developed (Table 2): the collagen peptidomimet-ics which mimic the collagen amino-acid sequence near the collagenase cleavage site; the collagen non-peptidomimetics which are synthesized based upon the conformation of MMP active site; and the tetracycline derivatives which inhibit the activity of MMPs without antibiotic activity (13, 56-57). Numerous preclinical studies using these MMP inhibitors in cancer models have demonstrated their effectiveness to delay primary tumor growth and inhibit experimental metastasis. Initiation of treatment when tumor burden is minimal has a more profound effect on tumor growth inhibition than at the time oflarge tumor bulk. Despite ofpositive preclinical results in the use ofMMP inhibitors, most clinical trials have not yielded significant beneficial effects in patients with advanced cancer (57). In the case of BAY12-9566, alarming reports show significantly poorer survival for groups treated with the drug than for placebo-treated group.
Table 2. The matrix metalloproteinase inhibitors for cancer therapy
Tanomastat (Bay 12-9566)
Prin omastat (AG3340) B MS-275291 MMI 270 (CGS27023A) Metasat (COL-3)
Peptid o mimetic
Non-peptide mimetic Non-peptido mimetic Non-peptido mimetic Tetracycline derivative
(2nd generation of BB-94) Broad spectrum
(e.g. MMP-2, 9, 11, 13, 14) Broad spectrum Broad spectrum Broad sperrum Gelatmases (MMP-2, 9)
In view of the disappointing results of synthetic MMP inhibitors in clinical trials, we and other investigators have recently explored the potential applications of TIMP gene overexpression for cancer gene therapy (58-60). Antitumor effects have been shown following systemic or local delivery of TIMP-1, TIMP-2, and TIMP-3 genes in animal models (60-63). However, stimulation of mammary tumorigenesis has been reported following systemic TIMP-4 gene delivery. TIMP-4 has been shown to up-regulate Bcl-2 and Bcl-X(L) protein and inhibit apoptosis in human breast cancer cells (64). Given the multifunctional nature of TIMP proteins, further preclinical studies will be needed before initiation of clinical gene therapy trial in patients with cancer.
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