Antimetastatic Activity of a Novel Mechanism-Based Gelatinase Inhibitor

Abstract

Matrix metalloproteinases (MMPs), and in particular gelatinases (MMP-2 and MMP-9), play a key role in cancer progression. However, clinical trials in which MMP inhibitors were tested in cancer patients have been disappointing. Whereas many reasons have been postulated to explain the failure of the clinical trials, lack of inhibitor selectivity was a major limitation. Thus, despite the consensus opinion that MMP-mediated proteolysis is essential for cancer progression and that certain MMPs represent important targets for intervention, effective and selective inhibition of those MMPs remains a major challenge in drug development. We previously reported the first mechanism-based MMP inhibitor, designated SB-3CT, which is a selective gelatinase inhibitor. Here we report that SB-3CT (5-50 mg/kg/d) is a potent inhibitor of liver metastasis and increases survival in an aggressive mouse model of T-cell lymphoma. This study shows that mechanism-based inhibition of gelatinases represents a novel approach to inhibitor design that promises to be a successful anticancer therapy. (Cancer Res 2005; 65(9): 3523-6)

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

“…Employing a gelatinase-specific, mechanism-based inhibitor called SB-3CT in this aggressive T-cell lymphoma liver colonization assay, we could show the dual antimetastatic efficacy of gelatinase inhibition (26). Application of this inhibitor resulted in reduced number, as well as size of metastases (26). Now these data can be ascribed to the different phases and proinvasive or proproliferative functionality of MMP-9 or MMP-2, respectively.…”

“…Elucidation of distinct roles of the two gelatinases in the in vivo context can also explain the bipronged efficacy of the most potent gelatinase-specific synthetic inhibitors described thus far. Employing a gelatinase-specific, mechanism-based inhibitor called SB-3CT in this aggressive T-cell lymphoma liver colonization assay, we could show the dual antimetastatic efficacy of gelatinase inhibition (26). Application of this inhibitor resulted in reduced number, as well as size of metastases (26).…”

“…The greatest progress has been made when inhibitors were synthesized which were relatively specific for gelatinases (22) or even displayed mechanism-based binding to gelatinases (23,24). Indeed, these gelatinase-specific inhibitors were efficient in inhibiting aggressive metastasis in the well-established syngeneic and immunocompetent L-CI.5s lymphoma liver metastasis model (25,26). In these approaches, a bipronged effect of the respective inhibitor could be observed, namely inhibition of the metastatic potential, as well as inhibition of metastatic foci outgrowth (26).…”

“…Indeed, these gelatinase-specific inhibitors were efficient in inhibiting aggressive metastasis in the well-established syngeneic and immunocompetent L-CI.5s lymphoma liver metastasis model (25,26). In these approaches, a bipronged effect of the respective inhibitor could be observed, namely inhibition of the metastatic potential, as well as inhibition of metastatic foci outgrowth (26). Application of synthetic inhibitors did not allow analysis of whether host-derived or tumor cell -derived gelatinases are important for metastasis nor did it elucidate distinct functions of the two gelatinases (24).…”

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

“…A potent mechanism-based thiirane sulphur-containing anti-MMP2 and -9 inhibitor that forms a reversible covalent bond with the active site glutamate (Figure 2), performs impressively in an aggressive murine model of T-cell lymphoma (Kruger et al, 2005). Recently, the design of the prototypic inhibitor was modified and a new generation of mechanism-based MMP2-specific MMPIs were developed (Ikejiri et al, 2005).…”