Matrix Metalloproteinase Inhibition as a Novel Anticancer Strategy: A Review with Special Focus on Batimastat and Marimastat

Abstract

Matrix metalloproteinases (MMPs) are a homologous family of enzymes that are involved in tissue remodeling and morphogenesis. Collectively, these enzymes are capable of degrading all components of the extracellular matrix, and they play an important role in normal physiologic conditions, such as wound healing and other processes involving tissue remodeling. However, increased activity of these enzymes now has been observed in a number of different pathological conditions, and it has been hypothesized that such increased activity of MMPs might play a role in the pathogenesis of these conditions. Cancer is one such condition; extracellular matrices constitute the principal barrier to tumor growth and spread, and there is growing experimental evidence that malignant tumors utilize MMPs to overcome these barriers. Consequently, inhibitors of MMPs represent an attractive target for a new class of anticancer agents. Marimastat and batimastat are potent broad-spectrum inhibitors of all the major MMPs and have been shown to prevent or reduce spread and growth of a number of different malignant tumors in numerous animal models. Both agents are now in advanced clinical testing in a number of different solid tumors in North America and Europe. The purpose of this paper is to review available preclinical and emerging clinical data, using batimastat and marimastat as prototype MMP inhibitors in the cancer area. pharmacol. ther. 75(1): 69–75, 1997.

Introduction

It is well recognized that the most common reason for treatment failure of malignant tumors is metastases; at the time of first diagnosis of a solid tumor, approximately 30% will have clinically detectable metastases (Sugarbaker 1981). Of the remaining 70% without clinically detectable metastases, approximately one-half will have micro metastases, which initially are occult, but which eventually will become manifest and in most cases, will prove terminal (Weiss and Gilbert 1981; Liotta and Stetler-Stevenson 1993). Metastases are being formed on a continuous basis, commencing early in the life of the primary tumor and increasing with time (Weiss and Gilbert 1981; Liotta and Stetler-Stevenson 1993). As a consequence of this, most patients will have multiple metastases of different size, location, stage, etc. Also, it is reasonable to conclude that for each manifest metastasis, there is probably a number of occult metastases (Weiss and Gilbert 1981; Liotta and Stetler-Stevenson 1993). The heterogeneity in size, age, anatomical location, and biologic composition of the metastases makes effective surgical, radiologic, and chemotherapeutic intervention very difficult (Sugarbaker 1981; Weiss and Gilbert 1981; Liotta and Stetler-Stevenson 1993). Consequently, new treatment modalities specifically targeted towards metastasis formation are urgently needed. Matrix metalloproteinase (MMP) inhibition might represent such an approach. Below we will review the possible role of MMPs in tumor progression, as well as assess the progress that has been made in the therapeutic application of MMP inhibitors (MMPIs) in oncology. Batimastat and marimastat are by far the most advanced MMPIs in terms of preclinical and clinical development. Although a number of other MMPIs from various companies are being developed, very little information is available from the literature on these agents. Consequently, for the purpose of this review, we have used batimastat and marimastat as prototype MMPIs, and, therefore, have focused most of this review on these two agents. However, the field is rapidly evolving, and had this review been written 1–2 years down the road, there is no doubt that a number of other MMPIs would have been included.