batimastat and Skin-Neoplasms

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 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.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Colorectal Neoplasms; Enzyme Inhibitors; Female; Hemangioma; Humans; Hydroxamic Acids; Melanoma; Metalloendopeptidases; Mice; Ovarian Neoplasms; Pancreatic Neoplasms; Phenylalanine; Protease Inhibitors; Skin Neoplasms; Thiophenes

The expression of selected metalloproteinases and tissue inhibitors of metalloproteinases (TIMP) was examined in three squamous cell carcinoma (SCC) cell lines (FaDu, SiHa, A431) and a keratinocyte cell line (HaCaT) to determine which metalloproteinases function in SCC invasiveness. A Matrigel invasion assay was used to assess invasiveness of the cell lines. Only the FaDu cell line showed invasiveness in this assay, and invasion of Matrigel by FaDu cells was inhibited by treatment with the metalloproteinase inhibitor, batimastat. No correlation was found between mRNA expression for matrilysin, stromelysins 1-3, TIMP-1, or TIMP-3 and secretion of these proteins, indicating that the extracellular activity of these molecules is regulated post-transcriptionally. The SCC cell lines differed from the HaCaT line in that matrilysin and TIMP-1 proteins were detected in conditioned medium from all SCC cell lines, but not in medium from HaCaT cells. Only the invasive cell line, FaDu, released active stromelysin-1 into the culture medium. These results indicate that while matrilysin contributes to the invasive phenotype, activation of stromelysin-1 is a key regulatory step for invasiveness in SCC cells.

Topics: Biocompatible Materials; Carcinoma, Squamous Cell; Cell Movement; Collagen; Drug Combinations; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Keratinocytes; Laminin; Matrix Metalloproteinase 3; Neoplasm Invasiveness; Phenylalanine; Protease Inhibitors; Proteoglycans; Skin Neoplasms; Thiophenes; Tissue Inhibitor of Metalloproteinase-1; Tumor Cells, Cultured

Structural changes in the extracellular matrix are necessary for cell migration during tissue remodeling and tumor invasion. Specific cleavage of laminin-5 (Ln-5) by matrix metalloprotease-2 (MMP2) was shown to induce migration of breast epithelial cells. MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling.

Topics: Animals; Breast; Cell Adhesion; Cell Adhesion Molecules; Cell Division; Cell Line; Cell Movement; Cell Size; Collagenases; Epithelial Cells; Epithelium; Extracellular Matrix; Female; Fibrinolysin; Gelatinases; Humans; Kalinin; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Metalloendopeptidases; Mice; Phenylalanine; Protease Inhibitors; Rats; Recombinant Fusion Proteins; Skin Neoplasms; Thiophenes