Matrix metalloproteinase inhibition: A review of anti-tumour activity

Background: Matrix metalloproteinases are a homologous family of proteolytic enzymes. Collectively, these proteinases are capable of degrading all components of the extracellular matrix, including proteolytically resistant fibrillar collagens. Extracellular matrices constitute the principal barrier to tumour growth and spread, and there is now experimental evidence that malignant tumours utilise matrix metalloproteinases to overcome this barrier. Inhibitors of matrix metalloproteinases may therefore be of therapeutic value in the treatment of metastatic disease. Design: This review describes the activity of matrix metalloproteinase inhibitors (MMPIs), in experimental tumour models and in phase I/II clinical studies. Results: Studies with MMPIs in vitro have shown that these agents are not cytotoxic but can inhibit the degradation of extracellular matrix by tumour cells. In experimental tumour models in vivo, MMPI treatment caused inhibition of tumour growth and metastatic spread in both rodent syngeneic and human xenograft models. MMPIs have also been shown to inhibit angiogenesis, a process essential for the rapid growth of most malignancies. Conclusions: MMPI therapy has the potential to arrest tumour growth and spread. As a non-cytotoxic 'tumourostatic' approach it may offer an ideal complement to surgery, radiotherapy and chemotherapy in the successful long-term treatment of metastatic disease.