Matrix metalloproteinase inhibitors--an emphasis on gastrointestinal malignancies

Gastrointestinal malignancies are the commonest sites of human cancer collectively. Improved understanding of tumour biology in the last few decades has allowed the identification of cellular pathways responsible for the autonomous growth and replication in cancer cells. There is considerable preclinical evidence implicating matrix metalloproteinases (MMPs) in cancer dissemination and tumour angiogenesis. Effective MMP inhibitors (MMPIs) may, therefore, hold an important key in the treatment of gastrointestinal cancers. MMPIs are cytostatic agents and traditional values of tumour regression may not be the best measures of treatment efficacy. Biological correlation studies are increasingly being incorporated into the early development of these agents, but many of these studies lack preclinical validation and are often chosen on availability rather than biological plausibility. Disappointing results with many MMPIs that have entered phase III testing so far would prompt for identification of reliable surrogate biomarkers and incorporation of functional imaging in the clinical development of matrix metalloproteinase inhibitors in gastrointestinal malignancies. In this review, the integral part in which MMPs are involved in cancer growth and metastases will be presented. This is then followed by a discussion of the challenges that clinicians are facing in assessing the efficacy of MMPIs and finally a review of the clinical studies of the synthetic MMPIs in development.