Clinical potential of matrix metalloprotease inhibitors in cancer therapy

Matrix metalloproteases (MMP) are a family of enzymes that contribute to th e degradation of the extracellular matrix. The destruction of the extracell ular matrix eventually leads to tumour invasion, metastasis and angiogenesi s. Realising this mechanism of action, there is tremendous potential for in hibitors of MMP in cancer therapy. Extensive preclinical data have shown th at administration of matrix metalloprotease inhibitors (MMPI) to different animal models results in a reduction in primary tumour growth as well as in the number and size of metastatic lesions. Based on promising preclinical studies, synthetic MMPI have been developed and taken into clinical trials. These include marimastat, BAY-129566, CGS-27023A, prinomastat (AG-3340), E MS-275291 and metastat (COL-3). These drugs are all in different stages of clinical development, ranging from phase I to III. In general, musculoskele tal problems, such as joint stiffness and pain in hands, arms and shoulders seem to affect most patients in varying degrees, depending on the dose and type of compound administered. In addition to single agent therapy, severa l MMPI have entered trials of combination therapy. The objective of combini ng chemotherapy with an MMPI is to potentiate tumour cytotoxicity as well a s to reduce the size and number of metastatic lesions. Several compounds ha ve entered phase III combination therapy trials, but it is still too early to report any data. There is ongoing research in correlating biological end points, such as levels of MMP and markers of angiogenesis with clinical res ponse. As the field of MMP and their inhibitors continues to mature, its ro le in cancer therapeutics will be better defined.