Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment

Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of criti cal importance in tumor invasion and metastasis. Based on this evidence, th e pharmaceutical industry produced several web tolerated, orally active MMP inhibitors (MMPIs) which demonstrated efficacy in mouse cancer models. Pha se III clinical trials initiated in 1997-98 using marimastat, prinomastat ( AG3340), and BAY 12-9566 alone or in combination with standard chemotherapy in patients with advanced cancers (lung, prostate, pancreas, brain, GI tra ct) have recently been reported; no clinical efficacy was demonstrated. Bay er and Agouron have discontinued their ongoing Phase III drug trials of MMP Is in advanced cancer, In retrospect, the failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs ap pear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have be en established. Our understanding of MMP pathophysiology in cancer has expa nded considerably in the past 10 years. Current views indicate that: (1) mo st MMPs in tumors are made by stromal cells, not carcinoma cells; (2) cance r cells induce stromal cells to synthesize MMPs using extracellular matrix metalloproteinase inducer (EMMPRIN) and cytokine stimulatory mechanisms; an d (3) MMPs promote cell migration and the release of growth factors sequest ered in the extracellular matrix. MMPs have a dual function in tumor angiog enesis: MMP-2 and MT1-MMP are required in breaking down basement membrane b arriers in the early stage of angiogenesis, while other MMPs are involved i n the generation of an angiogenic inhibitor, angiostatin. In spite of consi derable recent progress in identifying multiple roles of MMPs in disease, o ur understanding of MMP function in cancer is far from complete (see Table 1). Based on accumulated data, it is recommended that future MMPI trials fo cus on: (1) patients with early stage cancer; (2) the use of MMPIs along wi th chemotherapy; (3) the measurement of MMPs in tumor tissue and blood as a means of identifying patients who are more likely to respond to MMPI thera py; and (4) identification of biomarkers that reflect activation or inhibit ion of MMPs lit vivo.