HUMAN COLLAGENASE IV AND ITS INHIBITORS

THE DEGRADATION OF THE COLLAGEN TYPE IV NETWORK IN BASEMENT MEMBRANES IS A CRITICAL EVENT IN MANY NORMAL AND PATHOLOGICAL CONDITIONS INCLUDING TISSUE REMODELLING, WOUND HEALING, TUMOR CELL METASTASIS, AND ANGIOGENESIS. THE 72 KD TYPE IV COLLAGENASE IS A NEUTRAL METALLOPROTEASE CAPABLE OF DEGRADING COLLAGEN TYPE IV THAT HAS BEEN IMPLICATED IN THE ABILITY OF MALIGNANT TUMOR CELLS TO METASTASIZE AND IN THE PROCESS OF ANGIOGENESIS. A NATURALLY OCCURRING INHIBITOR OF THE 72 KD ENZYME KNOWN AS TIMP-2 (TISSUE INHIBITOR OF METALLOPROTEASE-2) FORM A NONCOVALENT COMPLEX WITH THE 72 KD TYPE IV PROCOLLAGENASE AND SPECIFICALLY INHIBITS ITS ENZYME ACTIVITY. THUS, TIMP-2 IS A POTENTIAL CANDIDATE FOR THE DEVELOPMENT OF NEW STRATEGIES FOR THE TREATMENT OF METASTASIS AND ANGIOGENIC DISEASES. WE INTEND TO PRODUCE MILLIGRAM QUANTITIES OF BIOLOGICALLY ACTIVE TIMP-2 AND 72 KD TYPE IV COLLAGENASE BY RECOMBINANT DNA TECHNOLOGY AND CHARACTERIZE THEIR BIOCHEMICAL AND BIOLOGICAL PROPERTIES. AVAILABILITY OF THESE PROTEINS WILL ALLOW US TO STUDY THEIR ROLE IN DISEASE AND TO DEVELOP ANTIBODIES AND SPECIFIC DRUGS TO BE USED IN IMMUNODIAGNOSTIC AND TREATMENT OF CANCER.