MECHANISTIC APPRAOCH FOR DESIGN OF ANTI-METASTASIS DRUGS

THE GOAL OF THE PROJECT IS TO DEVELOP NEW ORGANIC COMPOUNDS THAT HAVE SPECIFIC ANTI-METASTATIC ACTIVITY FOR USE IN ADJUVANT TREATMENT OF CANCER PATIENTS TO INHIBIT OR DELAY THE DEVELOPMENT OF METASTATIC DISEASE. INHIBITION OF BASEMENT MEMBRANE DEGRADATION, AN IMPORTANT EVENT IN THE METASTATIC PROCESS WILL BE TARGETED. EVIDENCE EXISTS LINKING THE EXPRESSION OF A MATRIX METALLOPROTEASE, COLLAGENASE TYPE IV, WITH INVASIVE POTENTIAL OF TUMOR CELLS. THE METALLOPROTEASES CONTAIN A ZINCION THAT IS ESSENTIAL FOR ACTIVITY, THEREFORE CHELATIN GAGENTS SUCH AS EDTA ARE POTENT CHEMICAL INHIBITORS OF ACTIVITY. RAZOXANE (ICRF 159) AND OTHER BISDIOXOPIPERAZINES, ARE DERIVATIVES OF EDTA WHICH HAVE DEMONSTRATED ANTI-METASTATIC ACTIVITY IN VIVO. HOWEVER, RAZOXANE HAS A MULTITUDE OF UNDESIRABLE PHYSICAL-CHEMICAL PROPERTIES INCLUDING WATER INSOLUBILITY, POOR CHEMICAL AND BIOLOGICAL STABILITY, AND LOW BIOAVAILABILITY. IN ORDER TO DESIGN MORE EFFECTIVE ANTIMETASTATIC AGENTS BASED ON THIS SERIES OF COMPOUNDS, A KNOWLEDGE OF THE BIOCHEMICAL MECHANISM OF ACTION IS NEEDED. IN PHASE I, THE HYPOTHESIS THAT THE PRINCIPLE MECHANISM OF THE ANTI-METASTATIC ACTION OF THESE COMPOUNDS IS THROUGH INHIBITION OF COLLAGENASE TYPE IV WILL BE TESTED. THIS HYPOTHESIS IS SUPPORTED BY THE LITERATURE NAD BY PRELIMINARY RESULTS. SPECIFICALLY, A SERIES OF BISDIOXOPIPERAZINES CHOSEN FROM DERIVATIVES DESIGNED FOR INCREASED SOLUBILITY, STABILITY, AND BIOAVAILABILITY WILL BE TESTED FOR INHIBITION OF PURIFIED COLLAGENASE TYPE IV. LEAD COMPOUNDS WILL BE FURTHER CHARACTERIZED FOR INHIBITION OF IN VITRO INVASION AND, IN PHASE II, IN IN VIVO MODELS OF METASTASIS TO CORRELATE ENZYME INHIBITION WITH ANTI-METASTATIC ACTIVITY. THESE STRUCTURE-FUNCTION STUDIES WILL FORM THE BASIS FOR THE RATIONAL DESIGN OF NEW, MORE POTENT, ANTI-METASTATIC AGENTS.