ABLATION OF HUMAN CHORIOCARCINOMA XENOGRAFTS IN NUDE-MICE BY ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY (ADEPT) WITH 3 NOVEL COMPOUNDS

Three novel prodrugs have been designed for use as anticancer agents. Each is a bifunctional alkylating agent which has been protected to form a relatively inactive prodrug. They are designed to be activated to their corresponding alkylating agents at a tumour site by prior administration of an antitumour antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in a two-phase system called antibody-directed enzyme prodrug therapy (ADEPT). The K(m) and V(max). values for three different antibody-CPG2 conjugates were determined in relation to each prodrug. The K(m) values ranged from 4.5-12-mu-mol/l and the V(max) from 0.5-1.6-mu-mol/U/min. Athymic Nu/Nu mice with palpable transplanted human choriocarcinoma xenografts, which are resistant to conventional chemotherapy, were treated with anti-human chorionic gonadotropin antibodies conjugated to CPG2. This was followed by each of the three novel prodrugs. Significant increase in survival was obtained in three of the regimens tested using only one course of treatment. This demonstrates the potential of a tumour-localised bacterial enzyme to activate protected alkylating agents in order to eradicate an established human xenograft.