Selective activation of anthracycline prodrugs for use in conjunction with ADEPT

Abstract

A major limitation in the chemotherapy of cancer results from the lack of tumor specificity displayed by most anticancer drugs. In this regard, a great deal of research has been focused on the development of new chemotherapeutic agents that are able to effectively exploit the differences between neoplastic and normal tissues. Several cancerous tissues and tumors are rich in certain lysosomal enzymes as compared with those found in the normal tissues. Thus, a prodrug can be designed to selectively target such tumor cells where it can be activated to antineoplastic agent by tumor-associated antigen-targeted monoclonal antibody-enzyme conjugate (antibody directed enzyme prodrug therapy strategy) or by the action of an enzyme present at high levels in tumor tissues (prodrug monotherapy strategy). This approach protects the normal cells from the cytotoxic effects of the drug. In the last few years, a number of new MAb-based reagents has been clinically approved (Rituxan, Herceptin and Panorex), and several others are now in advanced clinical trials. This review focuses on the design of several different enzyme/prodrug combinations with an emphasis on mechanistic insight and clinical activity.