Development of prodrugs for ADEPT (antibody-directed enzyme prodrug therapy)

Anti body-Directed Enzyme Prodrug Therapy (ADEPT) is a targeting approach designed to improve the selectivity of anticancer drugs and to enable higher concentrations of drug to be generated at the target tumour than are currently possible with classical chemotherapy. ADEPT separates the cytotoxic from the targeting function of chemoimmunoconjugates in a multi-step system that has benefits over a one step chemo-, toxin- or radio-immunoconjugate. This review, whilst discussing the basic principles of ADEPT and the main requirements for all the components (enzymes, prodrugs and antibodies) of the systems, also summarises the latest results in the design and synthesis of prodrugs belonging to the main categories of anticancer compounds. The main features of ADEPT, such as targeting of cancer cells by the antibody-enzyme conjugates, enzymatic activation of the prodrugs, selection of the prodrugldrug and enzyme/prodrug systems are examined. A special emphasis has been placed on the prodrug/drug systems of potential clinical use, the rationale behind their design and the in vitro and in vivo results obtained with the different types of prodrugs. Analysis of ADEPT has indicated the potential for clinical use.