Targeting enzymes to cancers - new developments

Abstract

Two methods of using tumour located enzymes have been described. These are antibody directed enzyme prodrug therapy (ADEPT) and macromolecule directed enzyme prodrug therapy (MDEPT), where the tumour located enzyme converts a non-toxic prodrug into a cytotoxic drug at tumour sites. The alternative use of tumour located enzymes is to inactivate rescue agents that protect cells from antimetabolite action, and is described as ‘Antimetabolite with inactivation of rescue agent at cancer sites’ (AMIRACS). The leakiness of tumour blood vessels and poor lymphatic drainage allows enzymes to be targeted to many cancers by attachment to polymeric macromolecules (MDEPT), as well as to antibodies and antibody fragments (ADEPT). To avoid systemic toxicity, enzyme activity in blood and normal tissues must be very low before giving a prodrug or rescue agent. Antibodies directed against the enzyme component of macromolecular conjugates have proved to be very efficient at clearing normal tissues. Human enzymes which are over expressed by cancer cells can be exploited particularly if they require co-factors or co-substrates, either in situ or targeted to extracellular sites. Bacterial enzymes have advantages in specificity but require some form of immunological control in view of their immunogenicity. Prodrugs which generate drugs with very short half lives are desirable, and have been developed, including one which has a differential toxicity between prodrug and the active drug of 1000 to 10,000 fold. The range of antimetabolites available for AMIRACS was initially restricted to inhibitors of dihydrofolate reductase but has been greatly extended by the introduction of inhibitors of other enzymes. The limitations of these systems are discussed.