The use of prodrugs in targeted anticancer therapies

Chemotherapy is not very effective against common solid cancers especially once they have metastasised. However, prodrugs, activated by enzymes expres sed at raised levels in tumours, can deliver at least fifty-fold the normal dose and can cure animals with tumours normally resistant to chemotherapy. This approach has not yet proved to be practicable clinically because of t he rarity of human tumours expressing a high level of an activating enzyme. However; new therapies have been proposed to overcome this limitation of p rodrug therapy. Enzymes that activate prodrugs can be directed to human tum our xenografts by conjugating them to tumour associated antibodies. After a llowing for the conjugate to clear from the blood a prodrug is administered which is normally inert but which is activated by the enzyme delivered to the tumour. This procedure is referred to as ADEPT (antibody-directed enzym e prodrug therapy). Early clinical trials are promising and indicate that A DEPT may become an effective treatment for all solid cancers for which tumo ur associated or tumour specific antibodies are known. Tumours have also be en targeted with the genes encoding for prodrug activating enzymes. This ap proach has been called gene-directed enzyme prodrug therapy (GDEPT) or VDEP T (virus-directed enzyme prodrug therapy) and has shown good results in ani mal models. Polymer conjugates can also accumulate preferentially in a tumo ur because of the enhanced permeability and retention effect. Enzyme polyme r conjugates have been proposed as a means of activating a prodrug selectiv ely at a tumour site and the system is called polymer-directed enzyme prodr ug ther npy (PDEPT) or macromolecule-directed enzyme prodrug therapy. These new therapies may finally realise the potential of prodrugs in cancer chem otherapy.