Prodrugs in cancer chemotherapy

At present, chemotherapy is not very effective against common solid cancers especially once they have metastasised. However, laboratory experiments and studies on dose intensification in humans have indicated that some anti-cancer agents might be curative but only if the dose given was very much higher than that presently obtainable clinically. Prodrugs, activated by enzymes expressed at raised level in tumors, can deliver at least 50-fold the normal dose and can cure animals with tumors normally resistant to chemotherapy. This approach has not yet proved to be practicable clinically because of the rarity of human tumors expressing a high level of an activating enzyme. However, new therapies have been proposed overcome this limitation of prodrug therapy. Enzymes that activate prodrugs can be directed to human tumor xenografts by conjugating them to tumor associated antibodies. After allowing 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 tumor. This procedure is referred to as ADEPT (antibody-directed enzyme prodrug therapy). Early clinical trials are promising and indicate that ADEPT may become an effective treatment for all solid cancers for which tumor associated or tumor specific antibodies are known. Tumors have also been targeted with the genes encoding for a prodrug activating enzymes. This approach has been called genedirected enzyme prodrug therapy (GDEPT) or VDEPT (virus-directed enzyme prodrug therapy) and has shown good results in animal models. These new therapies may finally realise the potential of prodrugs in cancer chemotherapy.