Prodrugs in cancer chemotherapy.

Abstract

At present, chemotherapy is not very effective against common solid cancers, especially once they have metastasized. However, laboratory experiments and studies on dose intensification in humans have indicated that some anticancer agents might be curative, but only if the dose given was very much higher than that attainable clinically. Prodrugs activated by enzymes expressed at a high level in tumors can deliver at least 50-fold the normal dose and can cure animals with tumors normally resistant to chemotherapy. The approach is not practicable clinically because of the rarity of human tumors expressing a high level of an activating enzyme. However, new therapies have been proposed that 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). Using different combinations of antibody, enzyme and prodrug, many classes of human tumor xenograft have been shown to be very sensitive to this procedure although in most cases they are quite resistant to conventional chemotherapy. 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 prodrug activating enzymes. This approach has been called virus-directed enzyme prodrug therapy (VDEPT) or more generally GDEPT (gene-directed enzyme prodrug therapy) and has shown good results in laboratory systems. These new therapies may finally realize the potential of prodrugs in cancer chemotherapy.