Suicide gene therapy

Abstract

A major advance of the 20th century was the deciphering of the genetic code. As a result, novel technologies emerged, which led ultimately to the development of gene therapy. These advances raised hopes that many human diseases, including cancer, would become curable. Gene therapy for cancer can target both malignant or the nonmalignant, supporting cells (e.g., the vasculature) within a tumor. Different types of therapeutic proteins can be used, including tumor-suppressor proteins, cytokines, toxins, or prodrug-activating enzymes. This chapter deals with the latter, gene-directed enzyme prodrug therapy (GDEPT), a form of suicide gene therapy. This approach uses DNA or RNA technology to deliver a gene to cancer cells that encodes for a foreign prodrug-activating enzyme. After administration of a relatively nontoxic prodrug, the foreign enzyme catalyzes the conversion of the prodrug into a cytotoxic drug, which kills the cancer cells. The aim of GDEPT is to improve conventional cancer chemotherapy by selectively activating the prodrug at the tumor site, thus minimizing toxicity in nontumor tissues. GDEPT is one of the more popular areas of cancer gene therapy as evaluated by 52 clinical protocols (10.4% of total protocols) with a total of 567 patients (16.5% of total patients) in 2001, with some protocols reported as combination suicide gene therapy (83 protocols). In GDEPT, the gene expressing the enzyme is transduced into the cancer cell using a vector or vehicle. The gene needs to be expressed selectively and efficiently in the tumor cells to spare normal cells. The biggest challenge for GDEPT remains the selective targeting of the prodrug-activating enzyme to malignant cells. © 2008 Humana Press Inc.