B. Prodrug-Converting Enzymes (‘‘Suicide Strategy'')

The ‘‘suicide strategy'' in cancer gene therapy makes use of the combination of classical cytotoxic chemotherapy with gene transfer technology. The concept behind this strategy is to limit the action of a known cytotoxic drug to the local area of the tumor lesion without affecting the neighbouring normal cells. First, the cDNA of a prodrug-converting enzyme is delivered into the tumor by a suitable vector system followed by regional or systemic application of the corresponding nontoxic prodrug. Once the prodrug has reached the tumor cells it triggers the activity of prodrug converting gene in the tumor cells to express the prodrug-converting enzyme. The prodrug converting enzyme converts the prodrug to the cytotoxic drug. The conventional treatment of cancer by chemotherapy is highly toxic to neighboring cells and tissues and shows side effects which are dose-limiting. In case of suicide gene therapy, the cytotoxic effects of the drug are mainly restricted to the area of tumor, and for the time up to which the cancer cells express the prodrug-converting enzyme.

In addition, the efficacy of the suicide strategy is enhanced by the ‘‘bystander effect'' that involves the killing of even uninfected tumor cells in the neighborhood of infected cells due to

• •  Intercellular communication mediated by gap junctions.

•  Transfer of toxic metabolites via apoptotic vesicles or direct transmembrane diffusion.

•  Local anti tumor immune responses.

•  Systemic anti tumor immune responses.

Many prodrug converting enzyme systems are under development, a number of experimental or clinical investigations and validation of the system is in progress. The table below enlists some of these systems.