Figure 24.1 Suicidal gene therapy:

Several experiments conducted on immune-compromised animals (using intratumoral application of vector carrying HSV tk gene) showed a reduction of tumor volume of more than 50% of the controls under various experimental conditions and methods. In some cases even complete remissions have been observed. Similar experimental studies on immune-competent animals suggest that the immune system may play a supportive role in the efficacy of this approach. Promising results of tumor growth inhibition using suicidal gene therapy with side effects have been reported in case of the HSV tk system and all other suicidal gene therapy systems

Limitations of suicidal gene therapy includes

• •  Low efficacy of in vivo gene transfer: Just like other gene therapy strategies, the capability of the suicide gene therapy to kill cancer cells in experimental and clinical studies is curbed by overall low efficiency of in vivo gene transfer.

•  Incomplete transduction of tumors even with most efficient vectors available: It is being observed that even with the most efficient vector system and direct intratumoral vector transfer technique, only a few tumor cells get transduced with a nonuniform intratumoral vector distribution. Thus, very low antitumor efficacy is seen.

•  Bystander effect is a curse as well as a boon: It is a limitation when it shows toxicity to normal cells and a boon when it shows toxicity to tumor cells that has not been transfected with the suicide gene.

Limitations pertaining to suicidal gene therapy can be overcome to some extent:

• •  Vector distribution within the tumor can be improved by changing the delivery route of the vector and the way it is applied (route used could be either intravesical, intraperitoneal, intrathecal or intraventricular and the way it is applied could be repeated or bulk-flow).

•  By making use of replication-competent vectors.

•  By enhancing the bystander effect through the transfer of connections that increase the number of gap junctions and by receptor targeted delivery.