Suicide Gene Therapy by Herpes Simplex Virus-1 Thymidine Kinase (HSV-TK)

Abstract

Suicide gene therapy for cancer treatment proposed by Moolten [1] started more than 25 years ago and has gained momentum with little variations in the original technology. At the current statistics, worldwide 1550 clinical trials of gene therapy have been reported (http://www.wiley.co.uk/genmed/clinical) among them 7% using suicide gene therapy. HSV-TK is the most well characterized suicide gene used for cancer therapy and in other diseases without inducing significant systemic toxicity [2] [3]. Chemotherapeutic drugs used for cancer therapy are problematic because they do not discriminate in their mode of action. Currently available drugs in the market are not cancer specific so functional concentration level in tumors cannot be reached without off-target toxicity level. This is specifically true for solid tumors where vascularization is poor and necrotic at the center of the tumor due to low oxygen and nutrient supply [4][5]. However, when the drug is activated by locally enzymatic reactions in a timely fashion, the metabolite is toxic for the tissue. The most widely used suicide genes are Herpes Simplex Virus-1 Thymidine Kinase (HSV-TK), and Cytosine Deaminase (CD) from the virus Herpes simplex or the bacterium Escherichia coli respectively [6][7]. Prior research has focused on the mechanism of initiation and development of tumors. It starts with the mutation of 1 or several genes, then gradually attains more genetic mutation and genomic instability during the evolution of tumor/cancer. Almost all the genes fall in 2 categories – oncogenes (derived from proto-oncogene) and tumor suppressor genes. There are many ways to treat various tumors ranging from benign to metastatic. Among them surgery followed by chemotherapeutic drug treatments is the widely used method of choice that damages the DNA and renders the cells apoptotic. Additionally, tumors can be cured by more subtle ways by restoring the function of tumor suppressor genes or disabling oncogenes, to prime the immune cells to act and down-regulate angiogenesis and metastatic activities. Solid tumors can be treated by intra-tumor delivery of suicide genes. The protein product of these genes catalyzes the formation of highly toxic metabolites following the application of some lesser toxic prodrugs. This leads to apoptosis or programmed cell death of the treated cells [8]. The apoptotic cells invite immune cells that further clear the tumor zone by phagocytosis. Suicide gene therapy is also known as Gene Directed Enzyme/Prodrug therapy (GDEPT) or as Gene Prodrug Activation Therapy (GPAT). GDEPT can either take the form of CBT (cell