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Targeted Gene Therapy in Cancer:

In recent past the thought of using gene therapy as a modality in the handling of diseases other than genetically inherited, a monogenic disorder has taken origin. This is mainly understandable in the field of oncology where currently more than 100 clinical trials have been approved worldwide. Some of the exciting progress that has recently been made with admiration to both targeting the delivery of potentially therapeutic genes to tumor sites and regulating their expression within the tumor microenvironment. In order to specifically target malignant cells while at the same time sparing regular tissue, cancer gene therapy will need to combine highly selective gene delivery with highly specific gene expression, specific gene product activity, and, possibly, specific drug activation. Although the competent delivery of DNA to tumor sites remains a alarming task, development has been made in recent years using both viral (retrovirus, adenovirus, adeno-associated virus) and nonviral (liposomes, gene gun, injection) methods. In this report emphasis will be placed on targeted rather than high-efficiency delivery, although those would need to be joint in the future for effective therapy. To date delivery has been targeted to tumor-specific and tissue-specific antigens, such as epithelial growth factor receptor, c-kit receptor, and folate receptor, and these will be described in some detail. To increase specificity and safety of gene therapy further, the expression of the therapeutic gene needs to be tightly controlled within the target tissue. Targeted gene expression has been analyzed using tissue-specific promoters and disease-specific promoters (carcinoembryonic antigen, HER-2/neu, Myc-Max response elements, DF3/MUC). On the other hand, expression could be regulated outwardly with the use of radiation-induced promoters or tetracycline-responsive elements. One more novel possibility that will be discussed is the guideline of therapeutic gene products by tumor-specific gene splicing. Gene expression could also be targeted at circumstances specific to the tumor microenvironment, such as glucose deprivation and hypoxia. It has concentrated on hypoxia-targeted gene expression. Chronic hypoxia happens in tissue that is more than 100-200 microns away from a functional blood supply. In solid tumors hypoxia is widespread both because cancer cells are more prolific than the invading endothelial cells that make up the blood vessels and because the newly formed blood supply is jumbled. Measurements of oxygen partial pressure in patients' tumors showed a high percentage of severe hypoxia readings (less than 2.5 mmHg), readings not seen in usual tissue. This is a most important problem in the treatment of cancer, because hypoxic cells are resistant to radiotherapy and often to chemotherapy. However, severe hypoxia is also a physiological condition specific to tumors, which constructs it a potentially exploitable target. People have utilized hypoxia response elements (HRE) derived from the oxygen-regulated phosphoglycerate kinase gene to manage gene expression in human tumor cells in vitro and in experimental tumors. Other imaginative strategies include the use of internally expressed antibodies to target oncogenic proteins (intrabodies) and the make use of antisense technology (antisense oligonucleotides, antigenes, and ribozymes).