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For one to understand the principle behind gene therapy in cancer treatment, molecular level knowledge on oncogenesis is of great importance. Cancer is refers to uncontrolled abnormal cell proliferation leading to development of abnormal tissues. This cell division is autonomous. Most human cancers have been shown to develop as a result of stepwise accumulation of mutations that involve proto-oncogenes and tumor suppressor genes. It is estimated that there are more than one thousand proto-oncogenes and numerous tumor suppressor genes in the genome of human beings. It is not necessary for all these genes to undergo mutations for cancer to develop, but cancer have been characterized small number of mutations that either transform a given proto-oncogene into oncogenic state or affects a given tumor suppressor gene resulting in a defective tumor suppressor protein. There for cancer to develop, the’ breaks ‘of cell growth must be released (Tumor suppressor genes) and cell proliferation accelerated (conversion of pro-oncogene into oncogene). For example most human colon cancers are characterized with the presence of K-Ras oncogene and mutations in the P53 and APC tumor suppressor genes. The basis of gene therapy in cancer treatment is based on understanding that genes can be introduced into cells through transfection, and their mRNA can be translated into therapeutic proteins.
There are four approaches employed in cancer gene therapy and they include cytotoxic therapy, combination adjuvant therapy, corrective gene therapy and immunotherapy.
Corrective gene therapy
Mutations in tumor cells can be corrected or rectified using gene therapy. The common approach involves the replacement of native tumor suppressor gene. When these tumor cells produce the normal tumor suppressor protein, their growth is suppressed and they eventually under apoptosis. The alternative approach involves the inhibition of the proto-oncogenes by either addition of a gene with the ability to regulate and inhibit oncogene gene transcription or antisense cDNA transfection enabling it to bind oncogene mRNA hence preventing its translation into the oncogene protein product.
Cytotoxic gene therapy
In this approach cytotoxic therapy is augmented by either a drug resistance or sensitization approach. In the approach targeted at drug sensitization a gene is transfected to transform a give pro-drug from its inactive state to its active metabolite. This gives way for the conversion of drugs and high concentration of active drug in the cancer bed only. A good example in this approach is the gene calling for the herpes simplex virus thymadine kinase gene (TK). This is known to transform gangeiclovir into its active form s triphosphate. Triphosphate is a cytotoxic drug. In the drug resistance approach, a gene that is resistant to a given drug, that is a drug resistant gene, for example MDR1, is introduced into chemotherapy sensitive cells, for example hematopoietic stem cells enabling them to become resistant to cytotoxicity by chemotherapy. This allows the use of high doses of the anticancer drugs since cells highly sensitive to chemotherapy have been transformed to be less resistant.
The primary aim of immune therapy is immune system stimulation and overcoming of immunosuppression conferring it with the ability to kill tumor cells. One approach is the use of cytokine gene transfer to augment immunotherapy. The transfer of cytokine gene is performed in vivo whereby cancer cells or immune cells for example TILs and CTLs can be tranfected in vivo, resulting in the amplification of the immununity and anticancer response.
Another approach is the vaccination of the body using immune-therapy. A gene calling for a specific anti tumor antigen is introduced into a cancer cell. This enables the body recognize the cancer cell leading to its rejection. In other cases a gene coding for an alloantigen is introduced. The other approach involves generally introducing gene coding for a foreign antigen in tumor cells .an immune response specific for the tumor cell is mediated once the body recognizes the antigen in the tumor cells.
In this approach a gene is introduced the vector DNA, for example Viruses or plasmids. The regulation of these genes is under the promoter of the vector DNA. (Ensley, 2001).
The use of gene therapy as a modern method for treatment of various human diseases for example is faced with controversies. In cancer treatment, gene therapy hold the greatest promise compared to other approaches like, surgery and radiotherapy and chemotherapy. For example unlike chemotherapy and radiotherapy which have been shown to posses far reaching side effects on normal cells, gene therapy is specific for tumor cells. Furthermore, gene therapy is able to restore the cell regulation mechanism whose loss has been shown to be responsible for human cancers.
Despite its promising future there a number of cases that have indicated its limits. For example various studies have indicated that highly invasive tumors employ numerous oncogenic pathways. Hence any therapeutic approach including gene therapy may fail to rectify or inhibit some of the pathways. For example,failure of the phaseIII trial in the gene therapy involving Ad_P53 gene therapy in the treatment of ovarian cancer (Vorburger and Swisher, 2005).
There have also been serious adverse effects that have been related to gene therapy. The integration of Vectors in very vital regions in the genome has led to very serious medical complications. Good examples include the development of X-SCID disease and Leukemia as a result of gene therapy.
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