Cancer Gene Therapy I - Page 2

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Jan 30, 2001

Gene delivery systems

There are two major categories of gene transfer, in vitro and in vivo. The in vitro method involves removing tumor cells from the patient, incubation with a vector that contains the gene of interest, allowing the resultant cells to multiply, and finally reintroducing them into the patient. The in vivo method involves introducing the gene via a vector directly into the patient.1

There are two major types of vectors, viral, and non-viral.3

I. Viral systems- By using a virus as a delivery vehicle, the therapist is taking advantage of the viruses natural ability to infect a cell and to transfer its genetic material into the host's DNA. This method of transfer is called transduction. The researcher must first modify the virus in order to make it non-pathogenic. It is often further modified so that it no longer synthesizes viral proteins that can be recognized as antigenic by the patient's body.

A. Retroviruses are small viruses whose genetic material is made of RNA instead of DNA. By means of an enzyme, retroviruses are able to transform their RNA into DNA, which can be permanently integrated into the DNA of the host cell. The use of a retrovirus as a vector, therefore, can result in long-term expression of the transferred gene. The greatest disadvantage of retrovirus-based vectors is that they can only integrate into actively dividing cells (which consist of only about 20% of the tumor cells). Due to this as well as other problems, retroviruses are best suited to in vitro transduction. B. Adenoviruses have their genetic material in DNA. Using adenoviruses as vectors does not result in the gene being incorporated into the host's DNA, but instead is found in the cytoplasm of the cell. The main advantage of adenoviruses is that they can deliver genes to non-dividing as well as dividing cells. In this manner, they can infect a larger portion of cells in a tumor. A major disadvantage is that they can provoke a significant immune response in the host, which can make repeated administration of the vector ineffective. To overcome this problem, researchers modify the viruses so that they no longer produce viral proteins. C. Other viruses are under consideration for gene delivery systems. Herpes simplex virushas the potential for highly efficient transduction of genes, and for the long-term expression of the transgene. Adeno-associated virus is reported to incorporate genes into the host DNA, and to infect both dividing and non-dividing cells. This could provide advantages as described above for other viruses with these characteristics.

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