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THE INTERNATIONAL NEWSLETTER FOR THOSE FIGHTING OVARIAN CANCER!

Gene Therapy

Updated: Wednesday, June 15, 2005 12:06:18 PM

GENE THERAPY: Inside of each cell are structures called chromosomes, and inside each chromosome are genes which control the pattern of cell growth. Cancer is believed to be the result of either inherited (something your parent passes down to you), or acquired changes in the genes. These changes, whether inherited or acquired, may allow the cell to grow in an abnormal pattern and turn into a cancerous cell. Permanent changes (mutations) are most likely caused by either growing older, or through exposure to toxic substances, such as smoke, alcohol, pollution, radiation, the sun, etc. One researcher estimated that it takes a minimum of only six mutations to make a cell cancerous, and that some cancerous cells may have hundreds and hundreds of mutations. There are two primary types of genes which contribute to the development of cancer : oncogenes promote cell growth and division, while tumor suppresser genes limit cell growth.

Normal cells have genes, called tumor suppresser genes, which protect us from potentially cancerous cells in two primary ways : either by slowing/stopping cell division long enough to allow the damaged cells to repair themselves, or by killing the abnormal cells. If the tumor suppresser genes are damaged or mutated, cancerous cells are allowed to grow and divide unchecked. If the tumor suppresser gene is present and intact, it will stop cell growth and force defective cells to commit "suicide." Think of these genes like the brakes on your car. The two most common tumor suppresser genes are called pRB and p53 proteins. It is estimated that about 65-70% of all ovarian cancers have a mutated p53. It is estimated that the p53 gene is damaged in about 15% of early stage ovarian cancers, and in about 50% of advanced stage ovarian cancers. The mutated pRB is thought to be present in about 40% of all types of cancers.

Mutant versions of oncogenes encourage cells to grow and divide. Think of these cells like they are the gas in your car. If the oncogene is damaged and/or if it over-expresses itself, it is like pressing down on the gas pedal of your car. Over-expression allows and encourages cancer growth at a much faster rate than normal. An estimated 20-30% of ovarian cancer over-express the Her-2/neu factor. Other oncogenes involve mutant Ras proteins and kinase genes. It is estimated that about 20-30% of all cancers are thought to have mutated Ras proteins, and there are about 1,000 different kinases.

In gene therapy, the damaged gene is first identified and then replaced with a normal gene that can recognize the cancer cell. This process can either be done in vivo (inside the body) or in vitro (outside the body, in a test tube). Most of the time, cells with good genes are grown in the lab and then injected back into the patient to grow and multiply. Both processes need a vector, a carrier vessel like a boat or a taxi, to transfer the good gene into the cancer cell. The most common vectors are viruses which have been altered to prevent them from causing an infection. Then, an anti-virus drug is given (such as ganciclovir) to kill infected cells. The anti-virus drug will not kill normal body cells because normal cells will not be infected with the virus. Another example is to insert tumor suppresser genes, such as the p53, directly into the cancer cells.

There are two types of viruses used in gene therapy. The retrovirus can function only in the dividing cell, but it permanently changes the gene. The adenovirus, such as those which cause the common cold, can work on more cells because the cell doesn't need to be dividing. However, the changes are not permanent with this type of virus. Therefore, gene therapy using adenoviruses must be reapplied at regular intervals.

Gene therapy can also be used to insert a gene into normal body cells. One example of this would be to insert a gene to beef up the resistance of normal cells to chemotherapy drugs. This would then allow more chemo to be given to the cancer cells, instead of wasting it on perfectly normal, functional cells. Not only that, but the bone marrow could be protected from the damaging effects of chemotherapy. Think of this functioning as a fence between healthy body cells and the chemotherapy.

Another way gene therapy can be used is to combine it with an anti-angiogenesis compound. First, the virus infects only cancer cells. Then, an anti-angiogenic agent would affect only the targeted cancer cells. One can think of this as if the virus paints a target on the cancer cells, which the darts (anti-angiogenic protein) hit. Blood vessel development in healthy organs would not be affected by this treatment. This combination method has advantages over straight gene therapy, in that the infected tumor cells would produce more of the anti-angiogenic compound, allowing lower and less frequent doses. In addition, the infected cancer cells would have a "bystander" effect on their neighboring cancer cells. As long as the infected cell produced the compound, the tumor would be affected. Another example of combination therapy is to insert a normal p53 suicide gene, which then converts a non-toxic drug to a much more toxic drug, thus killing only the targeted abnormal cells...perhaps like putting beer in the garden, which attracts slugs into committing suicide in the beer.

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