Gene Therapy and Cancer

Shala Haukos

Copyright 1997

In 1997, an estimated 1.38 million Americans will be newly diagnosed with cancer (Blaese, 1997). The treatments available only cure half of them. Many new strategies, including gene therapy are in developmental stages for treating cancer. Nearly half of all gene therapy trials currently under way deal with cancer and experts believe a number of these applications will be in use within the next three to five years (Lyon, 1997).
Cancer is considered a genetic disorder. Studies have identified a small number of genes that must be mutated to bring about development of cancer or maintain the growth of malignant cells (Klug, 1996). Two main properties of cancer are uncontrollable cell division and the ability to spread or metastasize. Both are results of genetic alterations. Mutations in the cells that lead to certain forms of cancer, can be identified as inherited in some families. In most cases, however, it is difficult to identify a simple pattern of inheritance.
There are two ways to regulate cell division. One way is with tumor suppressor genes, which usually function to inactivate or repress cell division. These genes or their products or both, must be inactivated sporadically for cell division of take place. If they are permanently inactivated or lost through mutation, uncontrolled cell division occurs. Another way cell division is regulated is by proto-oncogenes, which usually promotes cell division also. These genes can be in an "on" or "off" mode and when in the "on" mode, cell division is promoted. When the genes or their products or both are inactivated, cell division is stopped. If they are permanently switched "on", cell regulation is stopped and tumor formation begins.
Oncogenes are the mutant form of proto-oncogenes. An example of a transformation of a proto-oncogene to an oncogene is the p53 gene, which encodes a nuclear protein that acts as a transcription factor. The p53 gene is usually a tumor suppressor gene that controls passage of the cell from one phase of mitosis to another. The mutations in p53 gene are estimated to be associated with over half of all cancers.
The most prevalent cause of death in cancer patients is metastasis, where cancer cells detach from the original tumor site and settle elsewhere in the body, to grow and divide producing another tumor. There are two kinds of tumors, benign and malignant. Benign tumors can be removed and usually do not return. The most important thing is that they do not invade other tissues and do not spread to other parts of the body. Benign tumors are also not considered cancerous. Malignant tumors are cancerous and go through metastasis, increasing the difficulty of treating all part of the body with cancer. New therapies need to be found to treat cancer.
The techniques for gene therapy are relatively simple. It starts with the gene in a human cell that contains DNA, which acts as the blueprint for making specific protein. All cells in the body carry the same genes in the chromosome of nucleus. Each cell copies only selected genes into individual molecules of messenger RNA, which then serve as templates from which proteins are constructed.
If a particular gene is mutated, its protein product may not be made at all or may work poorly or sometimes too aggressively. If a normal gene can be delivered, it can physically take the place of the flawed version on the chromosome. Most attempts at gene therapy are simply adding a useful gene into selected cell to compensate for a missing or ineffective version or to instill some entirely new property.
Some gene therapy groups are also planning strategies to make up for genetic mutations, which result in destructive proteins. One strategy is antisense therapy, which uses short stretches of synthetic DNA to act on messenger RNA transcripts of mutant genes, preventing transcripts from being translated into abnormal proteins. Another strategy is the use of small RNA molecules called ribozymes, which degregade messenger RNA that is copied from diverging genes. A different plan called intracellular antibody provides a gene for a protein that can block activity of a mutant protein itself.
There are two methods that genes are delivered to patients. Both methods use vectors that are able to deposit foreign genes into cells. The most common method is in ex vivo; a scientist removes cells from the selected tissue, exposes them to gene-transfer vectors in the lab and then returns the genetically corrected cells into the individual. The second method is in vivo where the scientist introduces vectors directly into the body.
The key to having a successful gene therapy strategy is having a vector that is able to serve as a safe and efficient gene delivery vehicle. The potential vectors that have drawn the most attention are viruses, which are a little more than self-replicating genes wrapped in protein coats. They enter cells and express their genes there, which makes them potential vectors. Also scientists can substitute one or more potentially therapeutic genes for the genes involved in viral replication and virulence.
Retroviruses have been studied most extensively because they splice copies of their gene permanently into the chromosomes of cells they invade. Although they seem almost the ideal vector they pose several challenges. They lack selectivity in that they deposit their genes into the chromosomes of a variety of cells which can work against the direct delivery of the vectors into the body. Cells that were not suppose to receive the foreign gene could reduce transfer to the targeted population.
Another problem is that retroviruses splice their DNA into host chromosome randomly, instead of into predictable sites. Depending on where the inserted gene lands, they might disrupt an essential gene or alter genes in ways that favor cancer development. The faults of retroviruses as gene delivery vehicles have been studied very closely by researchers and they have made good progress confronting them. They are altering the viral envelope to increase specificity. Efforts are also under way to ensure that retrovirus vectors will place genes less randomly into human chromosomes.
Varied forms of experimental gene therapies are used in treating cancer. Some involve imparting cancer cells with genes that give rise to toxic molecules when these genes are expressed, resulting in proteins which then kill the cancer cells (Blaese, 1997). Another form has been designed by Steven A. Rosenberg, M.D., Ph.D., chief of the National Cancer Institute's Surgery Branch. This strategy is designed to immunize patients against their own cancers by injecting them with their own tumor cells after they have been modified by certain genes. After the surgical removal of a small piece of tumor tissue, scientists will insert genes for TNF (a protein produced by the body in response to bacterial infections) or interleukin-2 (IL-2) directly into cells from that tumor. Both TNF and IL-2 are immune system substance capable of mediating antitumor activity. The gene-modified tumor cells are then returned to the patient under the skin (National Cancer Institute, 1991).
Immunotherapy is another gene therapy strategy. The goal is to enlist the body's own defenses to attack the tumor site. The problem with this approach is that the immune system doesn't always recognize cancer cells. Many tumors are undetected by the immune system. Techniques to detect tumors detectable have possibly been found. It is now possible to tag cancer cells with specific genes making them more visible to the immune system. When these cancer cells are tagged the immune system can identify and attack them more frequently.
Adding new treatment approaches may enable scientists to eliminate cancer cells that are not destroyed by surgery, radiation, or chemotherapy. Surgery is one of the most common treatments for cancers. The tumor is removed from the infected area, but the cancer can return because it can go through metastasis. Surgery often does not get all of the tumor that is being to be removed. Radiation therapy uses high energy rays to damage cancer cells and stop them from growing. Some side effects of radiation therapy are fatigue and redness and dryness of the skin exposed to the radiation. The effects of the radiation to the skin are only temporary and will generally go away during the recovery cycle. Doctors indicate rest is most important, patients must also stay active.
Chemotherapy uses drugs to kill cancer cells. The drugs are either given orally or by injection into a vein or muscle. This is systemic therapy, where the drug runs through the blood stream and entire system. The side effects of chemotherapy depend mainly on the drugs received and vary from person to person. The anticancer drugs affect rapidly dividing cells, in general. This includes blood cells, which means that patients are more likely to get infections, bruise or bleed easily. Patients may also lose their hair, appetite, have nausea, vomiting or mouth sores. These side effects are gradually reduced during the recovery cycle.
Imagine the loss of a job or no longer having health insurance. Many people are afraid of this. A company may feel that it is a risk factor to have an employee undergoing gene therapy treatment. Insurance companies do not want to pay for such treatments because they will be losing money. Using gene therapy, in general, for overall genetic selection or screening for a genetic disease in an unborn child seems as if someone is trying to play "god" or unethical to some people. Others feel the whole idea of gene therapy are going to get out of hand and tear the whole world apart. Many people are concerned that society will come to the belief that everything has been discovered and halt scientists quest for new discoveries. Advocates for people with disabilities are concerned about gene therapy because it could endanger societies willingness to accept differences because everyone of a new generation will look the same.
Now, imagine a cure for AIDS, and a cure for cancer. Imagine no more babies born with sickle-cell anemia or cystic fibrosis. These are just some of the possibilities that could result from gene therapy. Many breakthroughs are being accomplished by gene therapy, with more to come. By attempting to prevent disease in individuals rather than selecting against individuals according to their genotype, gene therapy would allow us to maintain our commitment to the value of moral equality in the face of biological diversity (Reich, 1995). Some people feel that gene therapy is a good way to maintain our world. Gene therapy offers the only true cure for many diseases.
I feel that gene therapy is an important breakthrough and an on-going scienctific miracle. I think that gene therapyshould concentrate on finding cures for diseases. The cloning process should be regulated heavily by the government because people will attempt to make the perfect solider, person, or clone people just to harvest their organs. The clones could bring a very sad element into an already sad, chaotic world. It could affect the whole, moral balance of the world. I feel that gene therapy for cures of genetic disorders, such as cancer, is one of the most hopeful because most everything else that has been studied or tried is not very effective. Overall, people just need to use their best ethical judgment in the emerging field of gene therapy.


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