Gene therapy is an experimental treatment used for a variety of medical conditions, including cancer. The technique uses viruses and other carriers (vectors) to transport healthy genes into human cells that contain defective or missing DNA. The treatment can restore a missing or altered function, or give the cell a new function. Gene therapy is the attempt to alter the problem of missing or damaged genetic material that contributes to the development of cancer in the human body.

Today, researchers are studying and testing numerous forms of gene therapy that may offer hope to cancer patients around the world. Some of the potential goals for gene therapy in the treatment of cancer are to:

• Change or fix an abnormal gene so that it functions normally.
  
  
• Inject healthy genes into cells to replace an absent gene or to compensate for one that is poorly functioning.
  
  
• Replace an abnormal gene with a normal one.

There are no proven methods to prevent or cure cancer using gene therapy. However, discoveries have been made regarding genes and their activities in cancer development. Methods of introducing genetic material into cells are varied, as are the results. Strategies include placing viral genetic material into tumors, which can override and change the defective genes of cancer cells. Techniques can also enhance the immune system to fight cancer and suppress the growth of blood vessels in malignant tumors to curb their growth.

Although gene therapy has shown great promise, it is important to remember that much more research is needed to produce safe, reliable and effective treatments of cancer.

Gene therapy is an experimental treatment for a variety of medical conditions, including cancer. To understand gene therapy, it is necessary to have a basic understanding of genes.

In the center of every human cell there are 46 chromosomes which are arranged in 23 pairs, with one of each pair coming from each of the biological parents. Twenty-two of these pairs, known as autosomes, are common to males and females. The 23^rd pair is known as the sex chromosomes and is responsible for determining gender (XY in males, XX in females).

Each chromosome contains long, tightly wound strands of DNA (deoxyribonucleic acid), which is the genetic blueprint for how the body is constructed and maintained. According to an international study known as the Human Genome Project (international project that began in 1990), if the DNA strands within each chromosome are uncoiled and connected, the resulting strand of DNA would be more than 5 feet long (1.5 meters) but only a tiny fraction of an inch in width. 

A DNA blueprint contains technology information that can be analyzed by qualified physicians and scientists. A strand of DNA is composed of four types of chemicals called bases: adenine (A), cytosine (C), guanine (G) and thymine (T). Therefore, the DNA sequence might read "ATGCGATGCG". These strands determine all genetic characteristics, such as hair color, eye color, height and a variety of other cellular activities. Segments of the DNA strand that have been identified as having specific effects on the body (e.g., manufacturing a protein) are called genes.

Strands of DNA are linked together at specific points along their length. They are linked together such that the base (A, C, G or T) on one strand is paired with a matching base on the other strand. For example, A pairs only with T, and G pairs only with C. When the bases are paired, the two together is called a base pair. The average-sized gene contains about 30,000 base pairs.

The number of base pairs possessed by a living creature, be it an amoeba or a human being, determines the size of its genome (the sum total of all its genetic information). The human genome is estimated to contain about 3 billion base pairs and more than 100,000 genes. It has been estimated that publishing the entire human genome would take 2 million pages, and reading it aloud from beginning to end would take almost 10 years.

Learning how to decode the human genome – the entire DNA blueprint of the human body – has been a serious challenge for those involved in the Human Genome Project but the potential benefits are enormous. Mapping the human genome not only allows scientists to read the genetic information, but also gives them a chance to change the information through gene therapy treatments. These treatments could have revolutionary effects on both diagnosis and treatment of diseases, such as cancer. Essentially, gene therapy can  potentially alter certain genetic elements for the better.

To understand gene therapy requires comprehension of several terms. These include:

• Genes. The basic unit of heredity. They are located in the nucleus (center) of a cell on strands called chromosomes. They human body has tens of thousands of genes.
  
  
• DNA (deoxyribonucleic acid). A complex substance in genes that contains genetic information needed to make the body’s proteins.
  
  
• Vector. A substance, such as a virus, fat or protein, used to supply genetic material to target cells. A gutless virus vector is a viral carrier in which the harmful genes have been removed.

Gene therapy is being developed at universities, research centers, corporations and medical centers around the world. Most of the studies are in early stages and they are not used in standard treatments. Several thousand people have taken part in clinical trials of gene therapy, mostly for cancer, in the United States. The U.S. Food and Drug Administration (FDA) has not yet approved the sale of any gene therapy products for regular clinical use.

For decades, researchers suspected that genes played a role in the development of conditions such as cancer. Some cancers tend to run in families, which suggest a genetic component is being passed from generation to generation. In combination with one’s environment and behavior (e.g., eating a high-fat diet), genetics appeared to play an important role in the development of cancer cells. However, the necessary technology to test this idea was not available.

A major advance in gene therapy occurred in the 1980s, when researchers learned how to transport healthy genes into human cells. They did this by grafting the healthy genes onto a weakened virus (an adenovirus), which was then injected into cells. The weakened virus then “infected” the cells with the healthy genes, causing the cells to follow the healthy new blueprint instead of the old harmful blueprint. The weakened virus was then destroyed by the body’s immune system.

In the 1990s, this strategy of gene therapy successfully treated a young woman’s case of hypercholesterolemia, which is extremely high cholesterol due to a genetic defect. Other human gene experiments followed. In 2003, the Human Genome Project, which identified the makeup of genes in human DNA, was completed. Researchers continue to work to translate these findings into medical treatments for cancer and other diseases.

Cancer is the result of mutations to genes that cause the abnormal growth of cells. These gene mutations can lead to abnormalities in cellular functioning. Mutations in genes begin with changes to the genetic coding of a single gene in a cell. The changes are passed to  other cells as the affected cell divides. Discovering the nature of genetic mutations in the development of cancer and methods of preventing or stopping them is the goal of gene therapy. Gene therapy for cancer may include the following techniques:

• Insert a normal gene to replace the DNA of the mutated one
  
  
• Exchange a normal gene for the mutated one
  
  
• Repair the DNA of the mutated gene
  
  
• Modify the internal management of the mutated gene
  
  
• Boost the body’s own immune system to fight the cancer cells
  
  
• Create “suicide” functions in abnormal genes for self-destruction of the cancer cells
  
  
• Add genes to cancer cells to increase their response  to chemotherapy and radiation therapy
  
  
• Block genes from forming blood vessels that nourish the tumors

Studies in gene therapy have produced successful results in some cancer patients:

• Clinical trials in which a virus was introduced into the cells of patients with bronchioloalveolar lung carcinoma (BAC) whose disease was advanced and incurable produced palliative relief of some symptoms with minimal side effects in most patients. One combination of gene therapy also was found to be successful in reducing the number and size of non-small cell lung cancer tumors in mice.
  
  
• Another set of clinical trials using a DNA–based treatment called antisense therapy eliminated tumors in patients with advanced melanoma. Several methods of gene therapy have produced a range of results with melanoma. A type of vaccine therapy that introduces certain genes into the cancer cells has been particularly successful in stimulating the immune system to react against the cancer cells.
  
  
• Researchers are using replacement methods for the p53 tumor suppressor gene to enhance genetic suppression of tumor growths in a number of cancers, including oral cancer, nasopharangeal cancer, esophageal cancer, lymphoma and others.
  
  
• Researchers have also studied the combination of radiation therapy and gene therapy to treat certain cancers. This combination has been successful in treating some prostate cancer tumors. Additional studies have shown that the combination also may be effective in treating malignant gliomas, an aggressive type of brain tumor.

Carriers called vectors are used to insert genes into target cells. The vector then substitutes its DNA for the target cell’s DNA. The target cell then follows the instructions of the vector’s DNA. Vectors used in gene therapy are usually genetically altered viruses. Viruses easily inject their genetic coding or DNA into target cells. There are two techniques of gene therapy where the insertion of DNA takes place:

• In vivo. This technique occurs in the body. The vector is directly introduced into the body by any delivery method such as inhalation or injection. The gene is then received by the target cells where the genetic coding is copied to the genome (genetic code) of the target cell. There is a variety of methods for inserting genetic material into cells, such as viruses or plasmids (non-viral DNA).
  
  
• In vitro. This technique involves taking target cells outside of the body. The vector is injected and then the cells are replaced in the body. This method is successful in initiating the immune system’s response. Two types of cells can be altered in this technique:
  
  
• Tumor cells. These can be genetically altered to be recognized as invaders by the immune system and destroyed when they are reintroduced into the body. This also enhances immune system identification of cells like them to attack them as well.
  
  
• Immune system cells. Certain immune system cells can be genetically altered to identify cancer cells. They are removed from the body and altered to enhance their cancer-fighting ability.

A variation of gene therapy is the choice of vector, the carrier that brings the genetic material to the targeted cell. There are two main categories:

• Viral vectors. Viruses are parasitic packages of genetic material encased in protein. Some may be harmless to humans, but many cause infectious diseases, ranging from colds to AIDS. Gutless virus vectors have had harmful material removed. Researchers are trying to create artificial viruses that provide effective treatment with no safety issues. Viral vectors include:
  
  
• Adenovirus. Most people have been exposed to this common cold virus. A risk of using it as a vector is that it can trigger an attack from the immune system. Also, it might last only a week or less. Improved adenovirus vectors are being studied.
  
  
• Adeno-associated virus (AAV). It is not known to cause any human illness. Because it does not trigger the immune system, it lasts longer than the adenovirus. However, it is tiny and cannot carry as much therapeutic DNA.
  
  
• Retroviruses, including herpes, HIV and tumor viruses. These may be used when a permanent vector is needed, because they can insert their genetic material into the cell’s chromosomes.
  
  
• Nonviral vectors. Scientists are developing gene carriers that do not have the safety concerns of viruses. Some of these are polymers, natural or synthetic compounds. Nonviral carriers include:
  
  
• Fats (lipids), such as liposomes and lipoplexes. These fatty shells can carry genetic material or medicine.
  
  
• Proteins. DNA-containing proteins engineered in laboratory studies.
  
  
• Transporons. Segments of DNA that can transfer genetic material.
  
  
• Plasmids. DNA molecules derived from bacteria.

Delivery methods are crucial to the proper introduction of the DNA. It must be received into the target cells with minimal immune system rejection and so that its replication can be effective and appropriately timed. Delivery methods are different for each target location and each vector. Each delivery method has its advantages and disadvantages, and each will have optimal results with certain vectors. Delivery methods include:

• Inhalation through the lungs
  
  
• Injection or perfusion into the site, such as skin or muscles
  
  
• Transplantation of cells that are injected with therapeutic DNA
  
  
• Systemic injection or IV drip to travel through the bloodstream
  
  
• Physical bombardment of cells to penetrate cell walls to introduce therapeutic DNA

Factors affecting delivery include:

• Cell permeability (the cell wall’s ability to be penetrated)
  
  
• Ability to overcome other physical barriers of cell, tissue and organ
  
  
• Target cell location
  
  
• Location of therapeutic DNA placement in the genome of the target cell
  
  
• Immune system attack on therapeutic DNA as an invader rendering it ineffective
  
  
• Correct amount of DNA and ability to repeat dosages as required
  
  
• Effectiveness of therapeutic DNA
  
  
• Size of therapeutic DNA replication required
  
  
• Appropriate and correct form of gene to correct the abnormal DNA
  
  
• Stability of therapeutic DNA in replacing defective DNA material
  
  
• Duration of inserted DNA expression
  
  
• Safety features involved to prevent disease formation or severe immune system response in the patient

Scientists are studying the most effective ways to deliver gene therapy. The greatest problem continues to be getting DNA to the targeted cell efficiently enough to make a difference. Through ongoing studies, researchers are making gains in understanding gene therapy and the treatment of cancer.

Scientists hope to use gene therapy for many purposes in fighting cancer, including to:

• Boost the immune system’s response. This can be done in several ways:
  
  
• Tumor recognition. When tumor cells are injected with the vector the immune system will respond to that tumor as an invader. This strengthens identification of the cancer cells for immune system attack.
  
  
• Immune cells’ survival. The cells of the immune system can be enhanced for greater survival.
  
  
• Increase in anti-tumor properties. Immune system cells can be strengthened to fight the cancer cells.
  
  
• Tumor modification. Tumors can be modified to contain anti-tumor properties.
  
  
• Increased sensitivity to chemotherapy.  Gene therapy can be used to heighten the cancer cells’ sensitivity to chemotherapy drugs that are designed to kill the cells and stop them from reproducing.
  
  
• Increased protection from chemotherapy and radiation therapy. Genes can be introduced into normal cells to help protect them from damaging side effects.
  
  
• Targeting of oncogenes. These are mutated genes that enable the growth of cancerous cells and their spread throughout the body.
  
  
• Enhancement of tumor suppressor genes. Insert DNA of tumor suppressor genes such as p53 designed to arrest mutated cell growth.
  
  
• Enhancement of suicide gene delivery. A gene encodes protein that is toxic to the cell or activates a chemotherapy drug to kill the mutated cell.
  
  
• Prevention of angiogenesis. Blood vessels are targeted to prevent them from forming and nourishing cancerous growths.

There is much hope and promise for the future of gene therapy, but obstacles must be overcome. The following challenges and risks need to be addressed to further develop technology related to gene therapy:

• Virus infection. More than the targeted cell can be infected by the viral DNA. Healthy cells may receive viral DNA replication, thereby damaging them.
  
  
• Gene target location. A misapplication of the location of the viral DNA could lead to not remedying the problem in the targeted gene because the genome location is wrong. The DNA must replicate to the exact site.
  
  
• Virus overexpression. The therapeutic gene could be over replicated, which may lead to overexpression of the genes, harming the patient.
  
  
• Cancer cell production. Viruses can affect healthy cells as well as mutated cancer cells which is not desired. They can also insert into the wrong gene location and cause cancer cell production.
  
  
• Dangers to reproductive cells. The DNA can infect reproductive cells, which has the potential to affect cells of future generations.
  
  
• Experimental treatments. Gene therapy is currently unproven and experimental. Because of this, gene therapy is applied in cases standard treatments are not considered to be beneficial.
  
  
• Limited knowledge. Very little is known about genes, their interactions with each other and the long-term consequences of gene therapy.
  
  
• Immune system’s response to vectors. If the immune system becomes hypersensitive to the adenovirus, for instance, the adenovirus must be altered to be effective. The alteration decreases the stength of the virus. Also, the hyperactivity of the immune system against the virus can lead to death.
  
  
• Cell integration. Lack of integration or reception into the cell is a factor.
  
  
• Controlled virus expression. The exact timing and amount of the correct therapeutic DNA is specific and varies from cell to cell. The exact expression must be maintained to control the disease as well as stability of gene expression.
  
  
• Damage to the host/patient. Any disease or severe immune system response arising from gene therapy is an undesirable risk.
  
  
• Cellular damage. If the damage of the cancerous mutations to cells and organs is irreparable, there are potential problems regarding the effectiveness of gene therapy administration.
  
  
• Host immune response. Immune system response against the introduced foreign DNA on repeated administration of the foreign DNA can eventually become severe and even life-threatening.
  
  
• Delivery methods.  Delivery methods present a challenge because the therapeutic DNA process is detailed and complex. Researchers continue to evaluate the most effective methods for delivering gene therapy.

Stem cells are immature cells that have the ability to develop into a variety of mature cells, such as red or white blood cells and platelets.

Harvesting and implanting stem cells from a patient’s own bone marrow or peripheral blood is known as autologous transplantation. Compared to embryonic stem cells, autologous stem cells are significantly more limited in their ability to develop into different cell types. This contributes to the ethical debate concerning embryonic stem cell research.

The potential of stem cell research is unlimited. Human embryonic stem cells are advantageous to cancer research development because they are self-generating cells and because they can be transformed to various types of cells in the body. For this reason, their use can be widespread in combating genetic defects leading to diseases such as cancer. Stem cells can be converted into the healthy cell type of the diseased cells.  

Several difficulties exist in the applications of stem cell treatment. One is that not enough is known about reactions in patient’s bodies to this genetic introduction. Introducing stem cells into the body is a complicated task, and it will take time to develop methods that are safe and efficient. Also, growing stem cells is more difficult and takes longer than expected.

Researchers are just beginning to realize the potential for gene therapy. By identifying more of the genes that place people at greater risk of cancer, additional diagnostic tests may developed to detect these genes. In turn, this may allow individuals the chance to change their lifestyle and habits or perhaps some of their genes.

Although this type of treatment offers great hope, it is important to remember that much more research is necessary before gene therapy is perfected. The goal is to develop specific, effective techniques that can target a specific gene or site, with little or no adverse effects.

Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor or healthcare professional the following questions about gene therapy:

1. Am I a candidate for gene therapy?
   
   
2. Can you refer me to an appropriate clinical trial for my cancer?
   
   
3. How does the therapy work?
   
   
4. What are the benefits and risks of the treatments?
   
   
5. What is the success of gene therapy with my type of cancer?
   
   
6. How will I be monitored with gene therapy?
   
   
7. What is my prognosis with the treatments?
   
   
8. Can gene therapy for my cancer affect any other medical conditions I may have?
   
   
9. Does use of other cancer treatments rule me out for gene therapy treatment?
   
   
10. Where can I obtain information about the Genome Project?