July 26, 1999 LEXINGTON, KY -- For the first time at the University of Kentucky, researchers are beginning a Phase II clinical trial to evaluate a gene therapy product that may be used as a treatment for ovarian cancer. The clinical trial will evaluate the effectiveness of the p53 gene inserted into an adenovirus (common cold virus) in combination with standard surgery and chemotherapy to treat ovarian cancer that has spread to the abdominal cavity.
"Gene therapy is a novel approach to the treatment of ovarian cancer, as well as several other types of cancer," said Holly Gallion, M.D., professor, Department of Obstetrics and Gynecology, UK College of Medicine, and principal investigator at UK for the clinical trial. "We hope that gene therapy will prove to be another effective tool to fight ovarian cancer, along with surgery and chemotherapy."
Many diseases, including cancer, result from defective, or mutated, genes in cells. The goal of gene therapy is to deliver a correct copy of the mutated gene directly to the nucleus of the abnormal cells, thereby restoring normal function of the gene.
To insert the corrective gene into the nucleus, the corrective gene can be encapsulated in liposomes, small balls made of molecules that resemble cell membranes, or viruses. The adenovirus, or common cold virus, often is used as the gene-delivery vector in gene therapy.
Ovarian cancer is the most serious of all gynecological cancers. It is the fifth most common cancer among women, accounting for 4 percent of all cancers in women. According to the American Cancer Society, about 25,200 new cases of ovarian cancer will be diagnosed in the United States in 1999, and about 14,500 women will die from it.
About 76 percent of ovarian cancer patients survive one year after diagnosis, and more than 40 percent survive longer than five years. If diagnosed and treated early, before the cancer has spread beyond the ovaries, 95 percent survive longer than five years. Unfortunately, only 25 percent of all ovarian cancers are found at this early stage.
"The disease has often spread to other organs when a diagnosis is made because the symptoms are very vague," Gallion said. "The most common symptoms are a feeling of pressure or fullness in the pelvis, abdominal bloating, and changes in bowel or bladder habits."
The two biggest risk factors for ovarian cancer are being over the age of 50 and having a family history of ovarian cancer.
Standard treatment for ovarian cancer is surgery followed by six months of chemotherapy.
Two major types of genes are abnormal in human cancers: oncogenes and tumor suppressor genes. Oncogenes stimulate cell growth and tumor suppressor genes inhibit cell growth, acting as the brakes to uncontrolled cell growth and division. The most common gene that is mutated in ovarian cancers is a tumor suppressor gene called p53. Data indicate that if you provide a copy of a working p53 gene to a cell that has a malfunctioning p53 gene, growth of a tumor can be slowed.
The clinical trial, sponsored by a pharmaceutical company, is open to advanced stage ovarian cancer patients who have a minimal amount of cancer remaining in the abdomen following surgery and who have not had more than one round of chemotherapy treatment. All participants in the trial will receive chemotherapy. Half of the women also will receive gene therapy treatment in which the cold virus containing a normal copy of the p53 gene is put into the abdominal cavity through a catheter. The gene therapy will be given about once a month for five consecutive days along with standard chemotherapy.
"This should be viewed only as a possible additional treatment for ovarian cancer, rather than a treatment that will replace surgery and chemotherapy," Gallion said.
"Gene therapy protocols require several additional approvals as compared to other clinical trials of drugs," said Daniel Wermeling, Pharm.D., associate professor, UK College of Pharmacy, and director, Kentucky Center for Clinical Research and Investigator Services (KCCRIS).
The company that developed the product submitted the protocol for review and approval to the Food and Drug Administration, the Recombinant DNA Advisory Committee of the National Institutes of Health (RAC) and the Office of Recombinant DNA Activities Advisory Committee (OAC).
At the UK Chandler Medical Center, the protocol was submitted for approval to the Institutional Review Board (IRB), the Institutional Biosafety Committee (IBC), UK Hospital's Infection Control, and the General Clinical Research Center (GCRC), which is located at the UK Chandler Medical Center and is where the drug will be administered to patients. The protocol also was reviewed by KCCRIS which assists investigators with the administrative processes involved with clinical trials.
"Additionally, the UK Hospital pharmacy and staff have specific instructions to follow in dispensing and handling the drug, such as using fume hoods and protective gear," Wermeling said.
No evidence exists to indicate that healthy people who accidentally are exposed to the altered adenovirus with p53 are harmed. The genes responsible for replication have been removed, so the altered adenovirus should not spread. Adenoviruses only rarely incorporate their genes into the cellular DNA. Consequently, although the effect of the gene therapy will be temporary, there is no concern that the gene therapy may harm the patient's cells.
"Because the prognosis for women with advanced ovarian cancer is poor, the search for new methods, such as gene therapy, to attack the disease is important and ongoing," Gallion said.
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