March 25, 1996
Media Contact: Sarah Goodwin at 404/727-5686, e-mail:

John Petros, M.D., assistant professor of surgery/urology at the Winship Cancer Center of Emory University, has been selected from among the nation's top scientists to present his research on metastatic prostate cancer at the 38th American Cancer Society Science Writers Seminar Sunday, March 24 in San Francisco.

Dr. Petros and a team of researchers at Winship Cancer Center have developed a novel means of delivering therapeutic DNA directly to prostate tumor cells in culture. This research focuses on achieving one of the most elusive goals of cancer gene therapy: the delivery and retention of high concentrations of a gene to metastatic tumor sites.

"Most researchers believe prostate cancer is a genetic disease caused by a complex array of DNA mutations, which are acquired in the prostate throughout life," said Dr. Petros. While only a small minority of prostate cancer cases have heredity as a primary cause, nearly all sporadic cases (approximately 90 percent of all prostate cancers), reveal acquired genetic abnormalities.

Current research into the genes and chromosomes that are altered in prostate cancer may yield sites that would be appropriate for genetic intervention through gene therapy.

"However even if the perfect genetic target were identified today, there exists no system to deliver the therapeutic DNA molecule," said Dr. Petros. The lack of a method to get a useful amount of the right gene to the appropriate site has frustrated genetic researchers since the beginning of this area of study. To accomplish this task, Dr. Petros and his team hope to take advantage of the inherent biology of advanced, hormone- independent prostate tumors.

Mortality from prostate cancer is the result of a metastatic tumor which has relapsed following hormonal manipulation by androgen (male hormone) withdrawal. While surgery or radiation can cure prostate cancer in its early stages, advanced disease is unresponsive to these conventional treatments.

Once the cancer has metastasized and the patient has been treated with androgen withdrawal, the tumor and its metastases exist in an androgen-deprived state. The tumor responds by increasing the amount of active receptors for androgen. The tumor scavenges for androgens, retaining any it finds. If a drug, or therapeutic DNA molecule, could be attached to an androgen molecule, presumably it would be selectively retained at these sites. The natural function of the androgen receptor, after it binds with androgen, is to undergo transport into the cell's nucleus to allow interactions with the cell's chromosomes there.

Dr. Petros has synthesized compounds that act like glue in tethering DNA to a potent androgen called DHT(dihydrotestosterone). In cell culture, his first experiment showed that indeed, the DHT did link up to androgen receptors, and that the large pieces of DNA riding piggyback on the DHT were delivered into human prostate cancer cells and into their nucleus. The cells treated with the DNA alone, without the "glue," did not take up the DNA.

"We hope the fact that metastatic prostate cancer in men expresses an abnormally large amount of the androgen receptor will aid in the retention of therapeutic DNA or any attached 'drug' at the appropriate sites," said Dr. Petros. "This would achieve the high concentrations needed for effective gene therapy."

Possible current gene targets for intervention include tumor-suppressor genes such as p53 and RB1, or a metastasis-suppressor gene, which are known to be faulty in prostate cancer. Other potential areas frequently deleted in this disease occur on chromosome 8 and chromosome 10.

"There is no therapeutic DNA molecule yet for prostate cancer," said Dr. Petros. "But we will be ready. While other investigators discover the areas which are faulty and in need of repair, we will continue to develop an efficient means of delivering the DNA to the tumor." The delivery system can be used for any type of rehabilitative DNA molecule in use now, and for any type of genetic mutation, as well as for new ones that evolve as research progresses." Experiments have not yet been conducted in animals or humans. Dr. Petros and his team continue to develop new and better compounds that will further streamline DNA delivery and make cellular uptake of DNA more efficient.

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