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Experimental RNA-based drug kills prostate cancer cells effectively and safely

Acting as a genetic Trojan horse, an experimental RNA-based drug -- the first of its kind -- tricks its way into prostate cancer cells and then springs into action to destroy them, while leaving normal cells unarmed.

The drug, developed at Duke University Medical Center, uses one type of genetic material, called targeting RNA, to enter cancer cells, and another type, called silencing RNA, to stop the expression of a protein that keeps the cells alive.

In tests in mice with prostate cancer, the drug shrank the size of their tumors by half, while the tumors in control mice that did not receive the drug continued to grow, said study co-author Bruce Sullenger, Ph.D., director of Duke's Translational Research Institute and chief of the Division of Experimental Surgery.

The mice showed no side effects from the treatment, Sullenger said.

"This study represents the first step in creating an RNA-based drug for cancer," said lead author James McNamara, Ph.D. a postdoctoral fellow in experimental surgery. "It provides a 'proof of principle' that an entirely RNA-based drug can work with minimal side effects, and it shows it is possible to overcome many of the obstacles that have hampered the development of RNA-based drugs."

The study is reported in the August 2006 issue of Nature Biotechnology, which is now available online. The research was funded by the National Institutes of Health.

Duke has filed a provisional patent application on the technology, according to the researchers.

"Scientists have made numerous attempts to transform silencing RNAs into natural anticancer agents, but such development has been challenging," said Paloma Giangrande, Ph.D., co-leader of the study and an assistant research professor in experimental surgery.

Scientists have encountered major obstacles when trying to deliver silencing RNAs to tumors, Giangrande said. Previous RNA-based drugs have been nonspecific, targeting all cel ls in the body and not just cancer cells. As a result, they have caused unwanted side effects.

The Duke team set out to produce a drug that would target only cancer cells. To accomplish this goal, the researchers designed a drug that combines two RNA "modules" that work in stages. One module contains targeting RNA, which attaches to a protein, PMSA, found only on the surface of prostate cancer cells. When that module binds to a cancer cell, the cell reacts by engulfing the entire drug molecule.

With the drug now inside the cancer cell, the second module, which contains silencing RNA, launches its effect. The silencing RNA seeks out and binds to the RNA for a specific cancer-causing protein, called PLK1, and tags it for destruction. This eventually leads to the death of the cancer cell.

The researchers first tested the drug in culture dishes containing cancer cells. They found that the drug effectively bound to prostate cancer cells, entered them and shut off production of the target protein, PLK1.

The researchers then moved into mouse experiments. They injected the drug directly into the mice's prostate tumors, administering one injection every two days, for a total of 10 injections over 20 days. By the end of the study, the tumors in the 10 treated mice had shrunk two-fold in volume, while the tumors in the 10 control animals had more than tripled in size.

"The animals themselves showed no signs of side effects," Giangrande said.

The scientists caution that much work remains to move the experimental drug into clinical use in humans. Among the next steps, Sullenger said, is to demonstrate conclusively that the drug can be delivered into the blood stream and still reach the tumor target without being destroyed by the body or causing adverse side effects.


Source:Duke University Medical Center

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