Cancer study says AAVP can transport TNF-alpha while avoiding damage to other tissues.

Researchers have developed a new method for delivering a therapeutic gene to the blood vessels of human melanoma tumors in mice. Once delivered, the gene produces a protein that damages blood vessels and disrupts the flow of blood to tumors but not to the surrounding tissue. The new method appears safer than previous techniques because it causes fewer side effects, according to the researchers.


In their study, the team found that hybrid vector adeno-associated virus phage (AAVP) made from a bacterial virus could effectively deliver the tumor necrosis factor-alpha (TNF-alpha) gene—a protein produced by immune cells that has been shown to inhibit the growth of tumors by causing damage to their blood vessels–in such a way that it does not also damage surrounding noncancerous tissues, which had been a severe risk factor with TNF-alpha previously.


Four days after the investigators injected AAVP vectors that contained the TNF-alpha gene into the tail vein of tumor-bearing mice, they detected TNF-alpha in the human tumor tissues. During the study the tumors became smaller and the number of blood vessels decreased, a sign of damage to the tumor vasculature. The scientists did not detect TNF-alpha or the targeted vector in noncancerous tissues of the mice, including the heart, lung, kidney, skeletal muscle, and brain tissue. Although they did find the targeted vector in the liver and spleen of the mice, the TNF-alpha gene was not expressed in those locations.


“TNF-alpha is a promising anticancer agent, but its use is limited because of its toxicity,” says Anita Tandle, Ph.D., of the NCI’s Center for Cancer Research. “Our findings show that a hybrid vector, such as AAVP, can be targeted to directly deliver TNF-alpha to tumors with minimal toxicity to other tissues. In addition, this vector has potential for use with other agents that target tumor blood vessels.”


Now the team is working to test the AAVP vector in animal models of spontaneous cancers, which should speed progress toward the evaluation of this treatment strategy in clinical trials.
 
The study, which will appear in the January 1, 2009 issue of Cancer, was led by researchers at the National Cancer Institute and The University of Texas M.D. Anderson Cancer Center in Houston.