A common, benign virus may be a more powerful foe of some cancer cells than previously thought. Research has indicated that the virus, adeno-associated virus type 2 (AAV2), can inhibit the growth of some cancer cells and, in some cases, cause cell death (apoptosis). But researchers from Penn State University recently reported at the annual meeting of the American Society for Virology that, in laboratory cultures, AAV2 entirely wiped out cancer cells of four different types: cervical, squamous cell, breast, and prostate, while leaving healthy epidermal cells intact.

Only single cell lines of breast, squamous cell, and prostate cancer were studied. Not so for human papillomavirus (HPV)-related cervical cancer, explains Dr. Craig Meyers, professor of microbiology and immunology at the Penn State College of Medicine and the lead investigator on the study.

"We did the experiment 30 or 40 times with all different types of [HPV-related] cervical cancer lines: preneoplastic, ...invasive carcinoma, HPV16, HPV18, HPV31," he says. "Every single time, they died at 6 days, like clockwork." The 6-day time frame for cell death held true for all four cell types studied.

AAV2, which is estimated to have infected 80 to 90 percent of the U.S. population, appears to recognize the cancer cells as being abnormal, the researchers contend, although they still don't know how or why it takes 6 days before apoptosis sets in.

"With the cervical cancer lines, AAV2 doesn't care if it's preneoplastic or invasive," Dr. Meyers continues. "So it has to be something that happens early in the carcinogenic process. But whatever it is, it remains into the invasive stage."

AAV2, says Dr. Selvarangan Ponnazhagan, an associate professor of pathology at the University of Alabama at Birmingham, is considered to be "replication incompetent," meaning that even after it has infected a cell and integrated into its genome, it needs the assistance of another virus, such as HPV, to replicate and invade its next cellular target.

In terms of AAV2's therapeutic potential, Dr. Ponnazhagan says, "One of the limitations you need to overcome is the ability of the virus to penetrate a good proportion of the tumor cells to have a killing effect."

In this study, however, AAV2 worked without another virus' help, Dr. Meyers notes. His lab has done other work with healthy cells showing the virus can replicate on its own.

Engineered, or recombinant, versions of AAV are increasingly being used as a delivery vehicle for gene therapy approaches to cancer and other diseases. But whether the wild-type (naturally occurring) version of AAV2 could be transformed into a therapeutic presents a number of unanswered questions, says Dr. Peter Beard, a senior scientist at the Swiss Institute for Experimental Cancer Research who has closely studied the virus. Chief among those is just how much virus would be required to have a therapeutic effect in vivo.

In addition, says Dr. Doug Lowy, chief of the NCI Laboratory of Cellular Oncology, it's possible that preexisting AAV antibodies or antibodies generated by the introduction of the therapeutic virus might limit its oncolytic activity. Nevertheless, he says, "It's certainly a provocative observation that's in line with previous observations on AAV."

The study results have generated significant interest, says Dr. Meyers. His intent is to conduct further investigations into the intracellular signaling pathways affected by AAV2. He is also working with colleagues at Penn State "to figure out what we need to do to get from the lab to clinical trials," he says. "That's a major goal right now."

By Carmen Phillips