The finding may eventually lead to more potent anti-cancer therapies that capitalize on the ability of viruses to reproduce in the body.

In animal studies, the new version dramatically reduced the size of human prostate cancer tumors grown in mice. Moreover, it completely eradicated the tumor mass in some of the animals, and it appears not to harm normal tissue.

"We took a crippled virus and essentially made it into a more effective killer of cancer cells," says Ian Mohr, Ph.D., Assistant Professor of Microbiology at NYU School of Medicine, who led the research and is an author of the study. "But we've only demonstrated this in mice. Clearly the next step is to see whether this more potent anti-tumor virus works in other animal models."

"We think this new virus offers great promise as a therapeutic strategy for the treatment of patients with prostate cancer," says Samir Taneja, M.D., Assistant Professor of Urology, an author of the study. "Eventually we hope to test this virus in humans but we still have many things to work out," says Dr. Taneja, whose laboratory is focused on finding new therapeutic strategies for treating prostate cancer.

The new study appears in the July 17 print edition of the Proceedings of the National Academy of Sciences.

Viruses are usually associated with disease. In recent years, however, scientists have turned a bane into a potential good by taking advantage of the ability of viruses to infiltrate human cells, where they can then reproduce.

Viruses have developed this ability over the course of millions of years of evolution, and they are especially agile pirates, commandeering a cell's own machinery to churn out more virus, and ultimately destroying the cell. The cell too has evolved its own defense against viral invasion.

Although this kind of viral research is still in its infancy -- and it is far too early to say whether it will ever result in new cancer therapies -- at least 10 different oncolytic (cancer-killing) viruses are, or are soon to be, in early clinical trials. Most of these viruses have been genetically engineered so that they will not cause disease, but will infect rapidly dividing cancer cells.

One of these viruses is the herpes simplex virus-1, well known as the cause of cold sores, but capable of causing a serious brain infection as well. In the early 1990s, scientists tinkered with two genes in the virus that disarmed its ability to cause the brain infection and its ability to reproduce in non-rapidly dividing cells.

The result was a weakened herpesvirus that didn't cause disease, but reproduced in rapidly growing cancer cells. This herpesvirus, however, isn't an ideal destroyer, says Dr. Mohr.

"Although the virus kills cancer cells, the process of weakening it often has a deleterious impact on its ability to replicate inside cells. The result is that the virus doesn't completely destroy the tumor mass, and the surviving cancer cells can simply grow," he says.

To get around this problem, Dr. Mohr's group observed the effect of the genetically engineered herpesvirus on human cancer cells grown in a laboratory dish. Then they isolated the viral strain that was the most effective killer of cells and discovered that it contained an extra genetic mutation that enabled more robust reproduction of the virus.

This extra mutation switches the expression of a protein called Us11 to an earlier time in the infection cycle of the virus, which prevents the cell from mounting a response to stop viral replication.

In the new study, Drs. Mohr and Taneja and their associate Jennifer MacGregor found that the new version of the genetically engineered virus was far more effective in killing prostate cancer cells in an animal model than was the older version of the same virus.

The NYU team injected the new version of the genetically engineered herpesvirus with the added mutation directly into human prostate cancer tumors they had implanted into mice that had no immune systems.

In another group of mice, they injected the older version of the herpesvirus, and in the last group they injected an inert solution that didn't contain virus.

Thirty-four days after the treatment, the tumors injected with two million virus particles of the new version were, on average, eight times smaller than the tumors injected with the older version of the virus.

Moreover, the tumor mass had completely disappeared in up to 40% of the animals injected with the new version of the virus.

The study was supported by a grant from the Department of Defense and an award from CapCure, the foundation for prostate cancer research established by Michael Milken.

16-Jul-2001