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Virotherapy and treatment Of Cancer


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Viruses that kill cancer

By Sean McNaughton, Globe Staff, 1/20/2004

The first clue that viruses could fight cancer came around the turn of the last century, when a woman with cervical cancer was bitten by a dog. She was injected with live, crippled rabies virus; her cancer shrank.


Subsequent decades brought more clues: Experiments in the 1920s confirmed that viruses killed tumors in mice. A handful of human patients benefited from viral injections in the 1940s. A 1956 National Cancer Institute study found viruses caused regression in half of the cervical cancer patients without making them ill. And in the '70s and '80s, doctors reported that patients' lymphomas shrank after bouts of measles.

But the clues were never definitive, the biology of viruses and cells was not well understood, some therapies made patients sick, and radiation and chemotherapy yielded more tangible results in the fight against cancer. So virotherapy was abandoned -- until a few years ago, when researchers armed with a new understanding of genomics and virology decided to try again.

Cancer virotherapy -- getting viruses to target cancer cells instead of healthy ones -- "went from an idea to human clinical trials in something less than 24 months," said Dr. David T. Curiel, part of a research team at the University of Alabama at Birmingham that laid the groundwork for virotherapy. "It's being used very, very aggressively, and new technologies are being developed."

One research team, lead by Dr. Robert L. Martuza, director of the neuro-oncology center at Massachusetts General Hospital, re-engineered a herpes virus to cure mice of an aggressive form of brain cancer.

"For the first time, we can harness these disease-causing viruses and make them into disease-curing viruses," Martuza said.

Theoretically, viruses are an ideal way to battle cancer because they are so good at choosing which cells to invade, getting around cell defenses, killing the cells, and then replicating themselves. Now, rapidly advancing molecular biology has given scientists pinpoint control in adding and deleting viral genes and increased the pace of research.

Experts caution that prescription drugs are several years away from market, but virotherapy research by academics and by biotech firms has yielded several phases of human trials on a broad range of cancers, from head and neck to prostate, lung, and brain cancers.

"Oncolytic viruses have really become very fashionable in the biological therapeutic world," said Leonard E. Post, senior vice president for research and development at Onyx Pharmaceuticals in Richmond, Calif. The company was showing promise at treating advanced colorectal cancer with engineered viruses, before it abandoned its virotherapy program last summer for business reasons.

Viruses' ability to target and kill cells efficiently raises the possibility that virotherapy could have fewer side effects than radiation or chemotherapy. Even tightly focused beams of radiation kill healthy cells, and chemotherapy will often kill six cancer cells for each healthy cell killed. Viruses, Martuza said, can be made to kill 1,000 or more cancer cells for each healthy cell killed.

Conventional therapies also exact heavy tolls on bone marrow -- limiting the amount that can be administered before the treatments themselves do too much damage to the body.

"We've shown these viruses don't harm bone marrow," Martuza said, so they could be added without compounding side effects. Several research projects found that chemo- and virotherapy were more effective when combined, because they target different cancer pathways and have have different levels of toxins.

Virotherapy is particularly promising in cancers that remain extremely resistant to traditional treatments, such as glioblastoma, the most common -- and most aggressive -- form of brain cancer. "Despite decades of research into chemotherapy agents, there has been no progress" in treating glioblastoma, said Martuza. "And radiation is maxed out."

Herpes and polio viruses engineered to be harmless have been successfully used to target glioblastoma, shrinking or eradicating the cancer in mice.

It's that power to discriminate among cells that makes viruses such good tools for finding -- and killing cancer cells. Viruses are also used in gene therapy and cancer vaccines, but in virotherapy, the virus itself is the treatment.

"Certain viruses attack only certain specific cells," said Robert A. Weinberg, MIT biology professor and a lead researcher at the Whitehead Institute for Biomedical Research who discovered the first human cancer gene. "They can be quite discriminating."

Viruses can tailor proteins on their outsides to fit lock-and-key into proteins that control access into healthy cells, bypassing cell defenses and allowing viruses to take control. Many cancers have telltale proteins that don't exist in healthy tissues, allowing scientists to engineer viruses that will target tumor cells but not healthy cells next door.

Researchers are also experimenting with viruses that infect cancerous and healthy cells alike -- but that remain dormant unless their host is cancerous.

Another area of research: Gaining control over the way viruses multiply.

"Many viruses destroy the cell in the process of replication, and they do it very efficiently" Dr. Kenneth K. Tanabe, viral oncology researcher and deputy director of the Mass. General cancer center, said. "Then they create progeny that infect other neoplastic cells."

Tanabe's team has engineered a herpes virus to target and kill diffuse, metastatic liver cancer. They deleted the gene that makes a chemical the virus needs to replicate. In healthy cells, the viruses get inside, but lack enough of the chemical to reproduce; In cancerous cells, which produce the chemical themselves, the virus is able to replicate and move on to attack other cancer cells.

Research has also shown that the presence of replicating viruses often primes the body's immune system to attack the cancer itself, delivering a one-two punch. Viruses injected into a mouse tumor attack the cancer directly -- and immune cells spread the attack to tumors in other parts of the body.

And that is one of the key drawbacks to virotherapy: By triggering an immune response, the viruses make themselves vulnerable to the patient's immune system.

"It's difficult to maintain an ongoing viral infection," Weinberg said, "because our cells tend to shut down infections in short order."

© Copyright 2004 Globe Newspaper Company.

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