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Altered cold virus devastates brain tumors in lab mice

Wednesday, May 7, 2003

WASHINGTON -- Scientists have genetically altered a common cold virus so that it can destroy the most lethal type of brain tumor while not harming healthy tissue nearby.

The experiment worked so well in mice that researchers hope to begin studying it in people with this aggressive brain tumor, called a glioblastoma, late next year.

The scientists implanted human glioblastomas inside the brains of mice, then injected the experimental virus directly into the tumors. Untreated mice died in 19 days, but 60 percent of the treated mice were alive and thriving for four months.

Then scientists euthanized the survivors to see what was happening inside their brains -- and found only empty cavities and scar tissue where the tumors once were.

"Everyone here is excited about it because we've never seen anything happen with the mice like that," said lead researcher Dr. Frederick Lang, a neurosurgeon at Houston's M.D. Anderson Cancer Center.

He cautioned that the dramatic results don't assure the virus will work in people: Scientists have cured lots of mice of cancer only to see the therapies fail in patients.

"This is an interesting study," said Dr. Len Lichtenfeld of the American Cancer Society. But he echoed Lang's caution, adding that mutant viruses could prove too toxic to use.

"We need to be very, very careful" in studying the experimental treatment, Lichtenfeld said. "There are too many situations where doctors and patients and families have gotten very, very excited about drugs and it's turned out ... that the drugs weren't effective. We need to avoid that."

Given $1 million

Still, the National Cancer Institute is intrigued enough that it is providing $1 million to produce enough of the mutant virus to begin human testing, said Lang, who hopes to start enrolling brain-tumor patients in a study of the treatment by winter 2004.

Glioblastomas are the most common primary brain tumor in adults, striking about 7,000 Americans a year, and the most lethal. Survival is only about a year, a dismal rate that hasn't changed in decades despite improvements in surgery and radiation and chemotherapy treatments.

So how could the mild, sniffle-causing adenovirus tackle such a killer?

Before the immune system detects and eliminates a cold, adenovirus spreads by infecting a cell and hijacking its reproductive machinery to make viral copies, killing the cell in the process.

The key is to harness the adenovirus so it infects only tumor cells and not healthy tissue, something scientists have tried with limited success since the mid-1990s.

This latest attempt uses a different approach.

In normal cells, the retinoblastoma, or Rb, protein helps block an invading virus from reproducing. Rb protein also can block the uncontrolled cell division that is cancer's hallmark -- and thus solid tumors lack properly functioning Rb.

Adenovirus contains a gene that disables Rb so it can take over healthy cells. M.D. Anderson's Dr. Juan Fueyo altered that gene, leaving a virus capable of infecting Rb-lacking cancer cells but not healthy cells.

Wave of dead cells

However, that mutant virus was relatively weak. So the next step was another genetic alteration that made it easier for the adenovirus to invade by binding to molecules called integrins that are common on the surface of cancer cells.

The resulting virus, dubbed "Delta-24-RGD," swept through some -- but not all -- of the mouse brain tumors like a wave, leaving dead cancer cells in its wake.

The big question is whether people's immune systems will attack the mutant virus before it can penetrate and spread through a brain tumor. The virus would have to be injected through the skull directly into the brain tumor, which could delay the immune reaction.

"It's going to be a race," Lang said. But "our studies suggest that there's a certain window of time between the immune system gearing up and the virus being stopped."


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