View articles by date | ON SCIENCE Home Page | View articles by topic

Using viruses to attack brain tumors

Since the mid-1990s researchers have been tantalized by the prospect of curing cancer with adenovirus, a common cold virus. Adenovirus is able to infect human cells quite effectively, because an adenovirus gene called E1B inactivates the human cell’s watchdog gene p53, a defense against infection that detects foreign DNA and signals the body to remove any cells that contain it.

This same defense also detects any damage to DNA, as a way of detecting and eliminating any mutations that might lead to cancer. Without the defense provided by p53, your body cannot protect itself from cancer-causing mutations. Cigarettes cause lung cancer because chemicals in tobacco smoke called benzo (a) pyrenes destroy p53 -- 70% of lung cancers have a damaged p53 gene.

How to cure cancer with adenovirus? Inactivate the adenovirus’s E1B gene. An adenovirus without E1B cannot disable p53 and so should be unable to grow in healthy cells -- but it would grow in, and so destroy, cells lacking p53. What cells lack p53? Cancer cells!

The approach was spectacularly successful in curing cancer in mice. In experiments carried out by cancer researcher Frank McCormick in 1992, 60% of lung cancer tumors just disappeared, and did not reappear later. Followup human trials, however, were very disappointing. Treatment of lung cancer patients with E1B deficient adenovirus produced little clinical benefit. Apparently almost all patients had had a cold at some point in their lives, and so possessed antibodies against adenovirus which were neutralizing the virus before it could do any good.
In work reported early this month, scientists at Houston’s M.D. Anderson Cancer Center are charging down this path again. It turns out that adenovirus directs a double barrel attack at human cells. With one barrel it directs E1B to shut down p53, while with another barrel it employs a gene called E1A to disable a human gene called Rb that in normal cells stops runaway cell division (Rb is called a “tumor suppressor” for this reason). The Texas researchers reasoned that a cell lacking a functioning Rb would have no way to prevent adenovirus from multiplying within it and killing the cell.

For this test, the researchers choose an aggressive, fast growing brain tumor. Glioblastomas are the most common primary brain tumor in adults, affecting about 7,000 Americans yearly. Few patients survive more than one year.

The Texas research team implanted human glioblastomas inside the brains of mice, then injected E1A deficient adenovirus (dubbed “Delta-24-RGD) directly into the solid tumors.

Sure enough, the approach works great in mice. While untreated mice died in 19 days, 60% of the treated mice were alive and thriving four months after the cancer was implanted. When these mice were euthanized and examined, the tumors were gone from their brains, destroyed completely by the E1A deficient adenovirus.

Will this approach work in humans? Scientists cured lots of cancer in mice with E1B deficient adenovirus only to see the therapy fail in humans, so no one is holding their breath that E1A deficient adenovirus will fare better. Still, the National Cancer Institute is hopeful enough that it has agreed to provide $1 million to produce enough of the E1A deficient virus to begin human testing.

The key issue of course is that mouse immune systems do not always provide an adequate defense against human adenovirus, allowing the procedure to work in mice while it would not in humans -- hence the failure of E1B deficient adenovirus therapy in humans. Only clinical testing can sort this issue out, which is of course why the National Cancer Institute is proceeding.

One cannot help but wonder, while we await these results, why researchers don’t try firing both of adenovirus’s barrels at once. If the natural virus finds it necessary to employ both E1A and E1B genes to successfully invade human cells, why not try attacking cancer cells with an adenovirus that is simultaneously deficient in both E1A and E1B?

©2003 Txtwriter Inc.





Txtwriter Home Page | BACKGROUNDERS | ON SCIENCE | Text Books | Book Reviews
This website is the copyright ©1998-2013 of Txtwriter Inc. All rights reserved.
Google