dimanche 16 mars 2008

Surviving Side Effects

Security fears spawn ways to treat radiotherapy’s downside:

After the September 11 attacks, Congress became worried that terrorists targeting the U.S. might explode a radiological weapon—most likely a “dirty” bomb, a kind of weapon that relies on a conventional explosive to spread radioactive materials packed around it. In 2004
Congress funded several research centers to create drugs to protect survivors and first responders from radiation injury. But the biggest beneficiary of this research might be a much different and far larger group of people: cancer patients.
Some 10.5 million Americans are living with cancer, according to the Nation-al Cancer Institute. These patients must conquer not one but two different diseases. “When we are talking about cancer survivors,” explains Andrei Gudkov, senior vice president for basic research at the Roswell Park Cancer Institute in Buffalo, N.Y., “we mean survivors both from the disease itself and from the treatment of the disease.” That is because the two common treatments—radiation therapy and chemotherapy—generally attack healthy tissue as well as tumors, causing long- and short-term complications. Radiotherapy sometimes even gives patients new tumors years later, Gudkov says. The complications also prevent many cancer patients from receiving doses large enough to treat the disease and survive. “So if we can reduce the chances of complications,” says radiation oncologist Mitchell Anscher of
Virginia Commonwealth University,“that’s half the battle right there.”
The 2004 legislation enabled the National Institute of Allergy and Infectious Diseases to create eight national Centers for Medical Countermeasures against Radiation in October 2005. The agency has spent $56 million in total so far, and it plans to commit another $82 million over the next three years.
One strategy seeks to neutralize free radicals, which form because ionizing radiation knocks electrons off molecules, turning them into positively charged, highly toxic compounds. Researchers are working on drugs that mimic superoxide dismutase, a natural enzyme that transforms free radicals in the body back to harmless molecules before they can cause damage. Joel Greenberger of the University of Pitts-burgh has shown in animals that manganese superoxide dismutase can protect the esophagus from damage during radiotherapy and up to 72 hours afterward. Phase I and II clinical trials testing the drug in patients with lung cancer are now under way. Anscher, Zeljko Vujaskovic of Duke University and others have shown that AEOL 10150, a small artificial molecule that mimics superoxide dismutase, protects against lung damage in rats.
Because so many more people now survive cancer over the long term than ever did before, researchers are also tackling one of the biggest problems that radiotherapy causes in these patients: fibrosis. Radiation oncologist Paul Okunieff of the University of Rochester calls this production of excess fiber like connective tissues the most common side effect limiting cancer radiation doses to soft tissue. Fibrosis causes pain and swelling and restricts muscles’ range of motion, lowering mobility and lung capacity. Anscher’s group has focused on con-trolling TGF-beta, an immune system protein that causes cells to grow too much fibrotic tissue. Using antibodies and small molecules to attack TGF-beta before radiotherapy, his group has been able to reduce later fibrotic growth in mice and rats.
Existing cardiovascular drugs might also alleviate other long-term problems. Statins not only lower cholesterol but also protect blood vessels, which can be weakened by radiation. Researchers have be-gun human trials to see if lovastatin given before radiotherapy prevents rectal bleeding, which often occurs two to three years after prostate cancer treatment. ACE inhibitors, used to lower blood pressure, can reduce radiotherapy damage to kidneys, lungs and brains.
Some drugs could treat radiation effects from both therapy and bombs. For instance, Martin Hauer-Jensen of the University of Arkansas works with SOM230, a drug that mimics the hormone somatostatin. The drug inhibits the secretion of enzymes that destroy the inner lining of the intestines after radiotherapy. Be-cause SOM230 can be given four hours after radiation, it should help in dirty bomb incidents. And the U.S. military seems especially excited about a drug from Cleveland Biolabs called Protectan CBLB502 to lessen radiation injuries in soldiers who have survived an atomic blast. According to Roswell Park’s Gudkov, who is also Cleveland Biolabs’s chief scientist, the drug targets a gene-activity regulator to boost production of superoxide dismutase, release immune cells that fight radiation damage, and limit apoptosis (cell suicide) in normal tissues—all properties useful in combating radiotherapy’s side effects as well.
Amid post-9/11 concerns, many new ways to treat cancer radiotherapy’s side effects will likely continue to emerge. As radiation oncologist John Moulder of the Medical College of Wisconsin puts it:“There’s a lot more money now that it’s called counterterrorism.”

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