It may not work against Godzilla, but a new drug could protect people from deadly doses of radiation. The compound, already in clinical trials to treat a blood disorder, may also make radiation therapy for cancer safer.
“What’s really exciting about this work is that not only have they found this countermeasure to mitigate radiation-induced [damage], but the fact that it works in a time window of 24 hours after exposure,” says radiation oncologist David Kirsch of Duke University Medical Center in Durham, North Carolina.
Radiation first strikes the bone marrow, wiping out the production of blood cells important for fighting infections, clotting, and carrying oxygen throughout the body. At high levels, radiation fries the gastrointestinal tract, damaging outer layers of the intestines and colon, and causing fluid loss, diarrhea, vomiting, and local infections, which can become more systemic and lead to death. The condition is known as radiation-induced gastrointestinal syndrome (RIGS), and there are currently no approved drugs to treat it.
Researchers had suspected that two proteins known as hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2) play a role in maintaining the integrity of the intestines during various times of stress. To test whether they were linked to RIGS, radiation oncologist Amato Giaccia of the Stanford University School of Medicine in California engineered mice to lack a family of proteins called PHDs that normally destabilize HIF-1 and HIF-2. Without the PHDs, mice have higher-than-usual levels of the HIF proteins. Whereas normal mice all died within 10 days of exposure to a high dose of radiation aimed at the abdomen, 70% of mice lacking PHDs were still alive after 30 days. “We were very surprised by the magnitude of the response,” Giaccia says.
Next, his team tried to replicate the results with a drug. They turned to dimethyloxalylglycine (DMOG), a compound known to block the PHD proteins and already in clinical trials to treat chronic anemia. Like mice lacking the PHDs, animals that received a dose of DMOG—even 24 hours after radiation exposure—survived longer than usual. Two-thirds of them were still alive 60 days after the exposure, the team reports today in Science Translational Medicine. DMOG didn’t alter the initial damage done to the gastrointestinal tract by radiation, but it helped the gut recover. Boosted levels of one HIF protein in particular, HIF-2α, the researchers showed, were key to the recovery.
“What we’re accomplishing with DMOG is that we’re modifying the physiology of the normal tissue to give it time to repair and regenerate,” Giaccia explains.
The new findings, Kirsch says, point toward an intervention that could be given in the 24 hours following a radiation emergency—such as the meltdown of nuclear reactors in Fukushima, Japan, in 2011—to save lives.
Giaccia would also like to find out if the findings can benefit cancer patients. A drug like DMOG, he says, might ease the toxicity that accompanies radiation therapy. Patients taking it might also tolerate higher doses of radiation, applied more broadly throughout the body, killing more cancer cells than current methods.
But Kirsch warns that it’s too soon to say whether DMOG, or other PHD-blocking drugs, can be used in cancer patients. “There’s some literature suggesting that targeting the HIF pathway could actually protect tumors from radiation,” he says, which would be counterproductive. “More studies need to be done to show that these compounds don’t affect tumor response.”