New oral drug may prevent death from radiation poisoning

U.S. Nuclear Regulatory Commission

 (U.S. Nuclear Regulatory Commission)

Large-scale radiation exposure, either from a nuclear power plant disaster or from the detonation of an atomic weapon, is extremely toxic – and almost always deadly.

But now, researchers say they have developed a new drug that could potentially save the human body in the case of a lethal radiation accident. The discovery could transform radiation therapy for cancer patients in the future, while aiding public safety in the event of a nuclear weapons crisis.

In a new study published in the journal Science Translational Medicine, scientists from Stanford University tested a class of small molecule drugs, known as PHD inhibitors, on mice doused with toxic amounts of radiation.  The drugs successfully protected the animals from radiation-induced gastrointestinal syndrome, a serious condition that usually causes death within two weeks of exposure.

According to lead researcher Amato Giaccia, radiation is so poisonous because it irreversibly damages the cells’ DNA, leading to cell death. While bone marrow and the brain are very susceptible to damage, the cells most sensitive to radiation poisoning are located in the gastrointestinal (GI) tract.

“The epithelial lining of the gastrointestinal tract – the small intestine and large intestine – these cells are tightly linked.  But with radiation, they will start dying by cell death,” Giaccia, a professor of radiation oncology at Stanford, told “Then the lining will break down, which results in fluid loss and diarrhea. The next thing that happens is you get sepsis – a bacterial infection that will kill you.”

Giaccia noted that preventing cell death in the GI tract is one of the most effective ways of saving someone from radiation death, as the symptoms of GI syndrome tend to be the most lethal effects of radiation exposure.

In order to protect the important cells in the gut, the researchers looked for drugs that could stimulate a molecular pathway that produces proteins called hypoxia-inducible factors, or HIF proteins.  These types of proteins are important for helping the intestine to absorb nutrients, strengthening the epithileal tissue and maintaining healthy fluid exchange in the GI tract.

This led them to PHD inhibitors, which are already being used clinically to treat conditions such as anemia caused by renal insufficiency.  PHD inhibitors work by targeting an enzyme called prolyl hydroxylase, which is known to suppress the HIF pathway and limit the production of HIF proteins.

“We chose this small molecule because it’s very able to inhibit the regulation of HIF protein, which is typically at low levels in a cell,” Giaccia said.  “Using this molecule, we were able to stimulate this HIF pathway, which then promoted epithelial integrity and new blood vessel formation, prevented cell death, and stimulated new tissue regeneration [in the GI tract].”

Using a specific oral PHD inhibitor called DMOG, the researchers were able to protect a group of mice from lethal doses of radiation when they gave them the drug just before exposure – and up to 24 hours after exposure.  The DMOG drug ultimately prevented fluid loss, diarrhea and sepsis from forming, and the mice were able to have normal levels of feces and pass comparable amounts of stool.

Giaccia hopes that their discovery will be beneficial for cancer patients who are required to undergo numerous radiation treatments.  Coupled with this drug, radiation therapy could be administered in higher doses with less toxic side effects.

“Radiation therapy is a very effective means of controlling cancer… but it’s really only useful for a localized tumor or a primary tumor; we can’t use radiation to treat widespread cancer growth,” Giaccia said. “…This can transform radiation from a localized treatment to a systemic treatment.”

But these findings have even broader implications.  Giaccia argued that stockpiles of the drug could be used for instances like the Fukushima Daiichi nuclear disaster, in which large populations are at risk of radiation exposure from a nuclear meltdown.  And it’s possible that such a drug could be utilized to save lives in the event of a nuclear attack.

While the results seem promising, Giaccia noted that the drug doesn’t prevent radiation from damaging the cells’ DNA – but rather modifies the consequences of that damage.

“There’s still DNA damage, in that those cells that have too much damage, those cells will die,” Giaccia said. “But the cells that were not damaged that much, we’re stimulating them to take over and restore the function of the normal tissue.”