Radiation sickness: A two-drug combination could block radiation’s double hit

A two-drug combination could help raise the odds of surviving toxic doses of radiation released through accidents like those at Chernobyl (above) or Fukushima, or by a nuclear or radiological weapon. (Kamil Porembinski/Flickr)

Radiation can have its benefits – look at radiation therapy for cancer, or imaging technologies like X-rays and CT scans that use radiation to peer within our bodies. But high doses, from malfunctioning medical equipment, accidents like those at Chernobyl or Fukushima, or nuclear or radiological weapons, can be toxic or even lethal.

Right now, there are treatments in development that could raise the odds of surviving exposure to toxic doses of radiation, but only if given within a few minutes or hours of exposure. Ofer Levy of Children’s Division of Infectious Diseases and his collaborator Eva Guinan at Dana-Farber Cancer Institute have hit upon a new-two drug combination that markedly increased survival in mice when given as late as 24 hours after exposure.

Radiation sickness affects nearly all of the body’s tissues, but has particularly harsh effects on the bone marrow, wiping out all the cells that make up our immune system. It also weakens the structure of our intestinal wall, giving bacteria a chance to cross into the bloodstream and wreak havoc.

BPI, a synthetic protein, is one half of the two-drug combination that Ofer Levy thinks could counter the effects of radiation poisoning. (Courtesy Ofer Levy)

In coming up with their approach, published last week in Science Translational Medicine, Levy and Guinan saw that patients receiving high doses of radiation or chemotherapy to kill off cells in their bone marrow (in preparation for a stem cell transplant) had high bloodstream levels of bacterial endotoxin, a protein that can drive intense inflammation. It’s carried by certain bacteria, including some abundant in the gut, and its presence in the blood suggested that gut bacteria had made it though the walls of the patients’ intestines.

They also found that, because of their radiation or chemotherapy treatments, these patients lacked an immune system protein that Levy had studied as a graduate student, called bactericidal/permeability-increasing protein (BPI). Produced by human immune cells called neutrophils, BPI binds to and mops up endotoxin like a sponge before it can cause any problems. “These observations led to the hypothesis that replenishing BPI could decrease the toxicity of radiation,” Levy says.

As Levy and Guinan see it, radiation gives the body a double hit:  It both opens the door to the bacteria getting into the bloodstream and shuts off the defense mechanism that would counter its toxin and keep it from driving people into shock. “Endotoxin is very potent and quickly triggers a very strong inflammatory response,” Levy notes. “Conventional antibiotics will kill the bacteria that get through the intestinal walls, but they don’t neutralize the harmful inflammatory effects of the endotoxin. That’s where BPI may provide substantial benefit.”

With this knowledge in hand, Levy and Guinan turned to a pair of drugs: a broad-spectrum antibiotic called ciprofloxacin (commonly known as Cipro) to kill off invading bacteria, and a synthetic version of BPI called rBPI21. “Cipro has been around for a long time and has a well established safety profile,” says Levy. “The synthetic BPI has been used in well over 1,000 patients, and while it’s not yet FDA-approved, it has been shown to be quite safe in all the trials it has been through thus far.”

Senior post-doctoral scientist Christine Palmer (L) and technician Christy Mancuso (R) analyze patient plasma samples under Ofer Levy’s direction.

The researchers gave the drugs, singly or in combination, to mice starting 24 hours after exposing them to lethal doses of radiation: 7 grays, an amount 700 times greater than that released during a standard X-ray. The mice that received both drugs had much higher survival rates than those who received the drugs singly or no treatment at all, and recovered their ability to produce new blood cells much more quickly. “Essentially the combination gives the body a chance to regroup and rebuild,” says Levy.

If the results hold through additional experiments, the drug combination could be a boon to both medicine and public health. “This combination could be used to help reduce the toxicity of bone marrow transplantation,” says Levy. “And given its efficacy when given 24 hours after a lethal radiation exposure, it could also be added to the government’s Strategic National Stockpile for mass casualty events like a nuclear accident.”