Novel research into
treatment for radiation poisoning

Drug might offer hope to radiation and cancer victims

June 25, 2010
by Brendon Nafziger, DOTmed News Associate Editor
An easily stockpiled drug that freezes cells in their life-cycle could aid victims in the wake of a nuclear power plant accident or detonation of a radiological bomb, as well as ease the brutal side effects of cancer treatment, researchers said this week.

The drug is part of an emerging group of chemicals investigated, thanks in part to government money, as a "radiomitigant," which would mitigate the effects of radiation exposure and prevent deaths from acute radiation syndrome. Currently, no such drugs are on the market, scientists say.

In research reported in the Journal of Clinical Investigation, a class of agents used in experimental cancer research was found to preserve the bone marrow from injury in mice after exposure to normally lethal blasts of whole-body ionizing radiation.

Critically, the drug worked even if delivered up to 20 hours after radiation exposure, important for use in a real-life disaster when emergency teams might not be able to reach victims immediately.


One of the main causes of death after full-body irradiation is hematopoietic syndrome, where the victim dies from lack of blood, as so much bone marrow is destroyed it can't replenish the blood supply. The drug, by preventing bone marrow cells temporarily from dividing, is able to keep more of the cells alive thereby protecting the animal, the researchers said.

"For the L[ethal] D[dose] 90, when you kill 90 percent of the animals with radiation, we protect 100 percent in that range," lead author Dr. Norman Sharpless told DOTmed News.


The idea for a drug to protect against radiation poisoning came to Sharpless, associate director for translational research at University of North Carolina's Lineberger Comprehensive Cancer Center in Chapel Hill, as he was watching the first season of Battlestar Galactica, he said.

"This guy needs this radiation resistance medicine, and he's running around, hiding from the bad robots," Sharpless said.

"I was sort of like, 'How would that work? How could one make a person radioresistant?'"

An oncologist, Sharpless had studied the cell cycle for most of his research career. It has been known for at least 50 years, he said, that cells dividing are more sensitive to DNA damage. This is partly why the highly proliferative cells like those in the gut and bone marrow are the most impacted by ionizing radiation and even chemotherapy agents, both of which can cause devastating double-strand DNA breaks.

Sharpless said researchers believe that cells in the non-dividing state, technically called the G1 phase, are better able to repair DNA damage. Also, there seems to be a checkpoint the cells pass through as they transition to the dividing phase, and those with DNA damage perish, likely as a precaution to prevent dangerous mutations.

Eventually, Sharpless got to work with drug companies experimenting on a class of drugs used in cancer research, which appear to prevent some cancer cells from dividing. While the drug companies hope to use them against cancer, Sharpless realized they might have potential in combating the effects of acute radiation syndrome.

"Some of these compounds have a very nice property -- they will cause certain cells in the bone marrow, cause them to go to sleep, go out of the cell cycle," Sharpless said.

According to Sharpless, the drug works by locking cells in the non-dividing phase by inhibiting substances their division is dependent on, called cyclin-dependent kinase 4 and 6. Critically, say the researchers, these CDK 4 and 6 inhibitors are basically non-toxic, as blood-making bone marrow is one of the few cell types to depend on CDK 4 and 6 to divide.

"This class of agents didn't cause global blocks," Sharpless said. "You need proliferating cells. Inhibiting proliferation globally is bad. That's what chemotherapy does."


In the study published Wednesday, mice were exposed to lethal doses of whole-body radiation form either X-ray or gamma ray sources. The animals received about 7.5 - 8.5 Gy, a more than lethal dose.

Some of the mice were given CDK 4 and 6 inhibitors, dubbed PD0332991, developed and mostly supplied by Pfizer, and 2BrIC, synthesized by Otava Ltd., either before or up to 20 hours after radiation exposure.

The scientists followed the animals for about a month, as most will normally die within 28 days from radiation-induced bone marrow damage, Sharpless said.

At 7.5 Gy, all mice treated with the inhibitors survived, while nearly all untreated mice died. Still, the mice aren't immune to radiation: at 8.5 Gy, only about 13 percent of treated mice survived after 30 days (none of the untreated ones did).

And Sharpless said the drug couldn't protect against damage to the gut or lungs, as those cells don't depend on CDK 4 and 6 to cycle.

Nonetheless, the researchers found that the treatment protected nearly all blood lineages, including platelets, which no available therapy can do, Sharpless said.

The researchers also worked out the effects of the inhibitors in human cell lines, to show that the drug only acts on cells "addicted" to CDK 4 and 6 for their replication.


Important for its usefulness is that, as a small molecule drug, a pill, it doesn't require refrigeration and could be stockpiled easily, or carried around in ambulances.

Also, its low toxicity makes it appropriate for the kind of mass casualty accident or attack where first responders will have to give treatment to potentially hundreds, or thousands, of people without being able to gauge how much radiation they got.

"There's no dosimetry. People don't wear these radiation badge detectors," said Sharpless. "You'd have to treat everybody."

Currently, if exposed to high levels of radiation, the care right now is supportive and not terribly effective -- giving people antibiotics or growth factors to stimulate blood production, or taking iodine to prevent the thyroid from taking up radioactive material "so you won't get thyroid cancer 14 years from now," Sharpless said.


The compounds used in the study are currently undergoing tests by pharmaceutical companies to be used as anti-cancer drugs. About four or five drugs are under review, although Sharpless said the results, so far, are not extremely positive. Most cancers don't require the CDK process to divide, he said. For those that do, while tumors would probably shrink after medication was delivered, he thinks the cancer would quickly rebound. The tumor would likely adapt and learn to grow without the CDK, Sharpless said.

Still, the drug could buy the patient a few more months.

"It's nontoxic, and just a pill. Five months of life for a pill -- you'd do it," Sharpless said.

Even if it's only a stop-gap against cancer, the drug might have other uses in the fight against the disease, namely by protecting patients from chemotherapy side effects.

Chemo, by causing double-strand DNA breaks in rapidly dividing cells, like cancers, also can kill blood-producing bone marrow cells, leading to anemia or dangerously low platelet counts.

By protecting those bone marrow cells, the drugs could make it easier for patients to endure chemo regimens, Sharpless said.

And as only a handful of known cancers use CDK to multiply, researchers would just have to test to make sure the patient wasn't afflicted by one of them. For now, Sharpless is interested in its use with small cell lung cancer, known to not depend on CDK 4 and 6 for replication, he said.


Research on the project has now transferred mainly to G-Zero Therapeutics, a company co-founded by Sharpless in 2007.

The work for the current research was partly funded by the National Institutes of Health, as the government has made discovering a countermeasure to radiation sickness a top research priority.

And while it's still some ways away from the clinic, Sharpless said development of the drug will use what is called FDA's two-animal rule. The scientists obviously can't irradiate human volunteers to test whether the drug works in people. Instead, researchers test effectiveness in two animal species.

As for helping to ease the side effects of chemotherapy, Sharpless expects they'll publish a paper on its role in chemotherapy later this year, one of two papers he expects to get out by January, as the team settles down to the nitty-gritty of detailed pharmokinetic research.