Nonlethal Exposure

Drug reduces radiation poisoning in mice

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While radiation has therapeutic applications, too much can damage cells. An acute side effect of radiation poisoning is damage to bone marrow. Bone marrow produces normal blood cells, and high doses of radiation can lead to low blood counts of red and white blood cells, and platelets.

People who receive a lethal dose of radiation, which can be the case with an accidental exposure, die of bone marrow failure. While some drugs can decrease toxicity when given before exposure to radiation, known as radioprotectants, there are no effective pharmacologic therapies (radiomitigants) to mitigate bone marrow toxicity when given after radiation exposure.

In a study published in the Journal of Clinical Investigation, a team led by University of North Carolina’s Norman Sharpless, MD, provided the first example of successful radiomitigation in mammals. Researchers found that oral treatment of mice with a drug that inhibits enzymes involved in cell division caused groups of bone marrow cells to temporarily stop dividing. The process is called pharmacological quiescence (PQ).

Several decades of research have shown that cells not dividing are resistant to agents that damage DNA, like radiation. Researchers were able to show that inducing PQ immediately before or up to 20 hours after radiation exposure could protect mice from a lethal dose of radiation. PQ protected normal blood cells, including platelets, red cells, and white cells.

PQ relies on using selective inhibitors of cellular enzymes, called CDK4 and CDK6. Related drugs have been used extensively in people with cancer, and CDK4/6 inhibitors are currently being tested in humans. These drugs, which can be given as a pill, are chemically stable and have little toxicity. Therefore, such compounds could be stockpiled for use in the event of an unexpected radiation
disaster. The research group showed that structurally different versions of CDK4/6 inhibitors provided protection from radiation; other types of kinase inhibitors did not.

Since radiation is used in cancer therapy, Sharpless believes PQ may have a role in treating cancer patients. Several common chemotherapy drugs cause bone marrow toxicity by damaging DNA; PQ might offer protection from chemotherapy toxicity, in addition to radiation toxicity.

However, PQ might also protect a patient's tumor from the toxicity of therapeutic DNA-damaging agents. Sharpless’ group showed that at least some cancers were not protected by inhibitors of CDK4/6.

University of North Carolina School of Medicine