Compound abates harmful effects of radiation therapy
By Alex Lyda
UT Southwestern Medical Center researchers are working on an ingestible compound that shields healthy tissue from the harmful side effects of radiation therapy, offering hope for targeted treatments that do not cause collateral damage or secondary cancers.
The findings, published Oct. 23 in Proceedings of the National Academy of Sciences, detail the molecular mechanisms by which the compound protects healthy cells during radiotherapy while leaving cancer cells exposed and vulnerable to radiation.
Bardoxolone methyl (BARD) was shown in an animal-model study to protect mice receiving radiation treatments of the colon, adding to evidence that the compound may make radiation less toxic as a treatment for other cancers if the compound is administered prior to treatment.
“Our latest study shows that taking this compound before therapy could reduce the side effects and perhaps permit more effective delivery of radiation therapy to cancer cells only,” said Dr. Jerry W. Shay, Professor of Cell Biology and the study’s senior author. “Preventing radiation from damaging healthy DNA is a huge step.”
Of all the types of damage that DNA can suffer, the most severe is when both sides of the molecule’s double helix break, which can occur with ionizing radiation. Double-stranded DNA breaks are the most dangerous type of DNA damage. Sometimes the repair is imperfect and can lead to mutations and cancer.
In the current study, when colonic epithelial cells were treated with BARD before irradiation, BARD protected and increased the survival of cells. Also, significantly fewer chromosomal aberrations were observed. To determine if the effect of BARD on DNA repair was due to changes in ionizing radiation-induced signaling, Dr. Shay and his team examined the appearance and disappearance of “repairosomes” – the stable complexes of proteins that carry out DNA damage recognition and incision reactions that are part of the repair process. Consistent with the chromosomal data, BARD treatment rapidly enhanced the repair of damaged DNA.
“The need for this sort of radioprotector is critical, and not just for cancer patients,” Dr. Shay said. “There is an urgent need to develop easily administered radioprotectants for first responders in nuclear accidents and also for astronauts aboard long-term space missions.”
For space exploration, available data suggest that lung and colon cancer are the largest potential human cancer risks, and quantitative risk-assessment information for mission planning is needed. For people facing kidney cancer and kidney disease, preserving these vital organs from damaging radiation is a public-health priority. One in every 10 adults in America – more than 20 million people – has some level of chronic kidney disease, according to the Centers for Disease Control and Prevention.
With NASA funding, the current BARD studies are being run by a private company, Reata Pharmaceuticals, which UT Southwestern helped start more than a decade ago.
Other UT Southwestern researchers who took part in the study were Dr. Tej Pandita, Professor of Radiation Oncology; Dr. Woodring E. Wright, Professor of Cell Biology and Internal Medicine; Dr. Sang Kim, a postdoctoral researcher in Cell Biology and study first author; Dr. Rakesh Kumar, a postdoctoral researcher in Radiation Oncology; Raj Pandita, a senior research scientist in Cell Biology; Ugur Eskiocak, a postdoctoral researcher at the Children’s Medical Center Research Institute at UT Southwestern; Aadil Kaisani, a student research assistant in Cancer Biology; Peter Ly, a postdoctoral research assistant in Cell Biology; and Crystal Cornelius, a research assistant in Cell Biology.
Dr. Shay and Dr. Wright share the Southland Financial Corporation Distinguished Chair in Geriatrics.