Scientists may have a way to double the efficacy and reduce the side effects of radiation therapy. Georgia Health Sciences University scientists have devised a way to reduce lung cancer cells' ability to repair the lethal¹（致命的） double-strand DNA² breaks caused by radiation therapy.

"Radiation is a great therapy -- the problem is the side effects," said Dr. William S. Dynan, biochemist and Associate Director of Research and Chief, Nanomedicine and Gene³ Regulation at the GHSU Institute of Molecular⁴ Medicine and Genetics. "We think this is a way to get the same amount of cancer cell death with less radiation or use the same amount and maybe cure a patient that could not be cured before."

Radiation therapy capitalizes on radiation's ability to kill cells by causing double-strand breaks in DNA. But the fact that varying levels of radiation are essentially⁵ everywhere -- food, air, the ground, etc. -- means all cells, including cancer cells, have internal mechanisms⁶ to prevent the lethal breakage.

GHSU scientists are targeting the natural defense⁷ mechanisms by packaging a piece of an antibody against one of them with folate（叶酸） , which has easy access to most cells, particularly cancer cells. Many cancers, including the lung cancer cells they studied, have large numbers of folate receptors so that cancer cells get a disproportionate share of the package.

Previous efforts to destroy cancer cells' ability to avoid radiation damage have focused on receptors on their surface, said Dr. Shuyi Li, molecular biologist, pediatrician（儿科医师） and corresponding author on the study in the International Journal of Radiation Oncology.

To get a more direct hit, the scientists took advantage of folate receptors as a point of entry by chemically binding⁸ folate with the small piece of their antibody, ScFv 18-2. The package heads straight for the cell nucleus⁹ where a different chemical environment breaks the bond, freeing ScFv 18-2 to attack the regulatory region of DNA-dependent protein kinase（蛋白激酶） , an enzyme¹⁰ essential to DNA repair.

"We are joining a targeting molecule¹¹ with a cargo," said Dynan. "This strategy targets one of the key enzymes¹² so it's harder to repair," Li said. This makes cancer cells more vulnerable to radiation.

Dynan and Li say the approach could be used to deliver any number of drugs directly inside cancer cells. Future studies include looking at other cell entry points as well as other targets to ensure they have the most effective package. Studies to date have been in human lung cancer cells in culture, so next steps also need to include animal studies.

Their approach mimics¹³ a natural process called endocytosis（内吞作用） in which cells engulf¹⁴ proteins and other substances they want to let inside but can't fit through normal doorways¹⁵.

Folate receptors already are being used as direct entry points for chemotherapeutic drugs, including clinical studies of a new strategy for ovarian cancer. GHSU is participating in clinical trials of a therapy that pairs an agent too toxic¹⁶ to be delivered through the bloodstream with folate to better target one of the most deadly cancers.

Dynan is the Georgia Research Alliance Eminent¹⁷ Scholar in Molecular Biology. Dynan and Li are both faculty¹⁸ members in GHSU's Medical College of Georgia. Dynan also is a faculty member in the College of Graduate Studies.