Technique Devised to Disable Cancer Cells’ Defenses Against Radiation

Radiation chiefly kills cells by inducing DNA damage, so the goal of the technique is to sensitize cells to radiation by disabling their ability to repair DNA. The technique sneaks RNA molecules into cells that shut down genes needed for DNA repair. The still-investigational technology could potentially allow oncologists to boost the tumor-killing effects of radiation, while using lower doses and reducing injury to healthy tissues.

In the laboratory, the scientists utilized modified lentiviruses to introduce the RNA molecules. The same types of viruses have been used in gene therapy research. Dr. Wang reported that her team is now testing whether a small peptide tag can direct RNA to brain tumors instead. The results are published in the March 1, 2012, issue of the journal Cancer Research.

Ya Wang, MD, PhD, professor of radiation oncology at Emory University School of Medicine and director of the division of experimental radiation oncology at the Winship Cancer Institute (Atlanta, GA, USA) senior author of the study. The first author Dr. Zhiming Zheng, is now at Shandong University in China.

Dr. Zheng and his colleagues focused on two genes, XRCC2 and XRCC4, which encode proteins required for separate pathways of DNA repair. XRCC2 and XRCC4, in general, are both more active in tumor cells than in healthy cells.

In the past, using RNA interference (RNAi) techniques to silence a gene was via targeting the coding region only. In this instance, Dr. Wang’s team utilized the RNAi technique to more efficiently knock down the gene via targeting both the coding region (making the RNA unstable) and noncoding region (blocking protein production), thereby making brain cancer and lung cancer cells two to three times more sensitive to X-ray radiation.

“Inhibition of DNA repair has been tried using drugs that inhibit repair enzymes,” Dr. Wang stated. “This approach--combining targeted genes and combining targeted regions of one gene-- made it possible to efficiently knock down either gene and achieve a greater sensitivity to radiation.”

RNAi is a technique that is widely used in the laboratory. It could be useful clinically as well because of the targeted ability to silence particular genes, but is still experimental for use in humans. Andrew Fire and Craig Mello received the 2006 Nobel Prize in Medicine for the discovery that short pieces of RNA, when introduced into cells, can silence a stretch of genetic code. Artificially introduced RNA adopts mechanisms inside the cell that the cell naturally uses for regulation.

Dr. Wang added that her team’s strategy of combining two ways to knock a gene down may be useful in the laboratory, among a wide range of fields of biology. “It may be particularly suited to suppressing genes that are difficult to approach by simpler methods,” she commented.

Related Links:
Emory University’s Winship Cancer Institute