IU scientists report first 3-D view of anti-cancer agent
Researchers from the IU School of Medicine and the IUPUI School of Science have created the first three-dimensional image of how a well-established chemotherapy agent targets and binds to DNA.
The study, which published online the week of March 17 in the early edition of the Proceedings of the National Academy of Sciences, may help scientists develop better chemotherapy drugs to treat a wide range of cancers.
Photo by: Kristie Goodwin, IU School of Medicine
This image shows how well-established chemotherapy agents (colored spheres) target and bind to DNA (dark grey).
Using X-ray crystallography, the scientists produced the first 3-D molecular-level images of bleomycin bound to DNA. X-ray crystallography is a widely used analytical technique in which X-rays are directed through crystals and results are deduced from the pattern of diffraction of the X-rays.
"Although bleomycin has been studied for 40 years and much is known about the mechanism of action of bleomycin, without an accurate 3-D picture you can't fully understand how the drug targets and sits on the DNA. If you want to improve on the properties of the drug, to make it a better chemo agent, you need to understand in great detail how it works," said Millie Georgiadis, associate professor of biochemistry and molecular biology at the IU School of Medicine and at the Purdue School of Science. She and Eric Long, professor of chemistry and chemical biology at the Purdue School of Science, are senior authors of the study.
A combination chemotherapy regimen including bleomycin was successfully pioneered at the IU School of Medicine by Dr. Lawrence Einhorn, an oncologist and an IU Distinguished Professor of medicine. This multi-agent therapy, which mutes the toxicity of bleomycin, is now the standard of care for testicular cancer. Because it causes lung damage, bleomycin is not typically used to treat other cancers.
"Our 3-D picture of the structure of bleomycin gives us a much better understanding of exactly how the drug interacts with the DNA so we can begin thinking about engineering a better drug, with less toxicity. Since it's a DNA targeting agent, there's no limit to what type of cancers we could target with bleomycin if we can decrease the toxicity," said Georgiadis, a structural biologist.
Many successful chemotherapeutics are DNA targeting agents.
The study was funded by American Cancer Society and the National Institutes of Health.
Co-authors of the study also include first author, Kristie Goodwin, a postdoctoral fellow at the IU School of Medicine, and Mark Lewis, a doctoral student in the Department of Chemistry and Chemical Biology at the time the study was conducted.
