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Researchers in the USA have obtained the first X-ray structure of the well-known anticancer agent bleomycin complexed to its target DNA. The study offers important clues as to the drug's mode of action and may point drug designers in the right direction to devise more targeted analogues for chemotherapy. Structural biologist Millie Georgiadis of the Indiana University School of Medicine and colleagues there and Eric Long and colleagues at the Purdue School of Science at Indiana University-Purdue University Indianapolis recognised that biomedical science did not have a clear view of the binding of this well-established chemotherapy agent to its target DNA. Bleomycin is a glycopeptide antibiotic, anticancer agent - a sugar-containing peptide structure - produced by the soil bacterium Streptomyces verticillus. It was first isolated in 1965 by Hamao Umezawa and colleagues. Umezawa had become well known prior to this as the discoverer of the tuberculosis drug kanamycin. Bleomycin, actually a group of compounds rather than a single structure, works by triggering free radical formation which break the DNA double helix, It is widely used for malignant tumours, such as germ cell tumours, lymphomas, head and neck and Kaposi's sarcoma. "Although bleomycin has been studied for 40 years and much is known about the mode of action of bleomycin, without an accurate three-dimensional picture you cannot fully understand how the drug targets and sits on the DNA," explains Georgiadis. Such studies could allow researchers to fine tune the properties of the drug with the aim of making it more selective in its targeting and so reduce side effects, which include lung damage. By its very nature, bleomycin is highly toxic. However, a combination chemotherapy regimen pioneered at the IU School of Medicine by oncologist Lawrence Einhorn mutes its side effects as a standard treatment for testicular cancer. Because it causes lung damage, bleomycin is not typically used to treat other cancers. Reducing such potentially devastating side effects at the fundamental level rather than through multiple-drug regimens could widen the use of this drug to other cancers. "Our 3D 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," adds Georgiadis, "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." Related links:
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Georgiadis, sharpening bleary bleomycin view Bleomycin complexed with DNA
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