Killing cancer cells: How anti-tumour agent works
Shedding light on the disease-fighting properties of Bleomycin, used in medications to treat a variety of cancers, a study by an Indian-origin scientist has revealed that the anti-tumour agent has the ability to cut through double-stranded DNA in cancerous cells, like a pair of scissors.
Bleomycin is part of a family of structurally related antibiotics produced by the bacterium, Streptomyces verticillus.
However, bleomycin may also cause severe or life-threatening lung problems, especially in older patients and in those receiving higher doses of this medication.
The new research is expected to help inform efforts to fine-tune the drug, improving its cancer-killing properties, while limiting toxicity to healthy cells.
Currently, three potent versions of the drug, labeled A2 , A5 and B2 are used in clinical use against cancer.
Bleomycin's cancer-fighting capacity was first observed in 1966 by Japanese researcher Hamao Umezawa.
Basab Roy, a researcher at Arizona State University in US, is particularly interested in the subtle biochemistry of bleomycin, including the specificity of its binding regions along the DNA strand and the drug's detailed mechanisms of DNA cleavage.
Cleavage of DNA is believed to be the primary mechanism by which bleomycin kills cancer cells, particularly through double-strand cleavages, which are more challenging for the cellular machinery to repair.
"There are several mechanisms for repairing both single-strand and double-strand breaks in DNA, but double-strand breaks are a more potent form of DNA lesion," said Roy.
For the new study, bleomycin A5 was used. Bleomycin A5 has similar DNA binding and cleaving properties as bleomycin A2 and B2.
From a pool of random DNA sequences, a library of 10 hairpin DNAs was selected, based on their strong binding affinity for bleomycin A5.
Hairpin DNAs are looped structures, which form when a segment of a DNA strand base-pairs with another portion of the same strand.
These hairpin DNAs were used to investigate double-strand cleavage by bleomycin.
Each of the 10 DNA samples underwent double-strand cleavage at more than one site.
Further, all of the observed cleavage sites were found within or in close proximity to an 8 base pair variable region, which had been randomised to create the original library.
Examination of the 10 DNA samples exposed to bleomycin revealed a total of 31 double-strand cleavage sites.
This study proposed for the first time, a plausible mechanism for DNA cleavage by bleomycin that may lead to tumor cell killing as well as identifying the most common sequences involved in DNA site binding and subsequent strand breakage.
The results appeared in the Journal of the American Chemical Society.
(Posted on 01-05-2014)