Tiny tweezers and yeast help St. Jude show how cancer drug works

The annoying bulges of an over-wound telephone cord that shorten its reach and limit a callers motion help to explain why drugs called camptothecins are so effective in killing cancer cells, according to investigators at St. Jude Children's Research Hospital and Delft University of Technology.

Using a type of nanotechnology called magnetic tweezers as well as yeast cells, investigators showed that a camptothecin drug called topotecan kills cancer cells by preventing an enzyme, called DNA topoisomerase I, from uncoiling double-stranded DNA in those cells. Instead, the DNA becomes locked in tight twists, called supercoils, which bulge out from the side of the over-wound DNA moleculemuch like the bulges in an over-wound telephone cord. If these supercoils accumulate and persist while the cell is trying to separate the two strands of DNA to make exact copies of the chromosomes during cell division, the cells will die.

Nanotechnology studies work at a scale of about 100 nanometers or less. For comparison, one nanometer is approximately 10 times the size of an atom; and 10 nanometers is one-thousandth of the diameter of a human hair.

In this first-of-its-kind study, researchers used the microscopic magnetic tweezers to monitor changes in the length of an individual DNA molecule caused by the action of a single topoisomerase I enzyme; and to study how the binding of a single topotecan molecule to this enzyme-DNA complex alters DNA uncoiling. Based on the results of those studies, scientists developed the supercoil theory to explain the drugs ability to kill cancer cells, and then tested that theory in yeast cells. Their conclusionthat accumulation of DNA supercoiling kills the cellsprovides a novel model for how topotecan works; and it provides insights into the drugs action that could help scientists in the clinical development of these agents. A report on this work appears in the advanced, online issue of Nature.

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Contact: Summer Freeman
St. Jude Children's Research Hospital

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