Nanotweezers Help Understand Actions of Chemotherapy Agent

NCI’s Alliance for Nanotechnology in Cancer is reporting about an interesting discovery, recently reported in the journal Nature:

The annoying bulges of an overwound telephone cord that shorten its reach and limit a caller’s motion help explain why drugs called camptothecins are so effective in killing cancer cells, according to investigators led by Mary-Ann Bjornsti, Ph.D., at St. Jude Children’s Research Hospital, and Nynke Dekker, Ph.D., at Delft Technology University. Using nanoscale magnetic tweezers (nanotweezers), the researchers 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 overwound DNA molecule much like the bulges in an overwound 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.
In this first-of-its-kind study, researchers used the nanotweezers to monitor changes in the length of an individual DNA molecule caused by the action of a single topoisomerase I enzyme. They also used the nanotweezers 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, the researchers developed the supercoil theory to explain the drug’s ability to kill cancer cells and then tested that theory in yeast cells. They concluded that the accumulation of DNA supercoiling kills the cells using a newly discovered biophysical mechanism. Their findings also provide insights into the drug’s action that could help scientists in the clinical development of these agents.

Source…
Paper: Antitumor drugs impede DNA uncoiling by topoisomerase I (.PDF) – Nature 448: 213-217 (2007)
Molecular Biophysics Group @ Delft Technology University…