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MEMPHIS, Tenn., July 9- The annoying bulges of an over-wound telephone cord that shorten its reach 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 both 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 molecule -- much 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, or to gain access to specific genes, 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. "Our work could help scientists in the clinical development of these agents," said Mary-Ann Bjornsti, Ph.D., a member of the St. Jude Department of Molecular Pharmacology. A report on this work appears in the advanced, online issue of "Nature."
Delft University nanotechnology researchers in the laboratory of Nynke Dekker developed the tweezers for studies in biophysics and adapted them to the current study in cooperation with Bjornsti, a co-author of the "Nature" report.
Other authors of the study include Daniel Koster, Elisa Bot and Nynke Dekker (Delft University, The Netherlands) and Komaraiah Palle, a postdoctoral fellow in the Bjornsti lab (St. Jude).
This work was supported in part by the Foundation for Fundamental Research on Matter (The Netherlands), the Netherlands Organization for Scientific Research, the National Cancer Institute at the National Institutes of Health and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org/.
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Topoisomerase I inhibitors
They also found that tumors varied greatly in the amounts of proteins that transport irinotecan into and out of their cells and in the amounts of proteins that break down irinotecan. These variations determine how well irinotecan will work in a particular tumor.
Selecting treatments based on what genes and proteins can tell us about how the tumor will respond to a drug, hasn't been very fruitful. Molecular profiling is far too limited in scope to encompass the vagaries and complexities of human cancer biology when it comes to drug selection.
Efforts to administer targeted therapies in randomly selected patients often result in low response rates at significant toxicity and cost.
Topotecan (Hycamtin) is a topoisomerase 1 inhibitor. Irinotecan (Camptosar) is a topoisomerase 1 inhibitor.
Even if you would have a high expression of TOPO1 in a genetic test, that has been associated with benefit from Topoisomerase I inhibitors, it doesen't necessarily mean it is going to work on your individual cancer cells. In genetic testing, cancer cells aren't even measured against your cancer cells. It is looking for "theoretical" candidates for a mutation-targeted therapy. It cannot test sensitivity to any of the mutation-targeted therapies.
It just tells you whether or not the cancer cells are potentially susceptible to the mechanism of attack. It cannot telll you if the targeted drug will actually work against your individual cancer cells. Tumor cells have such an uniqueness that not much is known of their respective reaction to targeted therapies.
Like the various influences on a flower seed that cause one blossom to turn out differently from another, there are biological processes in the body that affect the development of cancer in each patient and determine how that patient's cancer cells will uniquely react to treatment.