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How chemotherapy becomes more effective
Date:3/5/2012

This release is available in German.

Researchers from the University of Zurich have found a cellular brake that protects cancer cells from chemotherapy -- and they demonstrate which medication can be used to render it inoperative. Their study published in the journal Natural Structural and Molecular Biology provides the molecular basis for promising therapeutic advances.

Although many cancer drugs have already been in use for decades, their mode of action is still unknown. The new research results now challenge a mechanism of action that was previously proposed for a group of drugs and supported with experiments: the Topoisomerase I-inhibitor Camptothecin (Top1 inhibitor for short) and its derivatives used in chemotherapy, Topotecan and Irinotecan.

Problem: emergency cellular brake restricts effectiveness

For a long time, the toxicity of the top1-inhibitors was attributed to discontinuities in the cancer cells' DNA that inevitably caused breaks in the chromosomes during the duplication of the DNA. The team headed by Professor Massimo Lopes at the University of Zurich's Institute of Molecular Cancer Research has now identified a mechanism with which cancer cells protect themselves against damage caused by Top1 inhibitions: Using electron microscopy, the researchers were able to demonstrate that Top1 inhibitors can cause the replication forks that develop during the duplication of the DNA to be restructured. "Reversed" replication forks, or "chicken-foot" structures as they are also known, are formed. This remodeling of the replication forks provides the cancer cells with the time they need to repair the lesion in the DNA and thus prevent disparately cytotoxic chromosomal breakage.

"Until now, the assumed mechanism of action of Top1 inhibitors was comparable to a train hurtling towards an obstacle without
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Contact: Massimo Lopes
lopes@imcr.uzh.ch
41-044-635-3467
University of Zurich
Source:Eurekalert

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