Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How chemotherapy becomes more effective

05.03.2012
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 brakes that inevitably ends up derailing,” explains Massimo Lopes, commenting on the results. “What we have now discovered is the emergency brake, which the cells activate themselves to protect themselves from the inhibitor.” Arnab Ray-Chaudhuri, who made a considerable contribution to the study, draws the following conclusion: “Thanks to the discovery of this mechanism, we now understand why chemotherapy does not always work as expected with these drugs.”

The existence of such DNA structures was hypothesized many years ago, but it has only just been confirmed in human cells by Lopes’s group. These chicken-foot structures are even surprisingly common with clinically relevant doses of Top1 inhibitors.
Solution: render emergency brake inoperative

The new observations reveal an interesting coincidence: In pulling the emergency brake, a family of enzymes that recently attracted a great deal of interest as a potential target for new cancer therapies is involved in the restructuring: the poly-ADP-ribose polymerases, or PARPS for short. After all, PARP inhibitors increase the sensitivity of cancer cells to different drugs that harm the DNA, including Top1 inhibitors. The new study reveals why: PARP inhibition hinders the reversal of the replication forks and increases the number of chromosomal breaks caused by Top1 inhibitors. Massimo Lopes and his team thus provide a clear molecular basis for the clinical observations described and pave the way for promising therapeutic advances.
Massimo Lopes’s team is currently investigating whether the same or a similar mechanism is activated by other classes of chemotherapeutics and which cellular factors are involved in this molecular “emergency brake”. The aim is to identify tumors in which this mechanism is not active or inhibit the mechanism pharmacologically to improve the efficacy of chemotherapy.

Literature:

A. Ray Chaudhuri, Y. Hashimoto, R. Herrador, K.J. Neelsen, D. Fachinetti, R. Bermejo, A. Cocito, V. Costanzo and M. Lopes. Toposiomerase I poisoning results in PARP-mediated replication fork reversal. Nature Structural and Molecular Biology. 4 March, 2012. Doi: 10.1038/nsmb.2258

Beat Müller | idw
Further information:
http://www.uzh.ch/

More articles from Life Sciences:

nachricht Kidney tumor: Genetic trigger discovered
18.06.2018 | Julius-Maximilians-Universität Würzburg

nachricht New type of photosynthesis discovered
18.06.2018 | Imperial College London

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

Im Focus: Photoexcited graphene puzzle solved

A boost for graphene-based light detectors

Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...

Im Focus: Water is not the same as water

Water molecules exist in two different forms with almost identical physical properties. For the first time, researchers have succeeded in separating the two forms to show that they can exhibit different chemical reactivities. These results were reported by researchers from the University of Basel and their colleagues in Hamburg in the scientific journal Nature Communications.

From a chemical perspective, water is a molecule in which a single oxygen atom is linked to two hydrogen atoms. It is less well known that water exists in two...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Novel method for investigating pore geometry in rocks

18.06.2018 | Earth Sciences

Diamond watch components

18.06.2018 | Process Engineering

New type of photosynthesis discovered

18.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>