Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

NIH Study Uncovers New Mechanism of Action for Class of Chemotherapy Drugs

Published: Friday, November 02, 2012
Last Updated: Friday, November 02, 2012
Bookmark and Share
National Institutes of Health (NIH) researchers have discovered a significant new mechanism of action for a class of chemotherapy drugs known as poly (ADP-ribose) polymerase inhibitors, or PARP inhibitors.

They have also identified differences in the toxic capabilities of three drugs in this class which are currently being tested in clinical trials. The study, by scientists at the National Cancer Institute (NCI), part of NIH, and their colleagues, appeared in Cancer Research, Nov 1, 2012.

In recent years, drugs classified as PARP inhibitors have been shown to be promising anticancer agents for breast and ovarian cancer. Members of the PARP family of proteins are involved in a number of critical cellular processes, including DNA damage repair and programmed cell death. Prior to this study, PARP inhibitors were thought to work primarily by blocking PARP enzyme activity, thus preventing the repair of DNA damage and ultimately causing cell death.

In this study, scientists established that PARP inhibitors have an additional mode of action: localizing PARP proteins at sites of DNA damage, which has relevance to their anti-tumor activity. The trapped PARP protein–DNA complexes are highly toxic to cells because they block DNA replication. When the researchers tested three PARP inhibitors for their differential ability to trap PARP proteins on damaged DNA, they found that the trapping potency of the inhibitors varied widely.

"Critical to our research is that, while PARP inhibitors had been assumed to be of equivalent potency based on the degree to which they elicit PARP inhibition, we now know that they are not equivalent with respect to their potency to trap PARP," said Yves Pommier, M.D., Ph.D., NCI Center for Cancer Research. "Our findings suggest that PARP inhibitors should be categorized according to their potency to trap PARP, in addition to their enzyme inhibition abilities."

The PARP family of proteins in humans includes PARP1 and PARP2, which are DNA binding and repair proteins. When activated by DNA damage, these proteins recruit other proteins that do the actual work of repairing DNA. Under normal conditions, PARP1 and PARP2 are released from DNA once the repair process is underway. However, as this study shows, when they are bound to PARP inhibitors, PARP1 and PARP2 become trapped on DNA. The researchers showed that trapped PARP–DNA complexes are more toxic to cells than the unrepaired single-strand DNA breaks that accumulate in the absence of PARP activity, indicating that PARP inhibitors act as PARP poisons.

In collaboration with James Doroshow, M.D., deputy director for clinical and translational research at NCI, the investigators used PARP assays (ways of measuring PARP activity in cells and tissues) to compare three PARP inhibitor compounds that are currently in clinical testing: MK-4827, olaparib, and veliparib.

The scientists found that the three PARP inhibitors differed in their ability to inhibit PARP enzyme activity, with olaparib being the most potent inhibitor, followed by veliparib and then MK-4827. However, in terms of toxicity, MK-4827 was the most potent, followed by olaparib and then veliparib. Moreover, PARP1 complexes with MK-4827 and olaparib were shown to be more tightly bound to DNA than complexes with veliparib.

These findings suggest that there may be two classes of PARP inhibitors, catalytic inhibitors that act mainly to inhibit PARP enzyme activity and do not trap PARP proteins on DNA, and dual inhibitors that both block PARP enzyme activity and act as PARP poison.

"Our findings suggest that clinicians who use PARP inhibitors in clinical trials should carefully choose their drug, because we now suspect results may differ, depending upon the PARP inhibitor used," said Junko Murai, M.D., Ph.D., NCI Center for Cancer Research. "As a next step, we are working to categorize other leading PARP inhibitors based upon both PARP trapping and PARP inhibition."


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,500+ scientific posters on ePosters
  • More Than 5,000+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

“Sixth Sense” More Than a Feeling
NIH study of rare genetic disorder reveals importance of touch and body awareness.
Monday, September 26, 2016
“Sixth Sense” May Be More Than Just A Feeling
The NIH Study shows that two young patients with a mutation in the PIEZ02 have problems with touch and proprioception, or body awareness.
Friday, September 23, 2016
The Genetics of Blood Pressure
Researchers have identifed areas of the genome associated with blood-pressure including 17 previously unknown loci.
Wednesday, September 21, 2016
NIH Study Finds Link Between Depression, Gestational Diabetes
Researchers at NIH have discovered that the depression in early pregnancy doubles risk for gestational diabetes, and gestational diabetes increases risk for postpartum depression.
Tuesday, September 20, 2016
Detecting Bacterial Infections in Newborns
Researchers tested an alternative way to diagnose bacterial infections in infants—by analyzing RNA biosignatures from a small blood sample.
Wednesday, September 14, 2016
Finding Compounds That Inhibit Zika
Researchers identified compounds that inhibit the Zika virus and reduce its ability to kill brain cells.
Wednesday, September 14, 2016
Seeking Innovation to Combat Antimicrobial Resistance
Federal prize competition, with $20 million in prizes, seeks to develop new laboratory diagnostic tools to detect and distinguish antibiotic resistant bacteria.
Friday, September 09, 2016
Genetic Misdiagnoses of Heart Condition
Analysis found several genetic variations previously linked with a heart condition were harmless, leading to condition misdiagnosis.
Wednesday, September 07, 2016
Catalogue of Human Genetic Diversity Expands
The largest data set of human exomes to date has been assembled to better study seqence variants and their consequences.
Wednesday, September 07, 2016
Extreme Temperatures Could Increase Preterm Birth Risk
Researchers at NIH have found more preterm births among women exposed to extremes of hot and cold.
Friday, September 02, 2016
$12.4M Awarded to Neural Regeneration Projects
The National Institutes of Health will fund six projects to identify biological factors that influence neural regeneration.
Friday, September 02, 2016
Oxygen Can Impair Cancer Immunotherapy
Researchers have identified a mechanism within the lungs where anticancer immune resposnse is inhibited.
Friday, August 26, 2016
Diagnosing Bacterial Infections in Blood Samples
Researchers have diagnosed a bacterial infection from a blood sample in infants.
Wednesday, August 24, 2016
Stem Cell Therapy Heals Injured Mouse Brain
A team of researchers has developed a therapeutic technique that dramatically increases the production of nerve cells in mice with stroke-induced brain damage.
Tuesday, August 23, 2016
New Inflammatory Disease Discovered
NIH researchers have discovered a rare and potentially deadly disease - otulipenia - the mostly affects children.
Tuesday, August 23, 2016
Scientific News
Mass Spec Technology Drives Innovation Across the Biopharma Workflow
With greater resolving power, analytical speed, and accuracy, new mass spectrometry technology and techniques are infiltrating the biopharmaceuticals workflow.
One Step Closer to Precision Medicine for Chronic Lung Disease Sufferers
A study led by University of North Carolina at Chapel Hill, and National Jewish Health, has provided evidence of links between SNPs and known COPD blood protein biomarkers.
Gene Regulation in Brain May Explain Repetitive Behaviors in Rett Syndrome Patients
The research could be a key step in developing treatments to eliminate symptoms that drastically impair the quality of life in Rett patients.
Heart Arrhythmia Caused by Mosaic of Mutant Cells
Researchers have solved the genetic mystery of an infant suffering from heart arrhythmia.
Iron Nanoparticles Make Immune Cells Attack Cancer
Researchers accidentally discover that nanoparticles invented for anemia treatment can trigger the immune system’s ability to destroy tumor cells.
Crispr Toolbox Expanded By Protein
Researchers have shown a newly discovered CRISPR protein has two distinct RNA cutting activities.
CES Score May Predict Response to Cancer Treatment
Researchers identify new type of biomarker that helps predict prognosis and response to several types of cancer treatment.
Uncovering Cancer’s ‘Invisibility Cloak’
Researchers discover cancer cell mechanism to become invisible to the body's immune system.
Genetic Impact of Endurance Training
Research has found that endurance training changes genetic activity in thousands of genes, giving rise to large number of altered RNA variants.
Treating Sepsis with Marine Mitochondria
Mitochondrial alternative oxidase from a marine animal combats bacterial sepsis.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,000+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!