Navigation Links
New mechanism of action for PARP inhibitors discovered
Date:11/9/2012

PHILADELPHIA New understanding of how drugs called PARP inhibitors, which have already shown promise for the treatment of women with familial breast and ovarian cancers linked to BRCA mutations, exert their anticancer effects has led to the identification of ways in which the patient population that might benefit from PARP inhibitors could be expanded.

Yves Pommier, M.D., Ph.D., chief of the Laboratory of Molecular Pharmacology at the National Cancer Institute's Center for Cancer Research in Bethesda, Md., and colleagues reported these data in Cancer Research, a journal of the American Association for Cancer Research.

"In recent years, drugs classified as poly (ADP-ribose) polymerase (PARP) inhibitors have been shown to be promising anticancer agents for breast and ovarian cancers deficient in either BRCA1 or BRCA2," said Pommier. "Prior to our study, PARP inhibitors were thought to work primarily by blocking the DNA repair function of members of the PARP family of proteins, leading ultimately to cancer cell death."

In their initial studies, Pommier and his colleagues found that the PARP inhibitor olaparib was more toxic to cultured cells than genetic elimination of PARP1.

According to Pommier, these results indicated that olaparib must have additional modes of action, and their detailed cellular analyses identified a critical one: olaparib was trapping PARP proteins, specifically PARP1 and PARP2, at sites of DNA damage, and the trapped PARP protein-DNA complexes were highly toxic to cells.

When the trapping ability of olaparib was compared with that of two other PARP inhibitors under clinical development, it was found that the trapping potency of the three drugs differed markedly: niraparib was more potent than olaparib, which was in turn substantially more potent than veliparib. In contrast, olaparib was the most potent inhibitor of DNA repair function, followed by veliparib and then niraparib.

"Critical to this study, is the demonstration that PARP inhibitors are not equivalent with respect to their potency to trap PARP proteins," said Pommier. "Our findings indicate that PARP inhibitors should be categorized according to their potency to trap PARP, in addition to their ability to inhibit DNA repair. This is important because it might explain differences in the results of clinical trials using distinct PARP inhibitors."

In further experiments, the researchers identified several genetic mutations in post-replication repair and Fanconi anemia pathways that, like BRCA1 and BRCA2 mutations, sensitized cultured cells to the toxic effects of trapped PARP protein-DNA complexes.

"These data suggest that patients with cancers deficient in these PARP inhibitor-sensitizing genes might benefit from treatment with PARP inhibitors," said Pommier. "It is clear, however, that this hypothesis will require rigorous testing before being broadly translated to the clinic."


'/>"/>
Contact: Jeremy Moore
Jeremy.Moore@aacr.org
215-446-7109
American Association for Cancer Research
Source:Eurekalert

Related medicine news :

1. Mechanism found for destruction of key allergy-inducing complexes, Stanford researchers say
2. Researchers reveal underlying mechanism of powerful chemotherapy for prostate cancer treatment
3. Scientist receives $2.8 Million to study cell signaling mechanism and develop potential therapeutics
4. WSU researchers discover mechanism leading from trichomoniasis to prostate cancer
5. Human Airways Brush Mechanism Gives Clues to Lung Diseases
6. Mechanisms of acquired chemoresistance in ovarian cancer identified
7. Moffitt Cancer Center researchers discover how cancer cells hijack a mechanism to grow
8. New regulatory mechanism discovered in cell system for eliminating unneeded proteins
9. Researchers unfold the mechanisms underlying blood disorders
10. Study reveals new mechanism that might promote cancers growth and spread in the body
11. Zebrafish reveal promising mechanism for healing spinal cord injury
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/24/2017)... ... 24, 2017 , ... Healthcare Associates of McKinney announced today that ... at 8080 State Highway 121, Suite 210, McKinney, Texas 75070. It is in ... , As the practice has grown, the need for more space has been paramount. ...
(Date:2/24/2017)... ... February 24, 2017 , ... The International Association of Eating Disorders Professionals ... What You See” body image mannequin art competition. Selected from 15 submissions from around ... winner revealed at the 31st annual iaedp Symposium, March 22 – 26 in Las ...
(Date:2/24/2017)... Charlevoix, MI (PRWEB) , ... February 24, 2017 ... ... venue in Charlevoix, once again hosted their Military Wedding Giveaway, with the ... be hosted by Castle Farms with services generously donated from local vendors: A ...
(Date:2/23/2017)... ... February 23, 2017 , ... Rare ... audience, will be participating in Rare Disease Day events, hosted by the Rare ... Rare Disease Report, a website, weekly e-newsletter and quarterly publication, will be conducting ...
(Date:2/23/2017)... (PRWEB) , ... February 23, 2017 , ... ... an approved content provider for the National Institute for Health and Care ... social care-related organizations in the National Health Service (NHS) to search, order and ...
Breaking Medicine News(10 mins):
(Date:2/23/2017)... , Feb 23, 2017 Research and Markets ... Price Analysis and Strategies - 2016" report to their offering. ... The latest ... provides drug pricing data and benchmarks in the global Autism Spectrum ... What are the key drugs marketed for Autism ...
(Date:2/23/2017)... ITL Limited, ( ASX: ITD ), an innovative diversified ... year ended 31 December 2016 compared with the previous corresponding period. ... viewed here . Highlights ... Earnings per share of 2.2 cents (Dec 2015: ... 2015: $15.7m; up 11%) Profit before tax of ...
(Date:2/23/2017)... -- Research and Markets has announced the addition of ... report to their offering. ... The latest research Oesophageal Cancer Drugs Price Analysis ... the global Oesophageal Cancer market. The research answers the ... drugs marketed for Oesophageal Cancer and their clinical attributes? How are ...
Breaking Medicine Technology: