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:2/12/2016)... ... February 12, 2016 , ... Nearly every ... promote eye health. These articles generally list between five and 15 foods that ... Kleyne endorses every one of these lists and believes that nutritious eye healthy ...
(Date:2/12/2016)... ... February 12, 2016 , ... US Sport Camps is pleased to announce the ... in Norwalk, serves as the host site and directing the camps is PGA Professional ... had successful camps in recent years around Des Moines and are fortunate to have ...
(Date:2/12/2016)... ... 12, 2016 , ... The Central Coast Autism Spectrum Center (CCASC) invites teens ages 11-18 to ... of fun for teens with and without special needs to gather in a safe and ... event. The dance will take place on Saturday, Feb. 13 from 7 to 9:30 p.m. ...
(Date:2/12/2016)... ... 12, 2016 , ... Basketball is a game for everyone, not just those ... series, sign language translation is featured in the top right of the screen. Every ... lessons has a sign language translator to teach kids the game and how to ...
(Date:2/12/2016)... ... February 12, 2016 , ... Dignity Health named Dr. ... Emergency Room –Mesa. The new facility is licensed under Dignity Health Arizona ... Bingham is an excellent leader and will ensure our new freestanding emergency room delivers ...
Breaking Medicine News(10 mins):
(Date:2/11/2016)... Calif., Feb. 11, 2016 PRO-DEX, INC. (NasdaqCM: PDEX) ... ended December 31, 2015. The Company also filed its Quarterly ... year 2016 with the Securities and Exchange Commission today. ... 31, 2015 --> --> ... increased $2.6 million, or 95%, to $5.4 million from $2.8 ...
(Date:2/11/2016)... DUNKIRK, N.Y. , Feb. 11, 2016  Governor ... Athenex that will create 1,400 jobs throughout ... by a partnership with the SUNY Polytechnic Institute, includes ... the Conventus Building in Buffalo , ... square foot manufacturing facility in Dunkirk ...
(Date:2/11/2016)... , Feb. 11, 2016  MiMedx Group, Inc. ... utilizing human amniotic membrane and other birth tissues, human ... to develop and market advanced products and therapies, announced ... Markets, 2016 Global Healthcare Conference in New ... and CEO, Michael J. Senken , Chief Financial ...
Breaking Medicine Technology: