Navigation Links
New mechanism of action for PARP inhibitors discovered

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
American Association for Cancer Research

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:
(Date:11/29/2015)... ... November 29, 2015 , ... Key Housing, a top-rated ... announce their December, 2015, featured apartment community: Epic. In showcasing this featured apartment community ... the tight Bay Area rental market to efficiently find housing suitable to their needs ...
(Date:11/28/2015)... ... ... Safe storage for contraceptive devices may not always be easy to find. ... the other from Bradley Beach, New Jersey, there is an easy solution to the ... replace NuvaRings more often than necessary. As such, it affords peace of mind and ...
(Date:11/28/2015)... (PRWEB) , ... November 28, 2015 , ... Beginning November 30th at 6:00 a.m. EST ... the most savings. , With possible savings of up to 20% off orders $80 or ... homepage of the website every few hours. , As a competitive e-commerce website for skin ...
(Date:11/27/2015)... ... 28, 2015 , ... There is only one major question facing all law ... , This question has not been an easy question to answer. Especially when the ... the younger workforce don’t share the same discipline around working long hours. , ...
(Date:11/27/2015)... ... November 27, 2015 , ... According to an article ... of Toronto and the University of British Columbia suggested that laws requiring bicyclists to ... article explains that part of the reason for the controversial conclusion is that, while ...
Breaking Medicine News(10 mins):
(Date:11/29/2015)... 2015   National Decision Support Company (NDSC) continues ... including notable statewide implementations. As a result, ordering ... Select, more than 1 million times per month—all ... Select provides real-time feedback on the most appropriate ... been implemented at over 100 healthcare systems nationally, ...
(Date:11/27/2015)... 2015  Lannett Company, Inc. (NYSE: LCI ... acquisition of Kremers Urban Pharmaceuticals Inc. (KU), the ... company UCB S.A. (Euronext: UCB). ... KU from UCB for total consideration of approximately ... customary working capital adjustment, a deduction of certain ...
(Date:11/26/2015)... , Países Bajos, November 26, 2015 ... la terapia fotodinámica de Bremachlorin para el cáncer avanzado. ... la inmunoterapia con la terapia fotodinámica de Bremachlorin para ... Un nuevo enfoque combina la inmunoterapia con la terapia ... Clinical Cancer Research . --> ...
Breaking Medicine Technology: