Document Detail


The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo.
MedLine Citation:
PMID:  20739657     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.
Authors:
Victoria J Weston; Ceri E Oldreive; Anna Skowronska; David G Oscier; Guy Pratt; Martin J S Dyer; Graeme Smith; Judy E Powell; Zbigniew Rudzki; Pamela Kearns; Paul A H Moss; A Malcolm R Taylor; Tatjana Stankovic
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-25
Journal Detail:
Title:  Blood     Volume:  116     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-26     Completed Date:  2011-01-13     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4578-87     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology,  therapeutic use*
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins / genetics*
Cell Line, Tumor
Cell Proliferation / drug effects
Cells, Cultured
DNA Damage / drug effects
DNA-Binding Proteins / genetics*
Gene Knockdown Techniques
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*,  genetics
Lymphoma, Mantle-Cell / drug therapy*,  genetics
Mice
Mice, SCID
Mutation
Phthalazines / pharmacology,  therapeutic use*
Piperazines / pharmacology,  therapeutic use*
Poly(ADP-ribose) Polymerases / antagonists & inhibitors*
Protein-Serine-Threonine Kinases / genetics*
Tumor Suppressor Proteins / genetics*
Grant Support
ID/Acronym/Agency:
G9901249//Medical Research Council; //Cancer Research UK
Chemical
Reg. No./Substance:
0/AZD 2281; 0/Antineoplastic Agents; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Phthalazines; 0/Piperazines; 0/Tumor Suppressor Proteins; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.11.1/ATM protein, human; EC 2.7.11.1/Ataxia Telangiectasia Mutated Proteins; EC 2.7.11.1/Atm protein, mouse; EC 2.7.11.1/Protein-Serine-Threonine Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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