| The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. | |
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MedLine Citation:
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PMID: 20739657 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-25 |
Journal Detail:
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Title: Blood Volume: 116 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-26 Completed Date: 2011-01-13 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 4578-87 Citation Subset: AIM; IM |
Affiliation:
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School of Cancer Sciences, University of Birmingham, Birmingham, UK. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / pharmacology, therapeutic use* 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:
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//Cancer Research UK |
| Chemical | |
Reg. No./Substance:
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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/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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