scholarly journals The Adenovirus E4orf6 Protein Inhibits DNA Double Strand Break Repair and Radiosensitizes Human Tumor Cells in an E1B-55K-independent Manner

2004 ◽  
Vol 280 (2) ◽  
pp. 1474-1481 ◽  
Author(s):  
Lori S. Hart ◽  
Steven M. Yannone ◽  
Christine Naczki ◽  
Joseph S. Orlando ◽  
Stephen B. Waters ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Human Tumor ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Human Tumor Cells ◽  
Independent Manner ◽  
Dna Double Strand Break ◽  
Break Repair

The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4578-4587 ◽  
Author(s):  
Victoria J. Weston ◽  
Ceri E. Oldreive ◽  
Anna Skowronska ◽  
David G. Oscier ◽  
Guy Pratt ◽  
...  
Keyword(s):  
Cell Line ◽  
Tumor Cells ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Prolymphocytic Leukemia ◽  
Dna Double Strand Break ◽  
Break Repair

Abstract 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.

In tumor cells regulation of DNA double strand break repair through EGF receptor involves both NHEJ and HR and is independent of p53 and K-Ras status

2011 ◽  
Vol 101 (1) ◽  
pp. 147-151 ◽  
Author(s):  
Laura Myllynen ◽  
Thorsten Rieckmann ◽  
Jochen Dahm-Daphi ◽  
Ulla Kasten-Pisula ◽  
Cordula Petersen ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Egf Receptor ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dna Double Strand Break ◽  
Ras Status ◽  
Break Repair
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