Abstract | PURPOSE: METHODS AND MATERIALS: NSCLC Calu-6 and Calu-3 cells were irradiated in the presence of olaparib or vehicle under normoxic (21% O2) or hypoxic (1% O2) conditions. In vitro radiosensitivity was assessed by clonogenic survival assay and γH2AX foci assay. Established Calu-6 and Calu-3 subcutaneous xenografts were treated with olaparib (50 mg/kg, daily for 3 days), radiation (10 Gy), or both. Tumors (n=3/group) were collected 24 or 72 hours after the first treatment. Immunohistochemistry was performed to assess hypoxia ( carbonic anhydrase IX [CA9]), vessels (CD31), DNA double strand breaks ( DSB) (γH2AX), and apoptosis (cleaved caspase 3 [CC3]). The remaining xenografts (n=6/group) were monitored for tumor growth. RESULTS: In vitro, olaparib showed a greater radiation-sensitizing effect in Calu-3 and Calu-6 cells in hypoxic conditions (1% O2). In vivo, Calu-3 tumors were well-oxygenated, whereas Calu-6 tumors had extensive regions of hypoxia associated with down-regulation of the homologous recombination protein RAD51. Olaparib treatment increased unrepaired DNA DSB (P<.001) and apoptosis (P<.001) in hypoxic cells of Calu-6 tumors following radiation, whereas it had no significant effect on radiation-induced DNA damage response in nonhypoxic cells of Calu-6 tumors or in the tumor cells of well-oxygenated Calu-3 tumors. Consequently, olaparib significantly increased radiation-induced growth inhibition in Calu-6 tumors (P<.001) but not in Calu-3 tumors. CONCLUSIONS:
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Authors | Yanyan Jiang, Tom Verbiest, Aoife M Devery, Sivan M Bokobza, Anika M Weber, Katarzyna B Leszczynska, Ester M Hammond, Anderson J Ryan |
Journal | International journal of radiation oncology, biology, physics
(Int J Radiat Oncol Biol Phys)
Vol. 95
Issue 2
Pg. 772-81
(06 01 2016)
ISSN: 1879-355X [Electronic] United States |
PMID | 27020103
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Phthalazines
- Piperazines
- Poly(ADP-ribose) Polymerase Inhibitors
- Radiation-Sensitizing Agents
- Rad51 Recombinase
- olaparib
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Topics |
- Animals
- Apoptosis
(radiation effects)
- Carcinoma, Non-Small-Cell Lung
(pathology, radiotherapy)
- Cell Hypoxia
- Cell Line, Tumor
- DNA Damage
- Female
- Humans
- Lung Neoplasms
(pathology, radiotherapy)
- Mice
- Mice, Inbred BALB C
- Phthalazines
(pharmacology)
- Piperazines
(pharmacology)
- Poly(ADP-ribose) Polymerase Inhibitors
(pharmacology)
- Rad51 Recombinase
(analysis)
- Radiation-Sensitizing Agents
(pharmacology)
- Xenograft Model Antitumor Assays
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