Article Figures & Data
Figures
- Figure 1.
Effect of olaparib and/or radiation in NSCLC cell lines. A, clonogenic survival of exponential phase Calu-6 and A549 cells exposed to olaparib for 24 hours or continuously for the duration of the assay. B, Western blot analysis of PARP activity in Calu-6 and A549 cells treated with olaparib 2 hours before and 22 hours after radiation. Activated PARP is shown by smearing up the gel from 116 kDa due to the ribosylation effect. In the presence of olaparib, PARP can be visualized as a clean tight band on the blot. C, radiation dose–response curves of Calu-6 and A549 cells treated with vehicle or the indicated concentrations of olaparib 2 hours before and 22 hours after irradiation. The mean surviving fraction ± SE was plotted. D, Calu-6 cells were treated with 1 and 5 μmol/L of olaparib 2 hours before exposure to 1, 2, and 4 Gy. Cells were fixed 1 and 22 hours after irradiation and fluorescence intensity of the γH2AX signal determined. Mean values of 100 nuclei ± SE are presented, and all data were derived from at least 3 independent experiments. *, P < 0.01.
- Figure 2.
Effect of olaparib alone or in combination with fractionated radiation on a Calu-6 tumor xenograft. A, combination of olaparib with radiation treatment enhances the therapeutic response of Calu-6 xenografts. Tumors were randomized into 4 treatment groups (5 animals per group): vehicle (10% DMSO in PBS/10% 2-hydroxy-propyl-β-cyclodextrin daily for 5 days by oral gavage), olaparib (50 mg/kg daily for 5 days by oral gavage), 10 Gy fractionated radiotherapy (2 Gy daily for 5 days), and olaparib combined with 10 Gy fractionated radiotherapy (50 mg/kg given before 2 Gy daily for 5 days). The growth curves were plotted until the first tumor of each treatment group reached 1,000 mm3. B, number of days that tumors in each group took to reach 1,000 mm3 in tumor volume (RTV4; mean ± SE). A significant growth delay between fractionated radiotherapy and combination treatment was observed. *, P < 0.01.
- Figure 3.
Efficacy of olaparib as a single agent or in combination with radiation therapy on tumor vascular perfusion assessed by using a Calu-6 tumor DWC model. A, fluorescence intensity was monitored in real time to record the effects of olaparib and vehicle on the accumulation of BSA-Alexa. Imaging started by recording the background fluorescence, followed by addition of BSA-Alexa (i) until the fluorescence values plateau. At this point, vehicle control or olaparib were added (ii) and the accumulation of BSA-Alexa measured in real-time. The graphs show the effect of olaparib as a single agent (top) and in combination with radiation (bottom). B, relative increase in fluorescence normalized to controls (vehicle or radiation) on days 1, 3, and 5. C, BSA-Alexa distribution immediately after injection (2 minutes) and after administration of olaparib (50 mg/kg). The white arrows indicate opening of vessels 20 and 60 minutes after administration of olaparib. *, P < 0.01.
- Figure 4.
Olaparib caused relaxation in the ex vivo PE preconstricted rat tail artery. A, representative histogram of the dilatory effect of 500 μmol/L olaparib in 10 μmol/L PE preconstricted rat tail artery. B, dose–response of olaparib and nicotinamide in a PE preconstricted rat tail artery. Each assay was run with 3 arteries, and the experiment was carried out in triplicate.
- Figure 5.
Structures of olaparib, AG14361, ABT-888, and GPI-15427, a related compound of E7016.
Tables
- Table 1.
Schedule of the treatments and window imaging on days 1, 3, and 5 before and after treatment with vehicle and olaparib with or without radiation
Day Group 0 1a 2 3a 4 5a Vehicle Vehicle Vehicle Vehicle Vehicle Vehicle Olaparib Olaparib Olaparib Olaparib Olaparib Olaparib Vehicle + 5 × 2 Gy 2 Gy Vehicle (2 Gy) Vehicle (2 Gy) Vehicle (2 Gy) Vehicle (2 Gy) Vehicle Olaparib + 5 × 2 Gy 2 Gy Olaparib (2 Gy) Olaparib (2 Gy) Olaparib (2 Gy) Olaparib (2 Gy) Olaparib NOTE: In the combination treatments, the mice were irradiated with 2 Gy on day 0, and vehicle and olaparib were given 24 hours later on day 1 at the time of imaging. Once imaging was finished, the mice were given the next fraction (2 Gy) of radiation.
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↵aReal-time IVM imaging.
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Supplementary Data
Files in this Data Supplement:
- Supplementary Figures 1-4 - PDF file - 491K
Volume 10, Issue 10
