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• W2075818408 abstract "Radiation therapy often is delivered concurrently with conventional chemotherapy and biologics, which can result in either additive or supra-additive (i.e., synergistic) effects on local tumor control, a phenomenon referred to as radiosensitization. Many mechanisms of systemic therapy-induced radiosensitization have been identified, including the potentiation of radiation damage, inhibition of DNA repair, and cell cycle interference. The two major double-strand break (DSB) repair pathways, homologous recombination (HR) and non-homologous end joining (NHEJ), play a critical role in the response to ionizing radiation (IR) in mammalian cells. Furthermore, the link between attenuated DSB repair and radiosensitivity is well established, and emerging evidence suggests that pharmacologic inhibition of these pathways is a viable and potentially efficacious strategy for radiosensitization. We sought to develop a high-throughput screening assay for small-molecule inhibitors of IR-induced DSB repair protein foci formation, as a means to potentially identify novel radiosensitizers. Multiple parameters and experimental conditions were tested, including: cell density, timing of IR, fixation reagents, antibody staining conditions and confocal imaging settings. In addition, antibodies to several different DSB response and repair proteins were tested, including H2AX, DNA-PK, BRCA1 and Rad51. In these experiments, cells were seeded into plates, irradiated, incubated for 6 h, and then processed for analysis. Automated confocal microscopy was performed using a high content imager. Our antibody staining conditions were optimized to permit simultaneous detection of multiple protein foci in cells. Next, we developed a protocol to automatically detect and count the number of foci in each individual cell nuclei, which could be applied to each well of the plates. Our protocol was able to identify individual DAPI-stained nuclei and then detect individual foci within each nucleus in irradiated 384-well microplates. A foci intensity threshold was applied in order to exclude non-specific background spots. Using this automated protocol, we detected high levels of IR-induced foci formation with robust signal-to-noise ratios. We then utilized this optimized protocol in a pilot screen with a diverse collection of approximately 10,000 small molecules, to identify novel compounds which disrupt DSB repair foci formation. We have developed a robust and reproducible assay which can simultaneously identify and enumerate IR-induced foci for several key DSB repair proteins. We have applied this assay in a high-content, high-throughput small molecule screen for novel DSB repair inhibitors. These studies have the potential to identify numerous novel radiosensitizers." @default.
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• W2075818408 date "2013-10-01" @default.
• W2075818408 modified "2023-09-27" @default.
• W2075818408 title "High-Content, High-Throughput Screening for Novel Double-Strand Break Repair Inhibitors" @default.
• W2075818408 doi "https://doi.org/10.1016/j.ijrobp.2013.06.1732" @default.
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