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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Fokas, E; Prevo, R; Pollard, JR; Reaper, PM; Charlton, PA; Cornelissen, B; Vallis, KA; Hammond, EM; Olcina, MM; Gillies, McKenna, W; Muschel, RJ; Brunner, TB.
Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation.
Cell Death Dis. 2012; 3:e441 Doi: 10.1038/cddis.2012.181 [OPEN ACCESS]
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Brunner Thomas Baptist

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Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.
Find related publications in this database (using NLM MeSH Indexing)
Animals - administration & dosage
Ataxia Telangiectasia Mutated Proteins - administration & dosage
Cell Cycle Proteins - antagonists & inhibitors, genetics, metabolism
Cell Line, Tumor - administration & dosage
Cell Survival - drug effects, radiation effects
Checkpoint Kinase 1 - administration & dosage
DNA Damage - drug effects, radiation effects
Female - administration & dosage
Humans - administration & dosage
Isoxazoles - administration & dosage
Mice - administration & dosage
Mice, Inbred BALB C - administration & dosage
Pancreatic Neoplasms - drug therapy, genetics, metabolism, radiotherapy
Phosphorylation - drug effects, radiation effects
Protein Kinase Inhibitors - administration & dosage
Protein Kinases - genetics, metabolism
Protein Serine-Threonine Kinases - antagonists & inhibitors, genetics, metabolism
Pyrazines - administration & dosage
Radiation Tolerance - administration & dosage
Radiation-Sensitizing Agents - administration & dosage

Find related publications in this database (Keywords)
novel inhibitor
pancreatic cancer
tumor selectivity
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