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Title: An evaluation of the checkpoint kinase inhibitor V158411
Authors: Stephens, Peter Andrew
Issue Date: 2015
Publisher: Newcastle University
Abstract: The aim of this work was to characterise the checkpoint 1 kinase (CHK1) inhibitor V158411; its effect on DNA damage-induced checkpoint function in parallel with chemo/radio-potentiation in a panel of cell lines characterised for their CHK1 expression and activity. Furthermore, to determine the single agent cytotoxicity in a panel of cell lines; to identify potential pharmacodynamic biomarkers of CHK1 activity suitable for measuring the activity of inhibitors in the clinic; and to explore the role of p53 and identify other potential determinants of sensitivity to CHK1 inhibitors. V158411 on its own reliably reduces CHK1serine296 phosphorylation and gemcitabine-mediated induction of CHK1serine296 phosphorylation. Single agent V158411 reduces the fraction of cancer cells in G2 of the cell cycle and abrogates cisplatin and IR-mediated increases in the proportion of cells in G2. V158411 shows significant single agent activity in a number of cell lines. There was significant potentiation of ionising radiation with V158411. There was no significant chemopotentiation of either gemcitabine or cisplatin with coadministration with V158411. p53 status was not associated with significant differences in sensitivity to single agent V158411, chemo or radiosensitisation. However, loss of DNA-PKcs or the presence of a DNA-PKcs inhibitor conferred resistance to V158411. CHK1 and DNA-PKcs mRNA levels were found to be elevated in tumour samples compared to normal tissue levels. The LC50 of V158411 was shown to correlate with the inducible (2 Gy IR) phosphorylation of DNA-PKcsserine2096 in a panel of cancer cells.
Description: PhD Thesis
Appears in Collections:Northern Institute for Cancer Research

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