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Title: Comet assay measures of DNA damage are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo
Other Titles: Measures of DNA damage sensitivity are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo
Authors: Bowman, Karen J.
Al-Moneef, Manar M.
Sherwood, Benedict T.
Colquhoun, Alexandra J.
Goddard, Jonathan C.
Griffiths, T.R. Leyshon
Payne, David
Singh, Sadmeet
Butterworth, Paul C.
Khan, Masood A
Summerton, Duncan J.
Steward, William P.
McKelvey-Martin, Valerie J.
McKeown, Stephanie R.
Kockelbergh, Roger C.
Mellon, J. Kilian
Symonds, R. Paul
Jones, George D.D.
First Published: 8-Oct-2013
Publisher: Wiley-Blackwell for the International Union against Cancer (UICC)
Citation: International Journal of Cancer, 2014, 134 (5), pp. 1102-1111
Abstract: Bladder cancer patients suffer significant treatment failure, including high rates of recurrence and poor outcomes for advanced disease. If mechanisms to improve tumour cell treatment sensitivity could be identified and/or if tumour response could be predicted, it should be possible to improve local-control and survival. Previously, we have shown that radiation-induced DNA damage, measured by alkaline Comet assay (ACA), correlates bladder cancer cell radiosensitivity in vitro. In the present study we firstly show that modified-ACA measures of cisplatin and mitomycin-C-induced damage also correlate bladder cancer cell chemosensitivity in vitro, with essentially the same rank order for chemosensitivity as for radiosensitivity. Furthermore, ACA studies of radiation-induced damage in different cell-DNA substrates (nuclei, nucleoids & intact parent cells) suggest that it is a feature retained in the prepared nucleoids that is responsible for the relative damage sensitivity of bladder cancer cells, suggestive of differences in the organisation of DNA within resistant vs. sensitive cells. Secondly, we show that ACA analysis of biopsies from bladder tumours reveal that reduced DNA damage sensitivity associates with poorer treatment outcomes, notably that tumours with a reduced damage response show a significant association with local recurrence of non-invasive disease and that reduced damage response was a better predictor of recurrence than the presence of high-risk histology in this cohort. In conclusion, this study demonstrates that mechanisms governing treatment-induced DNA damage are both central to and predictive of bladder cancer cell treatment sensitivity and exemplifies a link between DNA damage resistance and both treatment response and tumour aggression.
DOI Link: 10.1002/ijc.28437
ISSN: 0020-7136
eISSN: 1097-0215
Version: Publisher Version
Type: Journal Article
Rights: Copyright © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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