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Comet assay measures of DNA damage are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo

journal contribution
posted on 2013-08-29, 12:00 authored by Karen J. Bowman, Manar M. Al-Moneef, Benedict T. Sherwood, Alexandra J. Colquhoun, Jonathan C. Goddard, T.R. Leyshon Griffiths, David Payne, Sadmeet Singh, Paul C. Butterworth, Masood A Khan, Duncan J. Summerton, William P. Steward, Valerie J. McKelvey-Martin, Stephanie R. McKeown, Roger C. Kockelbergh, J. Kilian Mellon, R. Paul Symonds, George D.D. Jones
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.

History

Citation

International Journal of Cancer, 2014, 134 (5), pp. 1102-1111

Alternative title

Measures of DNA damage sensitivity are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo

Version

  • VoR (Version of Record)

Published in

International Journal of Cancer

Publisher

Wiley-Blackwell for the International Union against Cancer (UICC)

issn

0020-7136

eissn

1097-0215

Copyright date

2013

Available date

2013-08-29

Publisher version

http://onlinelibrary.wiley.com/wol1/doi/10.1002/ijc.28437/abstract

Language

en

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