Immunohistochemical analysis of NAD(P)H:quinone oxidoreductase and NADPH cytochrome P450 reductase in human superficial bladder tumours: relationship between tumour enzymology and clinical outcome following intravesical mitomycin C therapy

Basu, Saurajyoti, Brown, John E., Flannigan, G. Michael, Gill, Jason H., Loadman, Paul M., Martin, Sandie W., Naylor, Brian, Scally, Andrew J., Seargent, Jill M., Shah, Tariq, Puri, Rajiv and Phillips, Roger M. (2004) Immunohistochemical analysis of NAD(P)H:quinone oxidoreductase and NADPH cytochrome P450 reductase in human superficial bladder tumours: relationship between tumour enzymology and clinical outcome following intravesical mitomycin C therapy. International Journal of Cancer, 109(5), pp. 703-709. ISSN (print) 0020-7136

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Abstract

A central theme within the concept of enzyme-directed bioreductive drug development is the potential to predict tumour response based on the profiling of enzymes involved in the bioreductive activation process. Mitomycin C (MMC) is the prototypical bioreductive drug that is reduced to active intermediates by several reductases including NAD(P)H:quinone oxidoreductase (NQO1) and NADPH cytochrome P450 reductase (P450R). The purpose of our study was to determine whether NQO1 and P450R protein expression in a panel of low-grade, human superficial bladder tumours correlates with clinical response to MMC. A retrospective clinical study was conducted in which the response to MMC of 92 bladder cancer patients was compared to the immunohistochemical expression of NQO1 and P450R protein in archived paraffin-embedded bladder tumour specimens. A broad spectrum of NQO1 protein levels exists in bladder tumours between individual patients, ranging from intense to no immunohistochemical staining. In contrast, levels of P450R were similar with most tumours having moderate to high levels. All patients were chemotherapy naïve prior to receiving MMC and clinical response was defined as the time to first recurrence. A poor correlation exists between clinical response and NQO1, P450R or the expression patterns of various combinations of the 2 proteins. The results of our study demonstrate that the clinical response of superficial bladder cancers to MMC cannot be predicted on the basis of NQO1 and/or P450R protein expression and suggest that other factors (other reductases or post DNA damage events) have a significant bearing on tumour response.

Item Type: Article
Additional Information: This work was supported by Cancer Research UK [grant number C459/A2579] and Kyowa Hakko, Ltd.
Uncontrolled Keywords: NQO1, cytochrome P450 reductase, mitomycin C, bladder cancer, bioreductive drug development, dt-diaphorase activity, hamster ovary cells, human colon, metabolic-activation, cancer-cells, differential toxicity, gene-expression, response assay, dna-damage
Research Area: Allied health professions and studies
Faculty, School or Research Centre: Faculty of Science (until 2011) > School of Pharmacy and Chemistry
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Depositing User: David Salliss
Date Deposited: 22 Jun 2007
Last Modified: 03 May 2011 09:25
URI: http://eprints.kingston.ac.uk/id/eprint/1432

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