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.

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.

• Authors: Saurajyoti Basu, John E Brown, G Michael Flannigan, Jason H Gill, Paul M Loadman, Sandie W Martin, Brian Naylor, Andrew J Scally, Jill M Seargent, Tariq Shah, Rajiv Puri, Roger M Phillips
• Journal: International journal of cancer (Int J Cancer) Vol. 109 Issue 5 Pg. 703-9 (May 01 2004) ISSN: 0020-7136 [Print] United States
• PMID: 14999778 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2004 Wiley-Liss, Inc.

Chemical References

• Antibiotics, Antineoplastic
• Mitomycin
• NADPH-Ferrihemoprotein Reductase
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human

Topics

• Administration, Intravesical
• Antibiotics, Antineoplastic (administration & dosage, therapeutic use)
• Disease-Free Survival
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunohistochemistry
• Mitomycin (administration & dosage, therapeutic use)
• NAD(P)H Dehydrogenase (Quinone) (drug effects, metabolism)
• NADPH-Ferrihemoprotein Reductase (drug effects, metabolism)
• Predictive Value of Tests
• Retrospective Studies
• Treatment Outcome
• Urinary Bladder Neoplasms (drug therapy, enzymology)