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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. Key words: NQO1; cytochrome P450 reductase; mitomycin C; bladder cancerThe ability to predict tumour response to chemotherapy has been and continues to be a major objective in cancer research with the emphasis currently being placed on the identification of molecular markers of tumour response. 1,2 Within the field of bioreductive drug development, the ability to individualise chemotherapy based on the activity of specific reductases and hypoxia in tumours forms one of the cornerstones of a concept known as enzyme-directed bioreductive drug development. 3 The key requirements for the successful clinical application of this concept include the development of drugs that are bioreductively activated by specific reductases and good correlations between tumour response and enzymology in experimental tumour models. Mitomycin C (MMC) is a clinically active agent used to treat a number of tumours and is regarded as the prototypical bioreductive drug. 4 Its mechanism of action has been extensively reviewed elsewhere [5][6][7][8] and involves a complex interplay between tumour physiology (oxygen tension and extracellular pH) and several reductase enzymes (both 1 and 2 electron reductases). The ability to predict cellular and tumour response to MMC based on tumour enzymology has been addressed by several research groups but the results are controversial, and there are conflicting reports on the relationship between tumour enzymology and chemosensitivity in the literature. This is particularly true in the case of the 2 electron reductase NAD(P)H:quinone oxidoreductase-1 (NQO1), which has been implicated in the bioreductive activation of MMC, especially under aerobic conditions. 5,6,9 Reports of good correlations between NQO1 activity (and mRNA expression) and response to MMC contrast sharply with reports of poor correlations in bot...
OBJECTIVE To assess the use of mitomycin C, by urologists within the UK, as a single‐dose intravesical agent. Current European recommendations are to use one dose after any new tumour resection. METHODS We assessed the current patterns of mitomycin C usage amongst British urologists, particularly with reference to one instillation after resecting a new bladder tumour, hypothesizing that British urologists would use mitomycin C in line with current guidelines. A one‐page questionnaire was mailed to 527 consultant urologists in the UK enquiring about their use of mitomycin C in superficial bladder cancer. A second mailing was sent to encourage nonresponders. RESULTS Of the 527 consultants, 320 (61%) replied, of which 313 (59%) questionnaires were evaluable. Of these 313 respondents, 299 (95%) used mitomycin C; 244 respondents (82%) advocated the use of one dose of mitomycin C after resecting a new tumour, but only 10 (4%) would use it immediately after tumour resection and 155 (64%) use it within 24 h. Most (98%) respondents favoured the use of a mitomycin C course after resecting multiple tumours or after multiple recurrences. Interestingly, 20 respondents (7%) would use mitomycin C as a first‐line therapy for carcinoma in situ and a further 23 (8%) would use it for G3T1 tumours. A minority (14%) would use it after nephrectomy for upper tract transitional cell carcinoma. Almost all respondents indicated a dose of 40 mg in 40 mL of diluent. Maintenance treatment with mitomycin C was advocated by 44 (15%) of respondents, mainly for recurrent multifocal Ta/T1 tumours. The perception of the side‐effects of mitomycin C was favourable, with 69% of respondents judging mitomycin C to be well tolerated with mild side‐effects. CONCLUSION Urologists adopt new ideas rapidly, as shown by the wide acceptance of the UK Medical Research Council study. The prompt use of mitomycin C needs to be reinforced, as efficacy is optimum within 6 h of resection. A few consultants persist in continuing with established practices, which have little evidence base. The publication of such survey results, with guidelines for treatment, should encourage those urologists whose practice is at variance from the norm to reflect on and change their practice.
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