NAD(P)H: Quinone oxidoreductase-1 C609T polymorphism analysis in human superficial bladder cancers:

Relationship of genotype status to NQO1 phenotype and clinical response to Mitomycin C.

Saurajyoti Basu, John E. Brown, G. Michael Flannigan, Jason H. Gill, Paul M. Loadman, Sandie W. Martin, Brian Naylor, Rajiv Puri, Andrew J. Scally, Jill M. Seargent, Tariq Shah, Roger M. Phillips

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

NAD(P)H:Quinone oxidoreductase-1 (NQO1) has been implicated in the bioreductive activation of the clinically active anticancer drug Mitomycin C (MMC) and a polymorphic variant of NQO1 which lacks functional enzyme activity (NQO1*2) has been linked with poor survival in patients treated with MMC. The relationship between NQO1 activity and cellular response to MMC is however controversial and the aim of this study was to determine whether the response of bladder cancer patients to MMC can be forecast on the basis of NQO1*2 genotype status. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue from 148 patients with low to intermediate grade (G1/G2) superficial (Ta/T1) bladder cancers and NQO1*2 genotype status determined by PCR-RFLP. NQO1*2 genotype status was retrospectively compared with clinical response to intravesical administered MMC with the primary end-point being time to first recurrence. NQO1 phenotype was determined by immunohistochemistry. Of the 148 patients genotyped, 85 (57.4%) were NQO1*1 (wild-type), 59 (39.8%) were NQO1*1/*2 (heterozygotes) and 4 (2.7%) were NQO1*2/*2. No NQO1 protein expression was detected in NQO1*2/*2 tumours. A broad spectrum of NQO1 protein expression existed in tumours genotyped as NQO1*1 and NQO1*1/*2 although tumours with NQO1*1 typically expressed higher NQO1 protein. A poor correlation existed between NQO1*2 genotype status and clinical response to MMC. The results of this retrospective study suggest that tailoring MMC therapy to individual patients with superficial bladder cancer on the basis of NQO1 genotype status is unlikely to be of clinical benefit.

Original languageEnglish
Pages (from-to)921-928
Number of pages8
JournalInternational Journal of Oncology
Volume25
Issue number4
DOIs
Publication statusPublished - Oct 2004
Externally publishedYes

Fingerprint

Mitomycin
Urinary Bladder Neoplasms
NAD
Oxidoreductases
Genotype
Phenotype
Neoplasms
Proteins
Heterozygote
benzoquinone
Restriction Fragment Length Polymorphisms
Paraffin
Formaldehyde
Retrospective Studies
Immunohistochemistry
Recurrence
Polymerase Chain Reaction
Survival
DNA
Enzymes

Cite this

Basu, Saurajyoti ; Brown, John E. ; Flannigan, G. Michael ; Gill, Jason H. ; Loadman, Paul M. ; Martin, Sandie W. ; Naylor, Brian ; Puri, Rajiv ; Scally, Andrew J. ; Seargent, Jill M. ; Shah, Tariq ; Phillips, Roger M. / NAD(P)H: Quinone oxidoreductase-1 C609T polymorphism analysis in human superficial bladder cancers: Relationship of genotype status to NQO1 phenotype and clinical response to Mitomycin C. In: International Journal of Oncology. 2004 ; Vol. 25, No. 4. pp. 921-928.
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abstract = "NAD(P)H:Quinone oxidoreductase-1 (NQO1) has been implicated in the bioreductive activation of the clinically active anticancer drug Mitomycin C (MMC) and a polymorphic variant of NQO1 which lacks functional enzyme activity (NQO1*2) has been linked with poor survival in patients treated with MMC. The relationship between NQO1 activity and cellular response to MMC is however controversial and the aim of this study was to determine whether the response of bladder cancer patients to MMC can be forecast on the basis of NQO1*2 genotype status. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue from 148 patients with low to intermediate grade (G1/G2) superficial (Ta/T1) bladder cancers and NQO1*2 genotype status determined by PCR-RFLP. NQO1*2 genotype status was retrospectively compared with clinical response to intravesical administered MMC with the primary end-point being time to first recurrence. NQO1 phenotype was determined by immunohistochemistry. Of the 148 patients genotyped, 85 (57.4{\%}) were NQO1*1 (wild-type), 59 (39.8{\%}) were NQO1*1/*2 (heterozygotes) and 4 (2.7{\%}) were NQO1*2/*2. No NQO1 protein expression was detected in NQO1*2/*2 tumours. A broad spectrum of NQO1 protein expression existed in tumours genotyped as NQO1*1 and NQO1*1/*2 although tumours with NQO1*1 typically expressed higher NQO1 protein. A poor correlation existed between NQO1*2 genotype status and clinical response to MMC. The results of this retrospective study suggest that tailoring MMC therapy to individual patients with superficial bladder cancer on the basis of NQO1 genotype status is unlikely to be of clinical benefit.",
author = "Saurajyoti Basu and Brown, {John E.} and Flannigan, {G. Michael} and Gill, {Jason H.} and Loadman, {Paul M.} and Martin, {Sandie W.} and Brian Naylor and Rajiv Puri and Scally, {Andrew J.} and Seargent, {Jill M.} and Tariq Shah and Phillips, {Roger M.}",
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NAD(P)H: Quinone oxidoreductase-1 C609T polymorphism analysis in human superficial bladder cancers: Relationship of genotype status to NQO1 phenotype and clinical response to Mitomycin C. / Basu, Saurajyoti; Brown, John E.; Flannigan, G. Michael; Gill, Jason H.; Loadman, Paul M.; Martin, Sandie W.; Naylor, Brian; Puri, Rajiv; Scally, Andrew J.; Seargent, Jill M.; Shah, Tariq; Phillips, Roger M.

In: International Journal of Oncology, Vol. 25, No. 4, 10.2004, p. 921-928.

Research output: Contribution to journalArticle

TY - JOUR

T1 - NAD(P)H: Quinone oxidoreductase-1 C609T polymorphism analysis in human superficial bladder cancers:

T2 - Relationship of genotype status to NQO1 phenotype and clinical response to Mitomycin C.

AU - Basu, Saurajyoti

AU - Brown, John E.

AU - Flannigan, G. Michael

AU - Gill, Jason H.

AU - Loadman, Paul M.

AU - Martin, Sandie W.

AU - Naylor, Brian

AU - Puri, Rajiv

AU - Scally, Andrew J.

AU - Seargent, Jill M.

AU - Shah, Tariq

AU - Phillips, Roger M.

PY - 2004/10

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