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NAD(P)H:quinone oxidoreductase 1 and nrh:quinone oxidoreductase 2 activity and expression in bladder and ovarian cancer and lower NRH:quinone oxidoreductase 2 activity associated with an NQO2 exon 3 single-nucleotide polymorphism.
Clin Cancer Res. 2007 Mar 01; 13(5):1584-90.CC

Abstract

PURPOSE

NRH:quinone oxidoreductase 2 (NQO2) is a homologue of NAD(P)H:quinone oxidoreductase 1 (NQO1). Despite 54% homology with human NQO1, NQO2 has little endogenous enzymatic activity. However, NQO2 has potential as a therapeutic target because the addition of the nonbiogenic electron donor dihydronicotinamide riboside (NRH) selectively potentiates the bioactivation of the alkylating agent tretazicar (CB 1954). The NQO activity of ovarian and bladder tumors was determined and the effect of NQO polymorphisms on NQO activity was investigated.

EXPERIMENTAL DESIGN

Intraperitoneal ovarian metastases and bladder tumor clinical samples were analyzed for NQO1 and NQO2 activity, mRNA expression by semiquantitative reverse transcription-PCR, and genotype by RFLP analysis.

RESULTS

NQO1 activity was higher in the bladder cohort than in the ovarian cohort (0-283 and 0-30 nmol/min/mg, respectively; P < 0.0001). In contrast, NQO2 activity was higher in the ovarian tissue than in the bladder samples (0.15-2.27 and 0-1.14 nmol/min/mg, respectively; P = 0.0004). In both cohorts, the NQO1 C609T single-nucleotide polymorphism (SNP) was associated with approximately 7-fold lower NQO1 activity. The NQO2 exon 3 T14055C SNP was associated with lower NQO2 activity relative to wild-type [median values of 0.18 and 0.37 nmol/min/mg in the bladder samples (P = 0.007) and 0.82 and 1.16 nmol/min/mg in the ovarian cohort (P = 0.034)].

CONCLUSION

This is the first observation reporting an apparent association between an NQO2 exon 3 SNP and lower enzymatic activity. The high NQO2 activity of intraperitoneal ovarian metastases relative to other tissues indicates a potential for tretazicar therapy in the treatment of this disease. In contrast, the low level of NQO1 activity and expression relative to other tissues suggests that NQO1-directed therapies would not be appropriate.

Authors+Show Affiliations

Northern Institute for Cancer Research, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom. david.jamieson@ncl.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17332305

Citation

Jamieson, David, et al. "NAD(P)H:quinone Oxidoreductase 1 and Nrh:quinone Oxidoreductase 2 Activity and Expression in Bladder and Ovarian Cancer and Lower NRH:quinone Oxidoreductase 2 Activity Associated With an NQO2 Exon 3 Single-nucleotide Polymorphism." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 13, no. 5, 2007, pp. 1584-90.
Jamieson D, Wilson K, Pridgeon S, et al. NAD(P)H:quinone oxidoreductase 1 and nrh:quinone oxidoreductase 2 activity and expression in bladder and ovarian cancer and lower NRH:quinone oxidoreductase 2 activity associated with an NQO2 exon 3 single-nucleotide polymorphism. Clin Cancer Res. 2007;13(5):1584-90.
Jamieson, D., Wilson, K., Pridgeon, S., Margetts, J. P., Edmondson, R. J., Leung, H. Y., Knox, R., & Boddy, A. V. (2007). NAD(P)H:quinone oxidoreductase 1 and nrh:quinone oxidoreductase 2 activity and expression in bladder and ovarian cancer and lower NRH:quinone oxidoreductase 2 activity associated with an NQO2 exon 3 single-nucleotide polymorphism. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 13(5), 1584-90.
Jamieson D, et al. NAD(P)H:quinone Oxidoreductase 1 and Nrh:quinone Oxidoreductase 2 Activity and Expression in Bladder and Ovarian Cancer and Lower NRH:quinone Oxidoreductase 2 Activity Associated With an NQO2 Exon 3 Single-nucleotide Polymorphism. Clin Cancer Res. 2007 Mar 1;13(5):1584-90. PubMed PMID: 17332305.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NAD(P)H:quinone oxidoreductase 1 and nrh:quinone oxidoreductase 2 activity and expression in bladder and ovarian cancer and lower NRH:quinone oxidoreductase 2 activity associated with an NQO2 exon 3 single-nucleotide polymorphism. AU - Jamieson,David, AU - Wilson,Kerrie, AU - Pridgeon,Simon, AU - Margetts,Jane P, AU - Edmondson,Richard J, AU - Leung,Hing Y, AU - Knox,Richard, AU - Boddy,Alan V, PY - 2007/3/3/pubmed PY - 2007/5/10/medline PY - 2007/3/3/entrez SP - 1584 EP - 90 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 13 IS - 5 N2 - PURPOSE: NRH:quinone oxidoreductase 2 (NQO2) is a homologue of NAD(P)H:quinone oxidoreductase 1 (NQO1). Despite 54% homology with human NQO1, NQO2 has little endogenous enzymatic activity. However, NQO2 has potential as a therapeutic target because the addition of the nonbiogenic electron donor dihydronicotinamide riboside (NRH) selectively potentiates the bioactivation of the alkylating agent tretazicar (CB 1954). The NQO activity of ovarian and bladder tumors was determined and the effect of NQO polymorphisms on NQO activity was investigated. EXPERIMENTAL DESIGN: Intraperitoneal ovarian metastases and bladder tumor clinical samples were analyzed for NQO1 and NQO2 activity, mRNA expression by semiquantitative reverse transcription-PCR, and genotype by RFLP analysis. RESULTS: NQO1 activity was higher in the bladder cohort than in the ovarian cohort (0-283 and 0-30 nmol/min/mg, respectively; P < 0.0001). In contrast, NQO2 activity was higher in the ovarian tissue than in the bladder samples (0.15-2.27 and 0-1.14 nmol/min/mg, respectively; P = 0.0004). In both cohorts, the NQO1 C609T single-nucleotide polymorphism (SNP) was associated with approximately 7-fold lower NQO1 activity. The NQO2 exon 3 T14055C SNP was associated with lower NQO2 activity relative to wild-type [median values of 0.18 and 0.37 nmol/min/mg in the bladder samples (P = 0.007) and 0.82 and 1.16 nmol/min/mg in the ovarian cohort (P = 0.034)]. CONCLUSION: This is the first observation reporting an apparent association between an NQO2 exon 3 SNP and lower enzymatic activity. The high NQO2 activity of intraperitoneal ovarian metastases relative to other tissues indicates a potential for tretazicar therapy in the treatment of this disease. In contrast, the low level of NQO1 activity and expression relative to other tissues suggests that NQO1-directed therapies would not be appropriate. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/17332305/NAD_P_H:quinone_oxidoreductase_1_and_nrh:quinone_oxidoreductase_2_activity_and_expression_in_bladder_and_ovarian_cancer_and_lower_NRH:quinone_oxidoreductase_2_activity_associated_with_an_NQO2_exon_3_single_nucleotide_polymorphism_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=17332305 DB - PRIME DP - Unbound Medicine ER -