Jamieson David, Wilson Kerrie, Pridgeon Simon, Margetts Jane P, Edmondson Richard J, Leung Hing Y, Knox Richard, Boddy Alan V
Northern Institute for Cancer Research, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.
Clin Cancer Res. 2007 Mar 1;13(5):1584-90. doi: 10.1158/1078-0432.CCR-06-1416.
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.
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.
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)].
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.
NRH：醌氧化还原酶2（NQO2）是NAD（P）H：醌氧化还原酶1（NQO1）的同源物。尽管与人类NQO1有54%的同源性，但NQO2几乎没有内源性酶活性。然而，NQO2有作为治疗靶点的潜力，因为添加非生物源性电子供体二氢烟酰胺核糖苷（NRH）可选择性增强烷基化剂曲他卡（CB 1954）的生物活化作用。测定了卵巢和膀胱肿瘤的NQO活性，并研究了NQO基因多态性对NQO活性的影响。
通过半定量逆转录聚合酶链反应分析腹膜内卵巢转移瘤和膀胱肿瘤临床样本的NQO1和NQO2活性、mRNA表达，并通过限制性片段长度多态性分析进行基因分型。
膀胱队列中的NQO1活性高于卵巢队列（分别为0 - 283和0 - 30 nmol/分钟/毫克；P < 0.0001）。相反，卵巢组织中的NQO2活性高于膀胱样本（分别为0.15 - 2.27和0 - 1.14 nmol/分钟/毫克；P = 0.0004）。在两个队列中，NQO1 C609T单核苷酸多态性（SNP）与NQO1活性降低约7倍相关。NQO2外显子3 T14055C SNP与野生型相比，NQO2活性较低[膀胱样本中的中位数分别为0.18和0.37 nmol/分钟/毫克（P = 0.007），卵巢队列中为0.82和1.16 nmol/分钟/毫克（P = 0.034）]。
这是首次观察到报告NQO2外显子3 SNP与较低酶活性之间存在明显关联。腹膜内卵巢转移瘤相对于其他组织的高NQO2活性表明曲他卡治疗该疾病具有潜力。相反，相对于其他组织，NQO1活性和表达水平较低表明针对NQO1的治疗不合适。
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