C609T Polymorphism of NAD(P)H Quinone Oxidoreductase 1 As a Predictive Biomarker for Response to Amrubicin

Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer (Impact Factor: 5.28). 09/2011; 6(11):1826-32. DOI: 10.1097/JTO.0b013e318229137d
Source: PubMed


Amrubicin is a promising agent in the treatment of lung cancer, but predictive biomarkers have not yet been described. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme known to metabolize amrubicinol, the active metabolite of amrubicin, to an inactive compound. We examined the relationship between NQO1 and amrubicinol cytotoxicity.
Gene and protein expression of NQO1, amrubicinol cytotoxicity, and C609T single-nucleotide polymorphism of NQO1 were evaluated in 29 lung cancer cell lines: 14 small cell lung cancer (SCLC) and 15 non-SCLC (NSCLC). The involvement of NQO1 in amrubicinol cytotoxicity was evaluated by small interfering RNA against NQO1.
A significant inverse relationship between both gene and protein expression of NQO1 and amrubicinol cytotoxicity was found in all cell lines. Treatment with NQO1 small interfering RNA increased amrubicinol cytotoxicity and decreased NQO1 expression in both NSCLC and SCLC cells. Furthermore, cell lines genotyped homozygous for the 609T allele showed significantly lower NQO1 protein expression and higher sensitivity for amrubicinol than those with the other genotypes in both NSCLC and SCLC cells.
NQO1 expression is one of the major determinants for amrubicinol cytotoxicity, and C609T single-nucleotide polymorphism of NQO1 could be a predictive biomarker for response to amrubicin treatment.

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    • "In an investigation of human metabolism of amrubicin in vitro using liver microsomes, amrubicin was shown to be metabolized by 54% under aerobic conditions.16 There was no relationship between POR gene expression levels and amrubicinol cytotoxicity in vitro.32 Accordingly, we speculate that POR is also a key enzyme in this process and future studies will include an assessment of the role of POR in amrubicinol cytotoxicity in vivo in specific microenvironments, such as in the liver cytosol or microsomes and under anaerobic or aerobic conditions. "
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    ABSTRACT: Amrubicin hydrochloride (AMR) is a key agent for lung cancer. NADPH quinone oxidoreductase 1 (NQO1) metabolizes the quinone structures contained in both amrubicin (AMR) and amrubicinol (AMR-OH). We hypothesized that 1 C609T polymorphism may affect AMR-related pharmacokinetics and clinical outcomes. Patients received AMR doses of 30 or 40 mg/m/day on days 1-3. Plasma sampling was performed 24 hours after the first and third AMR injections. Concentrations of AMR and AMR-OH were determined by HPLC and the 1 C609T polymorphism was assayed by RT-PCR. A total of 35 patients were enrolled. At a dose of 40 mg/m, the T/T genotype exhibited a tendency toward a relationship with decrease concentrations of AMR-OH on days 2 and 4. The genotype also showed a significant decrease of hematological toxicities ( < 0.05). 1 C609T polymorphism had a tendency of correlation with the plasma concentrations of AMR-OH, and thereby had significant correlations with hematologic toxicities.
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    ABSTRACT: Purpose: To evaluate the pharmacokinetics and cardiac repolarization effect (measured by QT/QTc interval) of amrubicin and its active metabolite amrubicinol in non-Japanese patients with advanced solid tumors. Methods: Patients received amrubicin 40 mg/m(2)/day as a 5-min infusion on days 1-3 of a 21-day cycle. During cycle 1, serial blood and plasma samples were collected on days 1-9 and time-matched triplicate electrocardiograms on the "off-drug" visit (1-5 days prior to start of treatment) and days 1-9. Results: Twenty-four patients were treated. Amrubicinol reached peak concentration 2-4 h after amrubicin administration and had a terminal half-life of 53 h. Distribution of amrubicinol into erythrocytes was fivefold greater than into plasma. The molar ratio of amrubicinol to amrubicin in blood was 0.67 on day 3. The presence of an NQO1 polymorphism did not alter drug exposure. The upper bound of the one-sided 95 % confidence interval for the time-matched, baseline-adjusted change from the off-drug day in QTcI (individual correction) was <10 ms at all times and was only >10 ms (10.20 ms) at a single time point for QTcF (Fridericia correction). No relationship was observed between blood amrubicin or amrubicinol concentrations and QTcF changes. All QTcF measurements were <480 ms, and none increased by >60 ms from baseline. Conclusions: Data suggest that amrubicinol is an important active metabolite in humans and that both compounds were not associated with clinically relevant QTc interval prolongation at the dose regimen studied.
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    ABSTRACT: Background: Nestin is a class VI intermediate filament protein expressed in stem/progenitor cells during the development of the central nervous system. Nestin is detected in various types of tumors and is involved in malignant processes. This study investigated the expression and function of nestin in small-cell lung cancer (SCLC). Methods: Expression of nestin and achaete-scute homolog 1 (ASH1) was studied in 21 lung cancer cell lines. To assess the function of nestin, a short hairpin RNA (shRNA) targeting nestin was transfected into two SCLC cell lines (DMS53 and SBC3), and cloned cells that showed apparent down-regulation of nestin were obtained. Nestin expression was also studied immunohistochemically in surgically resected SCLC primary tumors and metastatic SCLC tumors obtained from autopsy cases. Result: Nestin was expressed in nine of 10 SCLC cell lines. The nestin expression level was significantly higher in SCLC cell lines than in NSCLC cell lines (P < 0.01). There was a statistically significant positive correlation between the expression levels of nestin and ASH1 in SCLC cell lines. Nestin knock-down cells created by transfection with shRNA exhibited decreased invasion and cell proliferation capabilities. Furthermore, nestin was detected in SCLC tumor cells and tumor vessels in all clinical tumor specimens. Conclusion: Nestin is expressed in SCLC in association with neuroendocrine features and participates in malignant phenotypes, including cell growth. Therefore, nestin may be a novel therapeutic target for SCLC.
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