C609T Polymorphism of NAD(P)H Quinone Oxidoreductase 1 As a Predictive Biomarker for Response to Amrubicin
ABSTRACT 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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ABSTRACT: Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer characterized by early metastasis and high mortality. In recent years, monotherapy and combination therapy of amrubicin with cisplatin or carboplatin has been actively studied and shown promise for the treatment of extensive disease SCLC (ED-SCLC). In this article, we summarize clinical trials of both monotherapy and combination therapy with amrubicin conducted in Japan, the USA, and the European Union. The results suggest that the clinical outcome of amrubicin therapy may be associated with genetic variations in patients. Further study of combination regimens in patients of different ethnicities is warranted.Drug Design, Development and Therapy 01/2013; 7:681-9. DOI:10.2147/DDDT.S41910 · 3.03 Impact Factor
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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.Clinical Medicine Insights: Oncology 02/2013; 7:31-9. DOI:10.4137/CMO.S10839
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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.Lung cancer (Amsterdam, Netherlands) 05/2013; 81(2). DOI:10.1016/j.lungcan.2013.04.022 · 3.14 Impact Factor