title: C609T polymorphism of NAD(P)H quinone oxidoreductase 1 as a predictive biomarker for response to amrubicin.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takakuwa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Oguri
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ozasa
authors.forename: Takehiro
authors.initials: T
authors.lastname: Uemura
authors.forename: Eiji
authors.initials: E
authors.lastname: Kunii
authors.forename: Daishi
authors.initials: D
authors.lastname: Kasai
authors.forename: Mikinori
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Ken
authors.initials: K
authors.lastname: Maeno
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sato
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D018943:Anthracyclines / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D018943:Anthracyclines; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C116173:amrubicinol; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human