title: Upregulation of ERCC1 and DPD expressions after oxaliplatin-based first-line chemotherapy for metastatic colorectal cancer.
abstract: BACKGROUND
  The updated randomised phase 2/3 FIRIS study demonstrated the noninferiority of IRIS (irinotecan and S-1) to FOLFIRI (irinotecan, folinic acid, and 5-FU) for metastatic colorectal cancer. Meanwhile, in the subset analysis including patients who previously have undergone oxaliplatin-containing chemotherapy, the IRIS group showed longer survival than the FOLFIRI group. However, the molecular mechanism underlying this result is still unknown.
  
  
  METHODS
  The National Cancer Institute 60 (NCI60) cell line panel data were utilised to build the hypothesis. A total of 45 irinotecan-naive metastatic colorectal cancer patients who had undergone hepatic resection were included for the validation study. The mRNA expressions of excision repair cross-complementing group 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), and topoisomerase-1 (TOP1) were evaluated by quantitative RT-PCR. The expressions of ERCC1 and DPD were also evaluated by immunohistochemistry.
  
  
  RESULTS
  Sensitivity to oxaliplatin in 60 cell lines was significantly correlated with that of 5-FU. Resistant cells to oxaliplatin showed significantly higher ERCC1 and DPD expression than sensitive cells. In validation study, ERCC1 and DPD but not TOP1 expressions in cancer cells were significantly higher in FOLFOX (oxaliplatin, folinic acid, and 5-FU)-treated patients (N=24) than nontreated patients (N=21). The ERCC1 and DPD protein expressions were also significantly higher in FOLFOX-treated patients.
  
  
  CONCLUSIONS
  The ERCC1 and DPD expression levels at both mRNA and protein levels were significantly higher in patients with oxaliplatin as a first-line chemotherapy than those without oxaliplatin. The IRIS regimens with the DPD inhibitory fluoropyrimidine may show superior activity against DPD-high tumours (e.g., tumours treated with oxaliplatin) compared with FOLFIRI.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1, Honjo, Kumamoto, 860-8556, Japan. hdobaba@kumamoto-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Baba
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Okabe
authors.forename: Y
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Baba
authors.forename: M
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: A
authors.initials: A
authors.lastname: Chikamoto
authors.forename: T
authors.initials: T
authors.lastname: Beppu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism*; D004338:Drug Combinations; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D054547:National Cancer Institute (U.S.); D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010094:Oxonic Acid / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D005641:Tegafur / Q000008:administration & dosage; D014481:United States; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D004338:Drug Combinations; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D000077150:Oxaliplatin; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); C071447:ERCC1 protein, human; D004720:Endonucleases; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin