title: DNA-bound platinum is the major determinant of cisplatin sensitivity in head and neck squamous carcinoma cells.
abstract: OBJECTIVE
  The combination of systemic cisplatin with local and regional radiotherapy as primary treatment of head and neck squamous cell carcinoma (HNSCC) leads to cure in approximately half of the patients. The addition of cisplatin has significant effects on outcome, but despite extensive research the mechanism underlying cisplatin response is still not well understood.
  
  
  METHODS
  We examined 19 HNSCC cell lines with variable cisplatin sensitivity. We determined the TP53 mutational status of each cell line and investigated the expression levels of 11 potentially relevant genes by quantitative real-time PCR. In addition, we measured cisplatin accumulation and retention, as well as the level of platinum-DNA adducts.
  
  
  RESULTS
  We found that the IC50 value was significantly correlated with the platinum-DNA adduct levels that accumulated during four hours of cisplatin incubation (p = 0.002). We could not find a significant correlation between cisplatin sensitivity and any of the other parameters tested, including the expression levels of established cisplatin influx and efflux transporters. Furthermore, adduct accumulation did not correlate with mRNA expression of the investigated influx pumps (CTR1 and OCT3) nor with that of the examined DNA repair genes (ATR, ATM, BRCA1, BRCA2 and ERCC1).
  
  
  CONCLUSIONS
  Our findings suggest that the cisplatin-DNA adduct level is the most important determinant of cisplatin sensitivity in HNSCC cells. Imaging with radio-labeled cisplatin might have major associations with outcome.
authors.affiliation: Department of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands. rh.brakenhoff@vumc.nl
authors.forename: Sanne R
authors.initials: SR
authors.lastname: Martens-de Kemp
authors.forename: Simone U
authors.initials: SU
authors.lastname: Dalm
authors.forename: Fiona M J
authors.initials: FM
authors.lastname: Wijnolts
authors.forename: Arjen
authors.initials: A
authors.lastname: Brink
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Honeywell
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Boudewijn J M
authors.initials: BJ
authors.lastname: Braakhuis
authors.forename: Ruud H
authors.initials: RH
authors.lastname: Brakenhoff
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D018736:DNA Adducts / Q000378:metabolism / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D009154:Mutation / Q000235:genetics; D010984:Platinum / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D018709:Statistics, Nonparametric; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018736:DNA Adducts; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C057270:cisplatin-DNA adduct; D010984:Platinum; D002945:Cisplatin