title: Resistance mechanisms following cisplatin and oxaliplatin treatment of the human teratocarcinoma cell line 2102EP.
abstract: BACKGROUND
  Oxaliplatin and cisplatin are widely used in cancer chemotherapy, however, their clinical efficiency is often limited by the development of resistance.
  
  
  METHODS
  We examined different mechanisms of resistance in the human teratocarcinoma cell line 2102EP following exposure to cisplatin or oxaliplatin. Cells were exposed ten times with IC90-doses of 30 microM cisplatin and 50 microM oxaliplatin, respectively. Different cell clones were tested for expression of resistance using the SRB-assay. Moreover, resistance mechanisms in terms of drug uptake, platinum-adduct formation, GSH metabolism, DNA mismatch repair and p53 protein function were investigated.
  
  
  RESULTS
  Three cisplatin cell clones with significant resistance factors of 2.0 to 2.6 were found. Two oxaliplatin cell clones showed only weak resistance, with resistance factors of 1.6 and 1.7, respectively. In all three cisplatin-exposed cell clones a decreased cellular uptake of cisplatin was found. Furthermore, mechanisms of DNA damage tolerance may also play a role in the development of cisplatin-resistance in these cells. However, only two cell clones showed a decreased level of platinum-DNA-adducts. An increased DNA-repair of platinum-DNA adducts was not seen. In addition, no differences in expression of mismatch-repair proteins MSH2 and MLH1, tumor suppressor protein p53, or glutathione metabolism were found. However, significant resistance mechanisms for the observed oxaliplatin resistance could not be identified, although in one oxaliplatin-exposed cell clone, there was some evidence that a decreased cellular uptake of oxaliplatin may contribute to the observed low level resistance.
  
  
  CONCLUSIONS
  The data add weight to the hypothesis that resistance mechanisms following oxaliplatin exposure may be similar to cisplatin. The precise mechanisms of resistance in the oxaliplatin-resistant cell clones are still not fully understood and current studies are underway to further eluciate this finding.
authors.affiliation: Department of Medical Oncology and Hematology, Martin-Luther-University Halle/Saale, Ernst-Grube-Str. 40, D-06120 Halle/Saale, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Rennicke
authors.forename: Wieland
authors.initials: W
authors.lastname: Voigt
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.forename: Angelika
authors.initials: A
authors.lastname: Fruehauf
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmoll
authors.forename: Claus
authors.initials: C
authors.lastname: Beyer
authors.forename: Wolfram
authors.initials: W
authors.lastname: Dempke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D018736:DNA Adducts / Q000096:biosynthesis / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000096:biosynthesis; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077150:Oxaliplatin; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D018243:Teratocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C057270:cisplatin-DNA adduct; D000077150:Oxaliplatin; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D005978:Glutathione; D002945:Cisplatin