title: Cisplatin resistance induced in germ cell tumour cells is due to reduced susceptibility towards cell death but not to altered DNA damage induction or repair.
abstract: To identify factors involved in cisplatin (CDDP) resistance of germ cell tumours (GCTs), we exposed NTERA-2 cells, and the platinum-adapted subline NTERA-2R to CDDP and compared their response. While both cell lines showed comparable proliferation, NTERA-2R cells were clearly more resistant to the drug than the parental NTERA-2 cell line. Interestingly, the two lines showed identical extent of DNA adduct formation and elimination, indicating that neither changes in CDDP uptake, nor altered drug efflux, DNA binding, or repair caused the difference in resistance. Similarly, no difference occurred in the time-course of γH2AX formation, which was not linked to 53BP1 accumulation. In contrast, NTERA-2R cells showed a more pronounced dose-dependent S phase delay, a transient G(2)/M-block, and subsequent release into immediate cell death. We thus conclude that the enhanced resistance against CDDP is linked to reduced susceptibility to cell death rather than to an altered DNA adduct formation or adduct removal.
authors.affiliation: Institute of Pharmacy, Hamburg University, Bundesstr. 45, 20146 Hamburg, Germany.
authors.forename: Annabelle E
authors.initials: AE
authors.lastname: Fenske
authors.forename: Stephanie
authors.initials: S
authors.lastname: Glaesener
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Juergen
authors.initials: J
authors.lastname: Thomale
authors.forename: Jochen
authors.initials: J
authors.lastname: Dahm-Daphi
authors.forename: Friedemann
authors.initials: F
authors.lastname: Honecker
authors.forename: Dorothee C
authors.initials: DC
authors.lastname: Dartsch
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics / Q000473:pathology*; D010718:Phosphatidylserines / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics / Q000473:pathology*; D013997:Time Factors; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D010718:Phosphatidylserines; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D002945:Cisplatin