title: Increased sensitivity to platinum drugs of cancer cells with acquired resistance to trabectedin.
abstract: BACKGROUND
  In order to investigate the mechanisms of acquired resistance to trabectedin, trabectedin-resistant human myxoid liposarcoma (402-91/T) and ovarian carcinoma (A2780/T) cell lines were derived and characterised in vitro and in vivo.
  
  
  METHODS
  Resistant cell lines were obtained by repeated exposures to trabectedin. Characterisation was performed by evaluating drug sensitivity, cell cycle perturbations, DNA damage and DNA repair protein expression. In vivo experiments were performed on A2780 and A2780/T xenografts.
  
  
  RESULTS
  402-91/T and A2780/T cells were six-fold resistant to trabectedin compared with parental cells. Resistant cells were found to be hypersensitive to UV light and did not express specific proteins involved in the nucleotide excision repair (NER) pathway: XPF and ERCC1 in 402-91/T and XPG in A2780/T. NER deficiency in trabectedin-resistant cells was associated with the absence of a G2/M arrest induced by trabectedin and with enhanced sensitivity (two-fold) to platinum drugs. In A2780/T, this collateral sensitivity, confirmed in vivo, was associated with an increased formation of DNA interstrand crosslinks.
  
  
  CONCLUSIONS
  Our finding that resistance to trabectedin is associated with the loss of NER function, with a consequent increased sensitivity to platinum drugs, provides the rational for sequential use of these drugs in patients who have acquired resistance to trabectedin.
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Colmegna
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Uboldi
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Frapolli
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy.
authors.forename: S A
authors.initials: SA
authors.lastname: Licandro
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Panini
authors.affiliation: Department of Research and Development (R&D), PharmaMar S.A., Colmenar Viejo, Madrid 28770, Spain.
authors.forename: C M
authors.initials: CM
authors.lastname: Galmarini
authors.affiliation: Department of Research and Development (R&D), PharmaMar S.A., Colmenar Viejo, Madrid 28770, Spain.
authors.forename: Nadia
authors.initials: N
authors.lastname: Badri
authors.affiliation: Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: V J
authors.initials: VJ
authors.lastname: Spanswick
authors.affiliation: Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Bingham
authors.affiliation: Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kiakos
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Erba
authors.affiliation: Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Hartley
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D004149:Dioxoles / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004149:Dioxoles; C468783:H2AX protein, human; D006657:Histones; D009944:Organoplatinum Compounds; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin