title: Markedly diminished drug resistance-inducing properties of vinflunine (20',20'-difluoro-3',4'-dihydrovinorelbine) relative to vinorelbine, identified in murine and human tumour cells in vivo and in vitro.
abstract: OBJECTIVE
  Vinflunine (VFL) is a novel Vinca alkaloid with markedly superior experimental in vivo antitumour activity to its parent molecule, vinorelbine (Navelbine, NVB), against a panel of murine and human tumours. The aim of this study was to establish whether there are differences in the rate and extent of development of resistance, both in vivo and in vitro, to these two newer Vinca alkaloids under identical selection conditions.
  
  
  METHODS
  Using P388 leukaemia cells in vivo, it was evident that VFL induced drug resistance far less readily than NVB, as shown by the number of passages required to select for total resistance. Under in vitro conditions, using A549 human lung carcinoma cells, it was also clearly shown by drug sensitivity determinations that VFL was a less-potent inducer of drug resistance than NVB. Resistance resulting from either in vivo or in vitro selection was associated with a classic multidrug resistance profile. Further characterization of the drug-resistance phenotype of the most highly resistant A549 sublines showed that the level of total beta-tubulin expression appeared to be modified exclusively in the NVB-resistant cells.
  
  
  CONCLUSIONS
  The clear demonstration that resistance to VFL developed far less readily than resistance to NVB both in vivo and in vitro may have potential clinical implications.
authors.affiliation: Division de Cancérologie Expérimentale I, Centre de Recherche Pierre Fabre, Castres, France. chantal.etievant@pierre-fabre.com
authors.forename: C
authors.initials: C
authors.lastname: Etiévant
authors.forename: A
authors.initials: A
authors.lastname: Kruczynski
authors.forename: J M
authors.initials: JM
authors.lastname: Barret
authors.forename: A S
authors.initials: AS
authors.lastname: Tait
authors.forename: M
authors.initials: M
authors.lastname: Kavallaris
authors.forename: B T
authors.initials: BT
authors.lastname: Hill
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D014404:Tubulin / Q000032:analysis; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; C111217:vinflunine; D014747:Vinblastine; D000077235:Vinorelbine