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

Purpose: Vinflunine (VFL) is a novel Vinca alkaloid with markedly superior experimental in vivo antitumour activity to its parent molecule, vinorelbin e (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 tw o newer Vinca alkaloids under identical selection conditions. Methods: Usin g P388 leukaemia cells in vivo. it was evident that VFL induced drug resist ance far less readily than NVB, as shown by the number of passages required to select for total resistance. Under in vitro conditions. using A549 huma n lung carcinoma cells, it was also clearly shown by drug sensitivity deter minations that VFL was a less-potent inducer of drug resistance than NVB. R esistance resulting from either in vivo or in vitro selection was associate d with a classic multidrug resistance profile. Further characterization of the drug-resistance phenotype of the most highly resistant A549 sublines sh owed that the level of total beta -tubulin expression appeared to be modifi ed exclusively in the NVB-resistant cells. Conclusion: The clear demonstrat ion that resistance to VFL developed far less readily than resistance to NV B both in vivo and in vitro may have potential clinical implications.