Comparative uptake, retention and action of vincristine, vinblastine and vindesine on murine leukaemic lymphoblasts sensitive and resistant to vincristine

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Abstract
The uptake and retention of vincristine (VCR), vinblastine (VBL) and vindesine (VDS) were evaluated comparatively with respect to their cytotoxic action on a murine lyphoblastic leukaemia (L5178Y). The same parameters were measured on a derived subline of cells resistant to VCR (L5178Y/r) in order to determine whether the different degree of resistance to each alkaloid correlates with the amount of drug associated with the cells. VCR was the most active on L5178Y cells (IC50 = 5.8.times.10-9M) while the activity of VBL and that of VDS were similar (IC50 4.4.times.10-8M and 3.5.times.10-8M, respectively). Nevertheless, a considerably larger amount of VBL was taken up by the cells compared to VDS, although there were no significant differences in their cytotoxic action. The VCR resistant cell line also expressed resistance to VDS, whose IC50 was increased by a factor of 11.4, but not to VBL. However, the uptake and retention of the three alkaloids were similarly reduced in L5178Y/r cells regardless of the degree of resistance expressed. Although a decreased drug uptake and/or retention by the cells provides an explanation for the resistance to vinca alkaloids, they do not seem to be the only factors accounting for the resistance shown by the cell line which we have isolated. The results seem to indicate that part of the VBL taken up by the cells is not used to induce the cytotoxic effect, but is diverted to some cellular compartment(s) or rate controlling process(es) which are different from the target that mediates its cytotoxic action.