The correlation between vincristine cellular pharmacokinetics and its biological action was analyzed in L5178Y cells and in a multidrug resistant subline (VCR/G40) at the nM drug concentration range attained in serum during the clinical use of the drug. The reduced rate of drug influx and the higher drug efflux measured in VCR/G40 cells justify the lower drug accumulation characterized in these cells compared to the parental cells. Nevertheless this does not seem to be the sole reason accounting for the resistance expression since similar cytotoxic effects of vincristine on both cell lines were only attained when the intracellular drug concentration was ten times higher in resistant than in parental cells. Bearing in mind that the drug-binding kinetics have not been modified during the resistance development, our results indicate that some vincristine accumulated by resistant cells may be compartmentalized into these cells before its interaction with microtubules.
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