Aim: To find whether or not the doxorubicin (Dox) cellular pharmacokinetics plays a role in chemosensitizing effect of verapamil (Ver) on drug sensitive cells.
Methods: Cytotoxicity and cellular Dox contents (during accumulation and retention periods) were measured in the absence and presence of verapamil in Swiss-3T3 cells and compared with those in multidrug resistant (MDR) MCF-7Adr cells and drug sensitive MCF-7WT cells. mdr-1 mRNA expression in Swiss-3T3 cells was analyzed.
Result: Dox cytotoxicity was enhanced 2.0-fold in Swiss-3T3 cells by Ver (3 mumol.L-1) and 3.6-fold in MCF-7Adr cells by Ver (6 mumol.L-1), but not in MCF-7WT cells (Ver 6 mumol.L-1). Cellular accumulation of equi-effective concentrations of Dox increased at 6-h incubation in the presence of Ver in Swiss-3T3 (1.5-fold)i and MCF-7WT cells (2.1-fold) but decreased rapidly in MCF-7Adr cells by 20% to 50% compared to that in the absence of Ver. Cellular retention of Dox decreased after 10-min increase in the presence of Ver in Swiss-3T3 cells compared to that in the absence of Ver, that was similar to that in MCF-7WT cells, while the retention was augmented by Ver in MCF-7Adr cells. Slot blot analysis of RNA revealed no mdr-1 gene expression in Swiss-3T3 cells.
Conclusion: Changes in cellular accumulation and retention of Dox did not account for the chemosensitizing effect of Ver on Swiss-3T3 cells.