Doxorubicin cellular pharmacokinetics plays no role in chemosensitizing effect of verapamil on Swiss-3T3 cells.
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.