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 pharmacokin etics plays a role in chemosensitizing effect of verapamil (Ver) on dr ug sensitive cells. METHODS: Cytotoxicity and cellular Dox contents (d uring 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-7(Adr) cells and drug sensitive MCF-7 (WT) cells, mdr-1 mRNA expression in Swiss-3T3 cells was analyzed. RES ULT: Dox cytotoxicity was enhanced 2.0-fold in Swiss-3T3 cells by Ver (3 mu mol . L(-1)) and 3.6-fold in MCF-7(Adr) cells by Ver (6 mu mol . L(-1)), but not in MCF-7(WT) cells (Ver 6 mu mol . L(-1)). Cellular a ccumulation of equi-effective concentrations of Dox increased at 6-h i ncubation in the presence of Ver in Swiss-3T3 (1.5-fold) and MCF-7(WT) cells (2.1-fold) but decreased rapidly in MCF-7(Adr) 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 ce lls compared to that in the absence of Ver, that was similar to that i n MCF-7(WT) cells, while the retention was augmented by Ver in MCF-7(A dr) 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 Ve r on Swiss-3T3 cells.