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 7 Adr cells and drug
sensitive MCF 7 WT 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 μmol·L -1 ) and 3 6 fold in
MCF 7 Adr cells by Ver (6 μmol·L -1 ) , but not in MCF
7 WT cells (Ver 6 μmol·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) 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 cells compared to that in the absence of Ver, that
was similar to that in MCF 7 WT cells, while the retention was
augmented by Ver in MCF 7 Adr 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.