MODULATION OF DOXORUBICIN RESISTANCE IN P388 ADR CELLS BY RO44-5912, A TIAPAMIL DERIVATIVE/

We describe here investigations into the ability of a tiapamil derivat ive, Ro44-5912 to overcome multidrug resistance (MDR) in doxorubicin ( ADR)-resistant murine leukemic P388 cells. This compound has the formu la: C27H39NO4S2.1:2C(6)H(8)O(6), a M. W. of 858 and is structurally si milar to verapamil, an established inhibitor of P-glycoprotein (PGP). We have compared the MDR modulating properties of Ro44-5912 with verap amil in P388ADR cells. Doxorubicin concentration required to. achieve 50% inhibition of growth (IC50) for P388ADR cells was found to be 24 m u M. In contrast, treatment of P388ADR cells with Doxorubicin and 3 mu M verapamil decreased the IC50 value to 2.5 mu M. A further decrease was observed with 3 mu M Ro44-5912 treatment where an IC50 value of 1. 1 mu M was obtained. Doxorubicin accumulation was also determined by f low cytometry in order to determine whether the increased levels of ch emosensitivity observed for Ro44-5912 were reflected by increased cell ular drug uptake. The results revealed that Ro44-5912 at equivalent co ncentration, increased doxorubicin accumulation in P388ADR cells beyon d that obtained with verapamil whereas no effects were seen with the p arental P388 cells. The effect of Ro44-5912 on the binding of C219 mon oclonal antibody to PGP in MDR cells was also studied and found not to decrease C219 expression on P388ADR cells.