INFLUENCE OF S9788, A NEW MODULATOR OF MULTIDRUG-RESISTANCE, ON THE CELLULAR ACCUMULATION AND SUBCELLULAR-DISTRIBUTION OF DAUNORUBICIN IN P-GLYCOPROTEIN-EXPRESSING MCF7 HUMAN BREAST ADENOCARCINOMA CELLS

A triazinoaminopiperidine derivative synthesized as a modulator of mul tidrug resistance, S9788, was investigated in the human breast adenoca rcinoma MCF7(DXR) cell line expressing P-glycoprotein. In addition to being less sensitive to daunorubicin, the resistant cell Line showed d ramatic alterations in the subcellular distribution of daunorubicin, a s observed via fluorescence microscopy and quantified via tritiated da unorubicin nuclear distribution analysis. Compared to verapamil and cy closporin A at 2 and 5 mu mol/liter, S9788 proved to be more potent in restoring the cellular accumulation and the subcellular distribution of daunorubicin in the resistant cells. Significant activity of S9788 was observed at 2 mu mol/liter, which is clinically achievable, and S9 788 restored the nuclear distribution of the drug to the level observe d in the parental sensitive cell line. Consequently, the restoration o f the cytotoxicity of daunorubicin by S9788 was nearly complete (>90%) at 2 mu mol/liter, whereas cyclosporin A reached this level of activi ty at 5 mu mol/liter, and verapamil was always less active at both con centrations. These results suggest that the modulation of multidrug re sistance by S9788 is not only related to the enhancement of the cellul ar accumulation but also especially by the restoration of the subcellu lar distribution of the drugs to their nuclear sites of action. (C) 19 95 Wiley-Liss, Inc.