Effect of PSC 833 on the cytotoxicity and pharmacodynamics of mitoxantronein multidrug-resistant K562 cells

We examined the effect of PSC 833, a nonimmunosuppressive cyclosporin analo gue, on the cytotoxicity, accumulation and retention of an anthraquinone an tileukemia drug mitoxantrone (MIT). This was done in P-glycoprotein (PGP)-o verexpressing multidrug-resistant K562/D1-9 cells and compared with the eff ect of cyclosporin A (CsA). We also compared MIT with the effect of PSC 833 on the cytotoxicity of daunorubicin (DNR) and doxorubicin (DOX). While PSC 833 and CsA had no effect on the cytotoxicity, accumulation and retention of MIT in the parent K562 cells, PSC 833 and CsA restored accumulation and retention of MIT in K562/D1-9 cells dose-dependently. Consequently, there w as increased sensitivity of K562/D1-9 cells to MIT. The reversing activity of PSC 833 on the cytotoxicity of MIT was stronger than that of CsA, and wa s almost the same as the reversing activity of PSC 833 on the cytotoxicity of DNR and DOX. The resistance index of MIT decreased from 43.9-fold to 2.8 -fold by 0.4 mu M PSC 833, which is a clinically achievable plasma concentr ation. These results suggest that the combination of PSC 833 with MIT could be a promising treatment in reversing PGP-mediated MDR in leukemia patient s. (C) 2000 Elsevier Science Ltd. All rights reserved.