Effect of PSC 833 on the cytotoxicity and pharmacodynamics of mitoxantrone in multidrug-resistant K562 cells.
We examined the effect of PSC 833, a nonimmunosuppressive cyclosporin analogue, on the cytotoxicity, accumulation and retention of an anthraquinone antileukemia drug mitoxantrone (MIT). This was done in P-glycoprotein (PGP)-overexpressing multidrug-resistant K562/D1-9 cells and compared with the effect 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 was 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 was 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 microM PSC 833, which is a clinically achievable plasma concentration. These results suggest that the combination of PSC 833 with MIT could be a promising treatment in reversing PGP-mediated MDR in leukemia patients.
Fukushima
T
T
First Department of Internal Medicine, Fukui Medical University, Matsuoka, Japan. tfukus@fmsrsa.fukui-med.ac.jp
Yamashita
T
T
Takemura
H
H
Suto
H
H
Kishi
S
S
Urasaki
Y
Y
Ueda
T
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D006801:Humans; D020014:K562 Cells / Q000187:drug effects* / Q000473:pathology; D008942:Mitoxantrone / Q000494:pharmacology*
D000970:Antineoplastic Agents; D003524:Cyclosporins; D008942:Mitoxantrone; C070272:valspodar