EVIDENCE FOR REVERSAL OF MULTIDRUG-RESISTANCE BY QUININE IN LR73 CELLS WITHOUT ALTERATION OF NUCLEAR PIRARUBICIN UPTAKE AND DOWN-REGULATIONOF MDR1 GENE-EXPRESSION

Confocal laser microspectrofluorometry was used to investigate restora tion of nuclear pirarubicin (THP-DOX) accumulation and sensitivity by verapamil, quinine and S9788 in 2 variants of the Chinese hamster ovar y cell lines LR73, selected for resistance to doxorubicin (LR73D) or t ransfected with the mdr1 gene (LR73R), The 2 resistant cell lines pres ent a multidrug-resistance phenotype (MDR). Verapamil and S9788, which interact with P-glycoprotein (P-gp), were able to restore nuclear THP -DOX accumulation in LR73R and LR73D cells to a level equivalent to th at in sensitive cells. On the other hand, quinine was unable to increa se nuclear THP-DOX accumulation significantly even at a concentration of 50 mu M. All modulators completely restored THP-DOX sensitivity in resistant cell lines. Our results also show that verapamil and S9788 a llow high nuclear drug accumulation, whereas quinine did not affect nu clear accumulation. The effect of quinine on the mdr1 gene expression was determined by the use of reverse transcription coupled with polyme rase chain reaction. After a 2 hr treatment with 20 mu M of quinine, m dr1 gene expression increased slightly. (C) 1997 Wiley-Liss, Inc.