EFFECT OF QUININE ON THE MULTIDRUG-RESISTANCE AND INTRACELLULAR-DISTRIBUTION OF THP-DOX IN LR73 TUMOR-CELLS - COMPARATIVE-STUDY WITH VERAPAMIL AND S9788 BY CONFOCAL LASER MICROSPECTROFLUOROMETRY

Effectiveness of chemotherapeutic treatment is limited by multidrug re sistance (MDR) phenomenon mediated by the overexpression of P-glycopro tein 170 termed Pgp which serves as an efflux pump removing several ty pes of cytostatic drugs from the MDR cells. Several small molecules, f requently lipophilic cations and weak bases, are able to reverse in vi tro this resistance. Several studies have shown that MDR modulators in teract with Pgp. However, some molecules do nor interact with Pgp but are able to completely restore drug sensitivity (e.g., quinine). Benni s et al. (1995) have shown recently that in contrast to verapamil and S9788, quinine increases nuclear doxorubicin accumulation without modi fying its intracellular concentration. From this work the authors conc luded that quinine has essentially intracellular targets involved in d rug distribution (cytoplasm to nucleus) from sequestration compartment s. Their results have been obtained using spectrofluorometry on cell p opulations and fluorescence microscopy. By using confocal laser micros pectrofluorometry, we investigated restoration of nuclear THP-DOX accu mulation and sensitivity by verapamil, S9788 and quinine in 2 variants of the Chinese hamster ovary cells LR73, selected for resistance to d oxorubicin (LR73D) and transfected with the mdr1 gene (LR73R), as well as in the sensitive ones (LR73S). Results show that verapamil and S97 88 were able to restore THP-DOX sensitivity in resistant cells by incr easing nuclear THP-DOX accumulation. This restoration is the consequen ce of Pgp inhibition and redistribution of the anticancer drug from th e cytoplasm to nucleus. Quinine, in contrast restores the sensitivity of MDR cells to THP-DOX and decreased their resistance index, but has no effect on THP-DOX nuclear accumulation. This suggests that quinine modifies the molecular environment of anthracyclines and/or their bind ing to cytoplasmic targets involved in another mechanism of anthracycl ine action.