Evaluation of Quinidine Effect on the Antitumor Activity of Adriamycin and Mitoxantrone in Adriamycin-Sensitive and -Resistant P388 Leukemia Cells

Abstract

Utilizing the P388 murine leukemia cells sensitive (P388/S) and resistant (P388/ADR) to Adriamycin (ADR), we evaluated the effect of quinidine, an anti-arrhythmic agent, on the cytotoxic activity of ADR and Mitoxantrone (MITO), both in vitro as well as in vivo. Quinidine enhanced the cytotoxicity of both ADR and MITO in P388/S and P388/ADR cells, as assessed by the decrease in color intensity of formazan crystal in the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. A dose dependent inhibition of 3H-thymidine and 3H-uridine incorporation was observed when the P388/S and P388/ADR cells were exposed to quinidine alone. A non-toxic concentration of quinidine (5 microM) enhanced the DNA biosynthesis inhibition induced by ADR (55 to 65%) and MITO (37 to 44%) in P388/ADR cells, indicating reversal of resistance, while in P388/S cells only a minimal increase in DNA biosynthesis inhibition was observed. The combination of quinidine at doses of 50 to 100 mg/kg significantly potentiated the antitumor activity of ADR and MITO in P388/ADR bearing mice, whereas the potentiation of ADR and MITO antitumor response was lower in P388/S bearing mice. Quinidine increased the cellular levels of ADR by 53 to 126% in P388/ADR cells in vitro, but failed to indicate such elevated levels of cellular ADR in P388/S cells. This enhanced intracellular accumulation of ADR in P388/ADR cells, explains the therapeutic efficacy of ADR and MITO in P388/ADR, both in vitro as well as in vivo. Results suggest the efficacy of quinidine to ameliorate the antitumor effects of ADR and MITO in drug resistant tumor cells.

Amelioration of Doxorubicin Resistance by Pentoxifylline in Human Chronic Myeloid Leukemia Cells In Vitro

“…The response to 1.0 and 10.0 nM PTX was very low, PTX at IOOjuM concentration was chosen for the subsequent studies. Sensitization of CML cells with PTX and DOX gave synergistic effect of DNA biosynthesis inhibition in 9 samples (sample numbers 1, 3,5,7,8,9,10,13,16) (19,20) and altered rheological properties of blood cells (21). Multiple drug resistant nature of tumor cell is associated with a decreased drug accumulation and an ATP-dependent active efflux of the drugs (22,23).…”