Evaluation of quinidine effect on the antitumor activity of adriamycin and mitoxantrone in adriamycin-sensitive and -resistant P388 leukemia cells.

H Parekh, M Chitnis
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引用次数: 8

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.

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奎尼丁对阿霉素敏感耐药P388白血病细胞阿霉素和米托蒽醌抗肿瘤活性的影响。
利用对阿霉素(ADR)敏感(P388/S)和耐药(P388/ADR)的P388小鼠白血病细胞,在体外和体内研究了抗心律失常药物奎尼丁对ADR和米托蒽醌(MITO)细胞毒活性的影响。通过MTT(3-[4,5-二甲基噻唑-2-基]-2,5二苯基溴化四氮唑)测定,奎尼丁增强了P388/S和P388/ADR细胞的ADR和MITO的细胞毒性。当P388/S和P388/ADR细胞单独暴露于奎尼丁时,观察到3h -胸腺嘧啶和3h -尿嘧啶掺入的剂量依赖性抑制。在P388/ADR细胞中,无毒浓度的奎尼丁(5 μ m)可增强ADR诱导的DNA合成抑制(55 ~ 65%)和MITO诱导的DNA合成抑制(37 ~ 44%),表明耐药性逆转,而在P388/S细胞中,DNA合成抑制仅轻微增加。50 ~ 100 mg/kg剂量的奎尼丁联合用药可显著增强P388/ADR小鼠的ADR和MITO抗肿瘤活性,而P388/S小鼠的ADR和MITO抗肿瘤活性增强较弱。在体外实验中,奎尼丁可使P388/ADR细胞的ADR水平升高53 ~ 126%,但在P388/S细胞中未显示出这种升高。这种ADR在P388/ADR细胞内的增强积累解释了ADR和MITO在P388/ADR中的治疗效果,无论是在体外还是在体内。结果提示奎尼丁能改善耐药肿瘤细胞中ADR和MITO的抗肿瘤作用。
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