Sufficient levels of quinine in the serum circumvent the multidrug resistance of the human leukemic cell line K562/ADM
Sufficient levels of quinine in the serum circumvent the multidrug resistance of the human leukemic cell line K562/ADM
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DOI：
10.1002/1097-0142(19911015)68:8
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发表时间：
1991-10
期刊：
影响因子：
6.2
通讯作者：
E. Solary;I. Velay;B. Chauffert;J. Bidan;D. Caillot;M. Dumas;H. Guy
中科院分区：
文献类型：
--
作者：
E. Solary;I. Velay;B. Chauffert;J. Bidan;D. Caillot;M. Dumas;H. Guy
包括维拉帕米、奎尼丁、环孢素a和胺碘酮在内的多种药物已经在体外逆转了多药耐药（MDR）。这些药物的毒性使其无法在血清中达到足够的水平，从而在体内有效地规避耐多药。这组作者先前证明了广泛使用的抗疟药奎宁能够逆转大鼠结肠癌细胞对蒽环类药物的原发性耐药性。在本报告中，甲酸奎宁在逆转明确定义的MDR人白血病细胞系K562/ADM（阿霉素，Adria Laboratories, Columbus， OH）耐药方面的效率得到了证实。在培养基中，当奎宁和维拉帕米以相同的浓度使用时，奎宁在增加细胞毒性和增加ADM摄取方面的效果略低于维拉帕米。在K562/ADM细胞中，逆转MDR需要5 μg/ml的无毒剂量。在接受甲酸奎宁连续静脉输注的患者中，血清奎宁水平与血清增加K562/ADM细胞对ADM摄取的能力之间存在显著相关性（r = 0.84）。当以常规剂量（25 ~ 30 mg/kg/d）给药时，血清中奎宁浓度持续达到8 μg/ml以上，且无严重副作用；耳噪音和眩晕是剂量限制的副作用。在这些浓度下，奎宁诱导K562/ADM细胞的ADM摄取增加一倍以上。药代动力学数据表明，在临床试验中，奎宁作为人类血液恶性肿瘤耐多药耐药调节剂的有效性应在使用抗癌药物前24至36小时给予。
Reversal of multidrug drug resistance (MDR) has been achieved in vitro by a variety of agents including verapamil, quinidine, cyclosporine A, and amiodarone. The toxicity of these agents precludes the achievement of sufficient levels in the serum to circumvent efficiently the MDR in vivo. The authors previously demonstrated that quinine, the widely used antimalarial agent, is able to reverse primary resistance of rat colon cancer cells to anthracyclines. In this report, the efficiency of quinine formiate in reversing the doxorubicin (ADM) (Adriamycin, Adria Laboratories, Columbus, OH) resistance of the well‐defined MDR human leukemic cell line K562/ADM was demonstrated. In culture medium, quinine is slightly less effective than verapamil in increasing the cytotoxicity and uptake of ADM when both drugs are used at the same concentration. A nontoxic dose of 5 μg/ml is necessary to reverse the MDR in K562/ADM cells. In patients receiving quinine formiate in a continuous intravenous infusion, a significant correlation (r = 0.84) was found between the serum levels of quinine and the ability of sera to increase ADM uptake in K562/ADM cells. When quinine is administered at a conventional dose (25 to 30 mg/kg/d), serum levels consistently reach more than 8 μg/ml without severe side effects; ear noises and vertigo are the dose‐limiting side effects. At these concentrations, quinine induces a more than double increase in ADM uptake in K562/ADM cells. Pharmacokinetic data indicate that quinine should be administered 24 to 36 hours before anti‐cancer drugs in clinical trials that test its efficiency as a modifier of MDR in human hematologic malignant neoplasms.