Parekh H K, Advani S H, Chitnis M P
Cellular Chemotherapy Unit, Tata Memorial Center, Parel, Bombay, India.
Neoplasma. 1990;37(6):717-25.
The inherent, insensitive nature of human chronic myeloid leukemia (CML) cells to antiproliferative effects of adriamycin (ADR) disallows its utility in the clinics. Efforts were directed towards sensitizing CML cells to ADR and mitoxanthrone (MITO) cytotoxicity by employing quinidine, an antiarhythmic agent. Inhibition of radiolabeled thymidine incorporation into DNA was used as a measure of drug activity. A dose-dependent inhibition of DNA biosynthesis was observed with increasing concentrations of ADR (0.1 to 100 micrograms/ml), MITO (0.05 to 5 micrograms/ml) and quinidine (0.1 to 50 mumol/l). When the CML cells were exposed to quinidine and ADR/MITO simultaneously, the observed enhancement in the antiproliferative activity of the anticancer drug was markedly less as compared to the inhibition of DNA synthesis observed in CML cells pretreated with quinidine for 1 h prior to exposure to the cytotoxic drugs. Pretreatment of CML cells with quinidine resulted in a significantly (p less than 0.001) increased synergistic inhibition of DNA biosynthesis which was completely irreversible. Results highlight the utility of quinidine as a drug response modulator in a schedule-dependent manner to potentiate the cytotoxicity of ADR and MITO and warrants further studies into a possible role of quinidine to increase the chemotherapeutic efficacy of antineoplastic drugs in the clinics.
人类慢性粒细胞白血病（CML）细胞对阿霉素（ADR）的抗增殖作用具有内在的不敏感性，这使得它在临床上无法应用。研究致力于通过使用抗心律失常药物奎尼丁，使CML细胞对ADR和米托蒽醌（MITO）的细胞毒性敏感。将放射性标记的胸腺嘧啶核苷掺入DNA的抑制作用用作药物活性的指标。随着ADR（0.1至100微克/毫升）、MITO（0.05至5微克/毫升）和奎尼丁（0.1至50微摩尔/升）浓度的增加，观察到DNA生物合成呈剂量依赖性抑制。当CML细胞同时暴露于奎尼丁和ADR/MITO时，与在暴露于细胞毒性药物前先用奎尼丁预处理1小时的CML细胞中观察到的DNA合成抑制相比，观察到的抗癌药物抗增殖活性的增强明显较小。用奎尼丁预处理CML细胞导致DNA生物合成的协同抑制显著（p小于0.001）增加，且完全不可逆。结果突出了奎尼丁作为一种药物反应调节剂按时间依赖性方式增强ADR和MITO细胞毒性的效用，并值得进一步研究奎尼丁在临床上增加抗肿瘤药物化疗疗效的可能作用。
