Reversal of multidrug resistance by surfactants.
Reversal of multidrug resistance by surfactants.
复制标题
DOI：
10.1038/bjc.1992.217
复制
发表时间：
1992-07
影响因子：
8.8
通讯作者：
Sawyer, W H
中科院分区：
文献类型：
--
作者：
Woodcock, D M;Linsenmeyer, M E;Chojnowski, G;Kriegler, A B;Nink, V;Webster, L K;Sawyer, W H
Cremophor EL是一种非生物活性的增溶剂，已被证明可以逆转多药耐药（MDR）。使用流式细胞术评估柔红霉素（DNR）的平衡细胞内水平，我们发现，其他八种表面活性剂也将逆转MDR。所有的活性洗涤剂都含有聚乙氧基化部分，但它们的疏水组分没有相似之处。三个聚乙氧基化的表面活性剂，表现出最低的毒性，Cremophor，吐温80和Solutol HS 15的性能进行了更详细的检查。逆转DNR排斥所需的吐温80和Solutol的浓度比Cremophor低10倍。然而，当浓度大于或等于1：10（2）的前两种表面活性剂导致细胞破裂时，即使1：10的Cremophor也不裂解细胞。关于Cremophor对正常和MDR细胞类型中DNR吸收和外排的影响的研究表明，Cremophor主要通过锁定细胞的快速外排来增加细胞内DNR。这种药物外排的阻断可能是由Cremophor诱导的细胞膜流动性的实质性改变介导的，如膜探针的荧光各向异性降低所示。与这些数据一致，阿霉素加Cremophor共注射到携带多药耐药P388可移植肿瘤的小鼠中，与单独阿霉素治疗相比，显著增加了小鼠的存活时间。
Cremophor EL, a pharmacologically inactive solubilising agent, has been shown to reverse multidrug resistance (MDR). Using flow cytometric evaluation of equilibrium intracellular levels of daunorubicin (DNR), we found that eight other surface active agents will also reverse MDR. All the active detergents contain polyethoxylated moieties but have no similarities in their hydrophobic components. The properties of three polyethoxylated surfactants that showed the lowest toxicities, Cremophor, Tween 80 and Solutol HS15, were examined in more detail. The concentrations of Tween 80 and Solutol required to reverse DNR exclusion were 10-fold lower than for Cremophor. However while concentrations greater than or equal to 1:10(2) of the former two surfactants resulted in breakdown of cells, even 1:10 of Cremophor did not lyse cells. Studies of the effects of Cremophor on the uptake and efflux of DNR in normal and MDR cell types showed that Cremophor increases intracellular DNR primarily by locking the rapid efflux from the cells. This blockage of drug efflux may be mediated by a substantial alteration in the fluidity of cell membranes induced by Cremophor, as shown by decreased fluorescence anisotropy of a membrane probe. Consistent with these data, coinjection of adriamycin plus Cremophor into mice carrying a multidrug resistant P388 transplantable tumour significantly increased the survival time of the mice compared with adriamycin treatment alone.