Friche E, Jensen P B, Sehested M, Demant E J, Nissen N N
Department of Medicine, Finsen Institute-Rigshospitalet, Copenhagen, Denmark.
Cancer Commun. 1990;2(9):297-303.
Cremophor EL (polyoxyethylene castor oil) and Tween 80, used as solvents for cyclosporin A and VP-16, respectively, were found to reverse the multidrug resistant (MDR) phenotype. In daunorubicin (DNR) resistant Ehrlich ascites tumor cells (EHR2/DNR+), both solvents at percentages of 0.01% (v/v) enhanced DNR accumulation to sensitive levels. Cremophor EL and Tween 80 did not influence DNR accumulation in drug-sensitive cells (EHR2). The concentration of cyclosporin A alone that enhanced DNR accumulation in EHR2/DNR+ cells to sensitive levels was 5 micrograms/mL whereas 0.2 micrograms/mL of cyclosporin A dissolved in 0.001% (v/v) Cremophor EL enhanced DNR accumulation to sensitive levels, thus indicating synergy between Cremophor EL and cyclosporin A. Cyclosporin A had a negligible effect on DNR accumulation in the drug-sensitive cells. In clonogenic assays, the LD10 of DNR was 1 microM in EHR2/DNR+ cells. Combining 1 microM DNR with non-toxic amounts of Cremophor EL (0.001% and 0.002%, v/v) potentiated the cytotoxicity of DNR and resulted in a cell kill of 77% and 86%, respectively, in the resistant cells. In non-toxic amounts, CrEL and Tween 80 acted synergistically with reduced concentrations of verapamil, resulting in DNR accumulation approaching close to the sensitive level. Azidopine photoaffinity labeling of P-glycoprotein in plasma membrane vesicles from EHR2/DNR+ cells was inhibited 100% and 80%, by 0.003% (v/v) Cremophor EL or Tween 80, respectively. These data permit the conclusion that non-toxic amounts of CrEL and Tween 80 modulated DNR resistance by raising intracellular DNR levels, due to their abilities to bind to the plasma membrane P-glycoprotein.
分别用作环孢素A和依托泊苷（VP - 16）溶剂的聚氧乙烯蓖麻油（Cremophor EL）和吐温80，被发现可逆转多药耐药（MDR）表型。在耐柔红霉素（DNR）的艾氏腹水瘤细胞（EHR2/DNR+）中，两种溶剂浓度为0.01%（v/v）时均可将DNR蓄积提高至敏感水平。聚氧乙烯蓖麻油（Cremophor EL）和吐温80对药物敏感细胞（EHR2）中的DNR蓄积没有影响。单独使用时，能将EHR2/DNR+细胞中DNR蓄积提高至敏感水平的环孢素A浓度为5微克/毫升，而溶解于0.001%（v/v）聚氧乙烯蓖麻油（Cremophor EL）中的0.2微克/毫升环孢素A即可将DNR蓄积提高至敏感水平，这表明聚氧乙烯蓖麻油（Cremophor EL）与环孢素A之间存在协同作用。环孢素A对药物敏感细胞中的DNR蓄积影响可忽略不计。在克隆形成试验中，EHR2/DNR+细胞中DNR的LD10为1微摩尔。将1微摩尔DNR与无毒量的聚氧乙烯蓖麻油（Cremophor EL）（0.001%和0.002%，v/v）联合使用可增强DNR的细胞毒性，耐药细胞的细胞杀伤率分别达到77%和86%。在无毒量下，聚氧乙烯蓖麻油（CrEL）和吐温80与降低浓度的维拉帕米协同作用，使DNR蓄积接近敏感水平。0.003%（v/v）的聚氧乙烯蓖麻油（Cremophor EL）或吐温80分别对EHR2/DNR+细胞质膜囊泡中P - 糖蛋白的叠氮平光亲和标记抑制率为100%和80%。这些数据表明，无毒量的聚氧乙烯蓖麻油（CrEL）和吐温80通过提高细胞内DNR水平来调节DNR耐药性，这归因于它们与质膜P - 糖蛋白结合的能力。
