Batrakova E V, Kabanov A V
Moscow Institute of Biotechnology, Inc., Russia.
Bioconjug Chem. 1996 Mar-Apr;7(2):209-16. doi: 10.1021/bc950093n.
The chemosensitizing effect of Pluronic P85 block copolymer were studied using two human ovarian carcinoma sublines: the glycoprotein P (P-gp) multidrug resistant (MDR) SKVLB cells and non-MDR SKOV3 cells. The dramatic increase (up to 700 times) in the daunorubicin cytotoxic activity was observed in the presence of 0.01% (22 microM) to 1% (2.2 mM) copolymer in the case of SKVLB cells. By contrast, the copolymer induced a less than 3-fold increase in the drug activity in SKOV3 cells. As a result, the MDR subline demonstrated much higher response ("hypersensitivity") to the daunorubicin/ Pluronic compared to that of the non-MDR cells. The copolymer increased the cytotoxic effects of other MDR type drugs (doxorubicin, epirubicin, vinblastine, and mitomycin C) by a factor of 20-1000 and non-MDR type drugs (methotrexate and cisplatin) by a factor of 2-5.5. The daunorubicin influx in the cytoplasm and nuclei of SKVLB cells was also increased in the presence of the copolymer, while in SKOV3 cells, it remained practically unchanged. However, the hypersensitization of the MDR cells by the copolymer could not be merely explained by the P-gp modulation. Therefore, the possible role of the copolymer in inhibition of non-P-gp drug resistance is hypothesized, which may also explain the sensitization of MDR cells with respect to non-MDR type drugs as well as sensitization of parental cells. The concentration dependence of the IC50 in MDR cells indicates that just the copolymer unimers are responsible for the hypersensitization effect. The results obtained suggest that Pluronic P85 can be used as a delivery system to enhance the activity of antineoplastic agents against MDR tumors.
使用两个人类卵巢癌细胞系研究了普朗尼克P85嵌段共聚物的化学增敏作用：糖蛋白P（P-gp）多药耐药（MDR）SKVLB细胞和非MDR SKOV3细胞。在SKVLB细胞中，当存在0.01%（22微摩尔）至1%（2.2毫摩尔）的共聚物时，观察到柔红霉素细胞毒性活性显著增加（高达700倍）。相比之下，该共聚物在SKOV3细胞中诱导的药物活性增加不到3倍。因此，与非MDR细胞相比，MDR亚系对柔红霉素/普朗尼克表现出更高的反应（“超敏反应”）。该共聚物使其他MDR型药物（阿霉素、表柔比星、长春碱和丝裂霉素C）的细胞毒性作用增加20至1000倍，使非MDR型药物（甲氨蝶呤和顺铂）的细胞毒性作用增加2至5.5倍。在共聚物存在的情况下，SKVLB细胞胞质和细胞核中的柔红霉素流入量也增加，而在SKOV3细胞中，其实际上保持不变。然而，共聚物对MDR细胞的超敏化不能仅仅用P-gp调节来解释。因此，推测了共聚物在抑制非P-gp耐药性中的可能作用，这也可以解释MDR细胞对非MDR型药物的致敏以及亲本细胞的致敏。MDR细胞中IC50的浓度依赖性表明，正是共聚物单体会导致超敏化效应。所得结果表明，普朗尼克P85可作为一种递送系统，以增强抗肿瘤药物对MDR肿瘤的活性。
