Badary O A, Al-Shabanah O A, Al-Gharably N M, Elmazar M M
Department of Pharmacology, College of Pharmacy, Ain Shams University, Cairo, Egypt.
Anticancer Drugs. 1998 Oct;9(9):809-15. doi: 10.1097/00001813-199810000-00011.
Cremophor EL (CR) is a solubilizing agent and a modulator of P-glycoprotein (P-gp)-mediated anticancer multidrug resistance. The present study was undertaken to evaluate whether doxorubicin (Dox) pharmacokinetics, therapeutic activity and cardiotoxicity in Swiss albino mice is modified when combined with CR treatment. CR (2.5 ml/kg, i.p) given simultaneously with Dox (20 mg/kg, i.p.) increased Dox levels in plasma, heart, liver and kidneys of healthy mice. Using an Ehrlich ascites carcinoma (EAC)-bearing mice experimental model, CR (2.5 ml/kg) improved the survival and antitumor activity of Dox. The enhanced antitumor activity of Dox was related to a significant increase in EAC tumor cellular Dox content by CR. Furthermore, CR (1 microg/ml) potentiated the in vitro cytotoxicity of Dox in cultured EAC cells. In healthy mice, Dox-induced mortality was markedly reduced by simultaneous treatment with CR. CR enhanced DOX-induced increase in plasma lactate dehydrogenase, creatine phosphokinase (CPK) and CPK-MB isozyme activities, as well as the cardiac malondialdehyde level. CR also increased Dox-induced focal necrotic myocardial lesions. These findings suggest that CR increased DOX antitumor activity and cardiotoxicity as a result of enhancing its bioavailability, and decreased Dox-induced mortality in mice by a mechanism not yet defined.
聚氧乙烯蓖麻油（CR）是一种增溶剂，也是P-糖蛋白（P-gp）介导的抗癌多药耐药的调节剂。本研究旨在评估阿霉素（Dox）与CR联合治疗时，瑞士白化小鼠体内阿霉素的药代动力学、治疗活性和心脏毒性是否会发生改变。与阿霉素（20mg/kg，腹腔注射）同时给予CR（2.5ml/kg，腹腔注射）可提高健康小鼠血浆、心脏、肝脏和肾脏中的阿霉素水平。使用携带艾氏腹水癌（EAC）的小鼠实验模型，CR（2.5ml/kg）可提高阿霉素的存活率和抗肿瘤活性。阿霉素抗肿瘤活性的增强与CR使EAC肿瘤细胞内阿霉素含量显著增加有关。此外，CR（1μg/ml）可增强阿霉素对培养的EAC细胞的体外细胞毒性。在健康小鼠中，同时给予CR可显著降低阿霉素诱导的死亡率。CR增强了阿霉素诱导的血浆乳酸脱氢酶、肌酸磷酸激酶（CPK）和CPK-MB同工酶活性的增加，以及心脏丙二醛水平。CR还增加了阿霉素诱导的局灶性坏死性心肌病变。这些发现表明，CR通过提高阿霉素的生物利用度增加了其抗肿瘤活性和心脏毒性，并通过一种尚未明确的机制降低了阿霉素诱导的小鼠死亡率。
