Zou Y, Ling Y H, Van N T, Priebe W, Perez-Soler R
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Cancer Res. 1994 Mar 15;54(6):1479-84.
The lipophilic anthracycline antibiotic annamycin (Ann) was entrapped in liposomes of different size [median diameter: 1.64 microns, multilamellar liposomal Ann (L-Ann); 0.030 micron, small unilamellar Ann (S-Ann)] with > 90% entrapment efficiency and tested in vitro against four pairs of sensitive and multidrug-resistant (MDR) tumor cell lines and in vivo by the i.v. route in five tumor models: advanced s.c. B16 melanoma; s.c. M5076 reticulosarcoma; lung metastases of Lewis lung carcinoma; and s.c. KB and KB-V1 xenografts in nude mice. Predetermined optimal doses of the different formulations were used and the results were compared with doxorubicin (Dox). In vitro, Ann, either in suspension in 10% dimethyl sulfoxide (F-Ann) (1 mg/ml) or entrapped in liposomes, was able to partially overcome resistance in all four pairs of sensitive and MDR KB, 8226, P388, and CEM cell lines (resistance indexes 63, 269, 333, and 356 for Dox versus 4, 5, 19, and 8.7 for L-Ann, respectively). In vivo, both F-Ann and liposome-entrapped Ann were slightly more effective than Dox in inhibiting the growth of advanced s.c. B16 melanoma tumors. L-Ann was markedly more effective than Dox and moderately more effective than F-Ann in prolonging the life span of animals bearing s.c. M5076 and lung metastases of Lewis lung carcinoma tumors. All drugs were equally effective at optimal doses in delaying the growth of s.c. KB xenografts, whereas all Ann formulations were markedly more effective than Dox in delaying the growth of s.c. KB-V1 (MDR) xenografts. In all in vivo experiments, S-Ann was consistently more effective than L-Ann and L-Ann was more effective than F-Ann. These results indicate that (a) Ann is more effective than Dox by the i.v. route against several tumor models and that MDR tumors are partially not cross-resistant to Ann both in vitro and in vivo, (b) liposomes enhance the in vivo antitumor properties of Ann, and (c) small liposomes are more effective than large liposomes in enhancing Ann antitumor activity.
亲脂性蒽环类抗生素阿那霉素（Ann）被包裹在不同大小的脂质体中[中位直径：1.64微米，多层脂质体阿那霉素（L-Ann）；0.030微米，小单层阿那霉素（S-Ann）]，包封率>90%，并在体外针对四对敏感和多药耐药（MDR）肿瘤细胞系进行测试，以及通过静脉注射途径在五种肿瘤模型中进行体内测试：晚期皮下B16黑色素瘤；皮下M5076网状细胞肉瘤；Lewis肺癌肺转移瘤；以及裸鼠皮下KB和KB-V1异种移植瘤。使用了不同制剂的预定最佳剂量，并将结果与阿霉素（Dox）进行比较。在体外，悬浮于10%二甲基亚砜（F-Ann）（1毫克/毫升）中的Ann或包裹在脂质体中的Ann能够部分克服所有四对敏感和MDR KB、8226、P388和CEM细胞系中的耐药性（Dox的耐药指数分别为63、269、333和356，而L-Ann的耐药指数分别为4、5、19和8.7）。在体内，F-Ann和脂质体包裹的Ann在抑制晚期皮下B16黑色素瘤肿瘤生长方面均略比Dox更有效。在延长携带皮下M5076和Lewis肺癌肺转移瘤动物的寿命方面，L-Ann比Dox明显更有效，比F-Ann适度更有效。所有药物在最佳剂量下在延迟皮下KB异种移植瘤生长方面效果相同，而所有Ann制剂在延迟皮下KB-V1（MDR）异种移植瘤生长方面比Dox明显更有效。在所有体内实验中，S-Ann始终比L-Ann更有效，L-Ann比F-Ann更有效。这些结果表明：（a）通过静脉注射途径，Ann对几种肿瘤模型比Dox更有效，并且MDR肿瘤在体外和体内对Ann部分不存在交叉耐药性；（b）脂质体增强了Ann的体内抗肿瘤特性；（c）小脂质体在增强Ann抗肿瘤活性方面比大脂质体更有效。
