柔红霉素-白蛋白交联物逆转多药耐药KB/VCR细胞株对柔红霉素的耐药性

将柔红霉素(Dau)与牛血清白蛋白(BSA)交联, 以克服耐长春新碱(VCR)的KB细胞株(KB/VCR)对Dau的耐药性. Dau抑制KB和KB/VCR细胞生长的IC₅₀分别为3.3 μg·L^-1和0.26 mg·L^-1. KB/VCR细胞对Dau的耐药性是KB细胞的79倍. 反转录聚合酶链式反应结果显示, KB/VCR细胞有很高水平的mdr-1基因表达. Dau-BSA交联物和Dau杀伤KB/VCR细胞的EC₅₀别是12 μg·L^-1(指其中Dau含量)和0.24 mg·L^-1, 即Dau BSA对KB/VCR细胞的细胞毒作用是Dau的20倍. 药物蓄积实验显示，使用Dau-BSA时，KB/VCR细胞内Dau蓄积量较使用Dau者增加1.4倍(24 h时)；药物外排实验显示，加入Dau时, Dau迅速从KB/VCR细胞排出, 而使用Dau-BSA时Dau能在KB/VCR细胞内长时间维持较高浓度. 结果提示，Dau与BSA交联后，能克服多药耐药细胞对Dau的耐药性.

Daunorubicin-albumin conjugate reverses resistance in multidrug resistant KB/VCR cells to daunorubicin

Daunorubicin (Dau)-bovine serum albumin (BSA) conjugate (Dau-BSA) via a glutaraldehyde bridge was used to overcome tumor cells resistance to Dau. A multidrug resistant variant of KB cell line (KB/VCR) was established in vitro by repeat exposure of the cells to vincristine. KB/VCR cells were 79 times more resistant to Dau than parent KB cells. There was high expression of mdr-1 gene in KB/VCR cells. EC₅₀ of Dau for killing KB/VCR cells was 0.24 mg·L^-1 and that ofDau-BSA was 12 μg·L^-1 (equivalent to free Dau). Dau-BSA was 20 fold more cytotoxic to KB/VCR cells than equivalent free Dau. The measurements of drug uptake showed that the intracellular Dau concentration following the treatment of KB/VCR cells with Dau-BSA was 2.4 times of that in the cells treated with Dau. The analysis of drug efflux showed that after the preincubation of KB/VCR cells with Dau, cellular Dau was effluxed rapidly from the cells, while a relatively high concentration of Dau was kept for longer time in KB/VCR cells treated with Dau-BSA. These results indicate that it may be possible to overcome multidrug resistance by chemically modified Dau, such as by conjugation of the drug with proteins.