Kusunoki N, Takara K, Tanigawara Y, Yamauchi A, Ueda K, Komada F, Ku Y, Kuroda Y, Saitoh Y, Okumura K
First Department of Surgery, School of Medicine, Kobe University.
Jpn J Cancer Res. 1998 Nov;89(11):1220-8. doi: 10.1111/j.1349-7006.1998.tb00518.x.
The inhibitory effects of SDZ PSC 833 (PSC833), a non-immunosuppressive cyclosporin derivative, on the P-glycoprotein (P-gp)-mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs-A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC-GA5-COL150 cells, which overexpress human P-gp, was measured. Both PSC833 and Cs-A inhibited P-gp-mediated transport of doxorubicin and vinblastine in a concentration-dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC-GA5-COL150 cells. The values of the 50%-inhibitory concentration (IC50) of PSC833 and Cs-A for doxorubicin transport were 0.29 and 3.66 microM, respectively, and those for vinblastine transport were 1.06 and 5.10 microM, respectively. The IC50 of PSC833 for doxorubicin transport was about 4-fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P-gp and had higher lipophilicity than Cs-A. These results indicated that the inhibitory effect of PSC833 on P-gp-mediated transport was 5- to 10-fold more potent than that of Cs-A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P-gp and to the higher lipophilicity of PSC833.
将非免疫抑制性环孢素衍生物SDZ PSC 833（PSC833）对P-糖蛋白（P-gp）介导的阿霉素和长春碱转运的抑制作用与环孢素A（Cs-A）进行了比较。测定了抗癌药物和PSC833在过表达人P-gp的LLC-GA5-COL150细胞单层上的跨细胞转运。PSC833和Cs-A均以浓度依赖性方式抑制P-gp介导的阿霉素和长春碱转运，并增加了LLC-GA5-COL150细胞中阿霉素和长春碱的细胞内蓄积。PSC833和Cs-A对阿霉素转运的50%抑制浓度（IC50）值分别为0.29和3.66 microM，对长春碱转运的IC50值分别为1.06和5.10 microM。PSC833对阿霉素转运的IC50约比对长春碱转运的IC50小4倍，提示PSC833与阿霉素联合可能有效。PSC833本身不被P-gp转运，且比Cs-A具有更高的亲脂性。这些结果表明，PSC833对P-gp介导转运的抑制作用比Cs-A强5至10倍，PSC833的这种更高抑制作用可能与PSC833不被P-gp转运以及其更高的亲脂性有关。
