Sugiyama T, Sadzuka Y, Nagasawa K, Ohnishi N, Yokoyama T, Sonobe T
Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, University of Shizuoka.
Jpn J Cancer Res. 1999 Jul;90(7):775-80. doi: 10.1111/j.1349-7006.1999.tb00814.x.
We have compared the membrane transport and antitumor activity of pirarubicin with those of doxorubicin in M5076 ovarian sarcoma, which exhibits low sensitivity to doxorubicin. Pirarubicin was rapidly taken up by M5076 cells and the intracellular concentration of pirarubicin reached more than 2.5-fold that of doxorubicin. In terms of the 50% cell growth-inhibitory concentration in vitro, pirarubicin was more effective than doxorubicin. Thus, the intracellular concentration influenced the cytotoxicity of these anthracycline agents. On comparison of the nuclear uptake of pirarubicin and doxorubicin, the nucleus/cell ratio of pirarubicin was found to be about 40%, whereas that of doxorubicin reached more than 80%. As the intranuclear concentration of pirarubicin is dependent on nuclear transport, the increases in not only cell membrane transport, but also nuclear membrane transport contributed to the enhancement of the efficacy of pirarubicin. In M5076 solid tumor-bearing mice, pirarubicin reduced the tumor weight to 60% of the control level, although doxorubicin had no effect. These results were supported by the intracellular uptake of pirarubicin. Moreover, theanine, which inhibited the pirarubicin efflux from M5076 cells, increased by 1.3-fold the pirarubicin concentration in the tumor and enhanced the therapeutic efficacy of pirarubicin 1.7-fold. In conclusion, our results suggest that an increase in the concentration of an anthracycline derivative in tumor cells due to alteration of cell membrane transport results in enhancement of the antitumor activity.
我们比较了吡柔比星与多柔比星在对多柔比星敏感性较低的M5076卵巢肉瘤中的膜转运和抗肿瘤活性。吡柔比星被M5076细胞快速摄取，其细胞内浓度达到多柔比星的2.5倍以上。就体外50%细胞生长抑制浓度而言，吡柔比星比多柔比星更有效。因此，细胞内浓度影响了这些蒽环类药物的细胞毒性。比较吡柔比星和多柔比星的核摄取情况，发现吡柔比星的核/细胞比约为40%，而多柔比星的核/细胞比超过80%。由于吡柔比星的核内浓度取决于核转运，细胞膜转运和核膜转运的增加都有助于提高吡柔比星的疗效。在携带M5076实体瘤的小鼠中，吡柔比星将肿瘤重量降低至对照水平的60%，而多柔比星则没有效果。这些结果得到了吡柔比星细胞内摄取情况的支持。此外，抑制吡柔比星从M5076细胞外排的茶氨酸使肿瘤中吡柔比星浓度增加了1.3倍，并使吡柔比星的治疗效果提高了1.7倍。总之，我们的结果表明，由于细胞膜转运改变导致肿瘤细胞中蒽环类衍生物浓度增加，从而增强了抗肿瘤活性。
