Membrane transport and antitumor activity of pirarubicin, and comparison with those of doxorubicin
Membrane transport and antitumor activity of pirarubicin, and comparison with those of doxorubicin
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DOI：
10.1111/j.1349-7006.1999.tb00814.x
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发表时间：
1999-07-01
期刊：
影响因子：
--
通讯作者：
Sonobe, T
中科院分区：
文献类型：
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作者：
Sugiyama, T;Sadzuka, Y;Sonobe, T
我们比较了吡拉西坦和阿霉素在对阿霉素敏感性低的M5076卵巢肉瘤中的膜转运和抗肿瘤活性。吡拉西坦被M5076细胞迅速摄取，细胞内吡拉西坦浓度达到阿霉素的2.5倍以上。吡拉西坦比阿霉素更有效。因此，细胞内浓度影响这些蒽环类药物的细胞毒性。在比较吡拉西坦和多柔比星的核摄取时，发现吡拉西坦的核/细胞比为约40%，而多柔比星的核/细胞比达到80%以上。由于吡拉西坦的核内浓度依赖于核转运，因此不仅细胞膜转运的增加，而且核膜转运的增加有助于吡拉西坦功效的增强。在M5076实体瘤荷瘤小鼠中，吡拉西坦将肿瘤重量降低至对照水平的60%，尽管多柔比星没有影响。此外，茶氨酸抑制吡拉西坦从M5076细胞的流出，使肿瘤中的吡拉西坦浓度增加1.3倍，并使吡拉西坦的治疗功效增强1.7倍。总之，我们的研究结果表明，在肿瘤细胞中的蒽环类衍生物的浓度增加，由于改变细胞膜转运的结果在增强的抗肿瘤活性。
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 hy 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.