Jacobsen S E, Ruscetti F W, Longo D L, Keller J R
Division of Cancer Treatment, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702-1201.
J Natl Cancer Inst. 1991 Nov 20;83(22):1672-7. doi: 10.1093/jnci/83.22.1672.
Dolastatins 10 and 15, isolated from the shell-less marine mollusk Dolabella auricularia, are potent antineoplastic agents with unknown myelotoxic effects in vivo. The goal of this study was to determine whether the dolastatins inhibit the proliferation of normal hematopoietic progenitor cells. Assays to test inhibition of colony formation and of cell proliferation were performed in vitro with bone marrow cell preparations enriched for progenitor cells and with progenitor cell lines, respectively, using varying drug concentrations and exposure times. Dolastatins 10 and 15 both inhibited human and murine bone marrow cell colony formation in a concentration-dependent manner, with the concentration required for half maximal inhibition ranging from 0.1 to 1 pg/mL for dolastatin 10 and from 10 to 100 pg/mL for dolastatin 15. These concentrations are 25-fold to 100-fold lower than the concentration required for antineoplastic activity. Complete inhibition of human bone marrow cell colony formation was observed at concentrations of 10-100 pg/mL for dolastatin 10 and 1000-10,000 pg/mL for dolastatin 15. Committed progenitor cells and multipotential progenitor cells were similarly inhibited. The magnitude of inhibition of human hematopoietic cell colony formation was dependent on pre-exposure time to dolastatins 10 and 15, with a reversible effect up to 8 hours and with a 24-hour preincubation resulting in maximal (100%) and irreversible inhibition. Dolastatin 10 at a concentration of 10-100 pg/mL limited the proliferation of six human and four murine hematopoietic progenitor cell lines, as measured by tritiated thymidine incorporation, to between 34% and 83% of that occurring in the absence of the drug. These results indicate that the dolastatins are potent inhibitors of normal hematopoietic progenitor cell proliferation.
从无壳海洋软体动物耳状芋螺中分离出的多拉司他汀10和15是强效抗肿瘤药物，其体内骨髓毒性作用未知。本研究的目的是确定多拉司他汀是否抑制正常造血祖细胞的增殖。分别使用不同的药物浓度和暴露时间，对富含祖细胞的骨髓细胞制剂和祖细胞系进行体外试验，以测试对集落形成和细胞增殖的抑制作用。多拉司他汀10和15均以浓度依赖性方式抑制人和小鼠骨髓细胞集落形成，多拉司他汀10半数最大抑制所需浓度范围为0.1至1 pg/mL，多拉司他汀15为10至100 pg/mL。这些浓度比抗肿瘤活性所需浓度低25倍至100倍。在多拉司他汀10浓度为10 - 100 pg/mL和多拉司他汀15浓度为1000 - 10000 pg/mL时，观察到对人骨髓细胞集落形成的完全抑制。定向祖细胞和多能祖细胞受到类似抑制。人造血细胞集落形成的抑制程度取决于多拉司他汀10和15的预暴露时间，在长达8小时内具有可逆效应，预孵育24小时导致最大（100%）且不可逆的抑制。通过氚标记胸腺嘧啶核苷掺入法测定，浓度为10 - 100 pg/mL的多拉司他汀10将六种人类和四种小鼠造血祖细胞系的增殖限制在无药物时的34%至83%之间。这些结果表明，多拉司他汀是正常造血祖细胞增殖的强效抑制剂。
