顺铂、拓扑替康、柔红霉素和羟基脲对人骨髓间充质干细胞的作用

Effect of Cisplatin,Topotecan,Daunorubicin and Hydroxyurea on Human Mesenchymal Stem Cells

我们曾研究一些白血病常用的化疗药物对人间充质干细胞(MSC)的影响,并发现其独特的耐药性。本研究评估一些实体瘤常用的化疗药物如顺铂、拓扑替康、柔红霉素和可长期使用的口服化疗药物如羟基脲等对人MSC的作用。在体外培养系统中,比较人MSC与NB-4细胞系、人外周血单个核细胞(PBMC)对这些单一化疗药物的敏感性。单一化疗药物作用72小时后,继续将人MSC在正常培养液培养9天,用XTT方法测定细胞增殖恢复情况。AnnexinV/PI染色后,用流式细胞仪检测上述4种化疗药物诱导的细胞凋亡。结果表明:人MSC对4种化疗药物均较NB-4细胞耐药,拓扑替康、顺铂、羟基脲和柔红霉素对人MSC的IC50分别是其对NB-4细胞的IC50的636倍、24.8倍、20倍以上和2.4倍,但人MSC对拓扑替康、顺铂和柔红霉素较人PBMNC更敏感,拓扑替康、顺铂和柔红霉素对人PBMNC的IC50分别是其对人MSC的IC50的27倍以上、1.9倍和1.4倍。4种药物在临床浓度都明显抑制人MSC增殖,去除药物作用后,这种抑制作用持续存在。上述单一药物临床浓度作用于人MSC后48-72小时凋亡细胞增加。结论:顺铂、羟基脲、拓扑替康和柔红霉素单一药物均可造成人MSC持续损伤,其机制与细胞凋亡有关。

Mesenchymal stem cells （MSC） are important cellular component of the bone marrow microenvironment in supporting hemopoiesis. Li Jet al reported previously that MSCs are resistant to chemotherapy commonly used in hematologic malignancies but are relatively sensitive to anti-microtubule agents. However, the response of MSCs to other chemotherapeutic agents commonly used in solid tumour settings remains unknown. This study was purposed to evaluate the acute direct effects of 4 individual chemotherapeutic agents on human MSCs （hlVISC）, including cisplatin, topote- can, daunorubicin and hydroxyurea. Using an in vitro culture system, the chemosensitivity of hMSC was determined by XTI＂ assay and compared with NB-4 cells and normal peripheral blood mononuclear cells （PBMNC）. The recovery of cell numbers following exposure to chemotherapeutic agents and apoptosis induced by chemotherapy in hMSC were evaluated. The results showed that although h/VISCs were more resistant to the 4 agents above metioned than NB-4 cells, they were sensitive to topotecan, cisplatin and daunoruhicin than PBMNCs. The IC50 values of hMSCs for topotecan, cisplatin, hydroxyurea and daunorubicin were 636, 24.8, 〉 20 and 2.4 times of those of NB-4 cells respectively. The ICs0 values of human PBMNCs for topotecan, cisplatin and daunorubicin were 〉 27, 1.9 and 1.4 times of those of hMSCs respectively. Reduction of cell number was observed in hMSCs treated with the 4 drugs in clinically relative concentrations. Sustained suppression in hMSCs was observed following 3 days exposure to the 4 agents. It is concluded that the cisplatin, topotecan, daunorubicin and hydroxyurea alone can induce apoptosis of hMSCs and exert persistent suppressive effect on the proliferation of hMSCs even with short term exposure.