低剂量节拍化疗对人卵巢癌裸鼠移植瘤中ALDH1表达的影响  

Effect of low-dose metronomic chemotherapy on ALDH1 expression in human ovarian carcinoma xenograft tumor in nude mice

作　　者：吴小华 赵婷婷[1] 曹琴英[2] 杨波[1] 孙亚楠[1] 周楠[1] 梁磊[1] 

机构地区：[1]解放军白求恩国际和平医院妇产科,河北石家庄050082 [2]石家庄市妇产医院妇产科,河北石家庄050011

出　　处：《肿瘤》2015年第4期377-383,共7页Tumor

摘　　要：目的:探讨顺铂(cisplatin,DDP)最大可耐受剂量化疗(maximum tolerated dose chemotherapy with DDP,MTD-DDP)和DDP低剂量节拍化疗(low-dose metronomic chemotherapy with DDP,LDM-DDP)对人卵巢癌裸鼠移植瘤的作用及其对移植瘤中乙醛脱氢酶1(aldehyde dehydrogenase 1,ALDH1)表达的影响。方法:建立人卵巢癌SKOV3细胞裸鼠皮下移植瘤模型,并进行MTDDDP和LDM-DDP化疗,观察不同化疗模式对移植瘤生长的影响。制备裸鼠移植瘤原代细胞,并应用流式细胞分选术分选ALDH1阳性细胞。应用平板克隆形成实验和裸鼠体内成瘤实验检测ALDH1阳性细胞的克隆形成能力和裸鼠体内成瘤能力,蛋白质印迹法检测ALDH1阳性细胞中Ki-67、乳腺癌耐药蛋白(breast cancer resistant protein,BCRP)和CD133的表达水平。结果:MTD-DDP和LDM-DDP均可抑制裸鼠移植瘤的生长,LDMDDP的抑瘤作用更明显(P<0.001)。MTD-DDP组移植瘤原代细胞中ALDH1阳性细胞所占比率明显高于对照组(以0.9%氯化钠溶液代替DDP),LDM-DDP组移植瘤原代细胞中ALDH1阳性细胞所占比率明显低于对照组,差异均有统计学意义(P值均<0.001)。ALDH1阳性细胞的平板克隆形成能力(P<0.001)和裸鼠体内成瘤能力均高于ALDH1阴性细胞。ALDH1阳性细胞中Ki-67的表达水平低于ALDH1阴性细胞,而BCRP和CD133的表达水平高于ALDH1阴性细胞,差异均有统计学意义(P值均<0.001)。结论:LDM-DDP抑制卵巢癌裸鼠皮下移植瘤生长的作用较强,并可降低ALDH1阳性细胞所占比率。Objective： To investigate the influence of maximum-tolerated dose chemotherapy with cisplatin（MTD-DDP） and low-dose metronomic chemotherapyw ith DDP（LDM-DDP） on human ovarian carcinoma xenograft tumor in nude micea nd the expression of aldehyde dehydrogenase 1（ALDH1） in xenograft tumor.Methods： Murine subcutaneous xenograft tumors of human epithelial ovarianc ancer SKOV3 cells were established in nude mice and treated with MTD-DDPa nd LDM-DDP, respectively.The growth of xenograft tumor was observed. The xenograft tumopr rimary cells were established. ALDH1-positive cells were obtained by fluorescence-activated cell sorting. The abilities of colony formation and tumorigenicity of ALDH1-positive cells in vitro and in vivo were detected by colony formation assay and tumor formation in nude mice, respectively.The expression levels of Ki-67, breast cancer resistant protein（BCRP） and CD133 in ALDH1-positive cells were detected by Western blotting.Results： The growth of xenograft tumor in nude mice was inhibited by MTD-DDP and LDMDDP,and this inhibition effect was significant in LDM-DDP group（P 〈 0.001）. The proportion of ALDH1-positive cells in xenograft tumor primary cells waslo wer in MTD-DDP group and higher in LDM-DDP group as compared with that in the control group（0.9% NaCl solution）（both P 〈 0.001）. The abilities of colony formation and tumorigenicity of ALDH1-positive cells were higher than those of ALDH1-negative cells（both P 〈 0.001）. The expression level of Ki-67 was lower but the expression levels of BCRP and CD133 were higher in ALDH1-positive cells than those in ALDH1-negative cells（all P 〈 0.001）.Conclusion： LDM-DDP can effectively inhibit the growth of human ovarian carcinoma xenograft tumors in nude mice and reduce the proportion of ALDH1-positive cells.

关 键 词：卵巢肿瘤 顺铂 模型 动物 低剂量节拍化疗 基因 ALDH1 细胞 SKOV3 

分 类 号：R737.31[医药卫生—肿瘤]