三阴性乳腺癌模型裸鼠血管正常化后对紫杉醇的反应

Response of human triple-negative breast cancer to paclitaxel after vascular normalization in nude mice

目的:通过观察人三阴性乳腺癌(triple-negative breast cancer,TNBC)模型裸鼠血管正常化后对紫杉醇的反应,探讨重组人内皮抑素与紫杉醇在血管正常化时间窗内联用是否优于紫杉醇单用并分析磁共振成像(magnetic resonance imaging,MRI)在早期评估化疗的作用。方法:将人TNBC细胞株MDA-MB-231种植于36只BALB/c-nu雌性裸小鼠的右下腹部皮下,随机分成4组(模型组、重组人内皮抑素治疗组、紫杉醇治疗组及人内皮抑素联用紫杉醇治疗组),每组有7只完成实验。重组人内皮抑素于实验开始时给药,连续使用17 d,紫杉醇于实验第6天和第12天分别给药,所有用药均为腹腔注射,用量均为10 mg·kg^(-1)·d^(-1)。治疗前1 d及注射实验试剂后5、11、17 d进行MRI扫描,所有荷瘤鼠均在最后一次MRI扫描后颈椎脱位处死,切下瘤体,进行病理学及免疫组化检测,测定肿瘤微血管密度(microvessel density,MVD)及Ki67表达。结果:第17天,联用组移植瘤体积小于模型组及重组人内皮抑素治疗组(P<0.05),但与紫杉醇治疗组比较无显著差异。第11天,紫杉醇治疗组的慢弥散系数大于模型组,联用组慢弥散系数大于重组人内皮抑素治疗组(P<0.05)。解剖各组荷瘤鼠未见远处转移病灶。HE染色显示4组肿瘤外周均有明显坏死,且药物治疗组坏死程度均高于模型组。药物治疗组的MVD均小于模型组,且药物联用组均小于药物单用组(P<0.05)。药物联用组Ki67表达较重组人内皮抑素组明显降低,但与紫杉醇治疗组相比无显著差异。结论:在血管正常化时间窗内,重组人内皮抑素联合紫杉醇化疗对TNBC移植瘤虽有明显的抑瘤作用,但疗效未优于紫杉醇;慢弥散系数可以早期预测治疗效果。

AIM：To explore whether there is synergistic effect of recombinant human endostatin （ rh-Endo ） and paclitaxel （Pac） in the time window of vascular normalization and the role of magnetic resonance imaging （MRI） in early assessment of chemotherapy by observing the response of human triple -negative breast cancer （ TNBC） to Pac after vascular normalization in nude mice .METHODS：The human TNBC MDA-MB-231 cells were planted in the subcutaneous region of right lower abdomen of BALB/c-nu female nude mice .These nude mice were randomly divided into 4 groups （n=7）.rh-Endo was given for 17 consecutive days in rh-Endo group and rh-Endo＋Pac group.Pac was given on the 6th and 12th days in Pac group and rh-Endo＋Pac group.The dosage of both drugs was 10 mg· kg-1· d-1（ip）.On the day before the treatment and the 5th, 11th and 17th days after treatment, all the transplanted tumors were examined by MRI . All the mice were killed by cervical dislocation and their transplanted tumors were taken down for examinations after the last MRI on the 17th day.The changes of pathology, immunohistochemisty, microvessel density （MVD） and Ki67 expression were measured.RESULTS：On the 17th day, the volume of transplanted tumor in rh-Endo＋Pac group was smaller than that in model group and rh-Endo group （ P〈0.05 ） , and no difference between rh-Endo＋Pac group and Pac group was found.On the 17th day, the tumor inhibitory rates in rh-Endo group, Pac group and rh-Endo＋Pac group were 14.61%, 39.08%and 54.79%, respectively.The slow diffusion coefficient in Pac group was increased compared with model group , while it was decreased compared with rh-Endo＋Pac group （P〈0.05）.No distant metastatic lesion in the tumor-bearing mice was observed .The necrotic rates in rh-Endo＋Pac group and Pac group were higher than those in model group and rh-Endo group.The MVD in model group was higher than that in the other 3 groups.The MVD in rh-Endo＋Pac group was decreased compared with Pac group and rh-Endo group .The Ki67 level in rh-Endo＋Pac group was decreased compared with rh-Endo group , and no difference between rh-Endo＋Pac group and Pac group was detected .CONCLUSION：In the time window of vascular normalization , the combination of Pac and rh-Endo has a significant antitumor effect on TNBC , but this study did not observe a significant synergistic effect of the 2 drugs.The change of slow diffusion coefficient can predict the therapeutic effect in advance .