顺铂与重组人内皮抑素不同联合用药方案对裸鼠卵巢癌的疗效

目的 寻找重组人内皮抑素(rhES)使卵巢癌荷瘤鼠瘤组织微血管正常化时间窗.方法 建立卵巢癌移植瘤模型,通过动态观察重组人内皮抑素用药后肿瘤微血管α-平滑肌肌动蛋白(α-SMA),Ⅳ型胶原(CollagenⅣ)及缺氧诱导因子-1 α(HIF-1α)表达变化,确定rhES使肿瘤微血管正常化时间窗.按rhES使肿瘤微血管正常化时间窗前、中、后3个时间段分别给予顺铂治疗并设对照,通过抑瘤率,微血管密度(MVD),肿瘤细胞增殖活性等方面评价疗效.结果 在rhES用药第4、6天肿瘤微血管趋于成熟,基底膜,周细胞增加,α-SMA阳性表达微血管数与对照组比较明显升高,分别为(15.3±5.2)比(4.3±2.1)个/mm2 (P ＜0.01);(16.4±4.6)比(6.6±2.4)个/mm2(P ＜0.01),Ⅳ型胶原阳性表达的微血管与对照组相比也明显升高,分别是(14.7±4.3)比(6.7±5.1)个/mm2(P＜0.01);(18.4±5.5)比(7.1±1.7)个/mm2 (P ＜0.01).在rhES用药第4、6天肿瘤乏氧区HIF-1α表达降低.rhES+ DDP(d4 ～6)组与其他各组比较抑瘤率最高,微血管密度降低,增殖核抗原(PCNA)表达下降.结论 rhES使卵巢癌移植瘤微血管正常化时间窗为用药第4～6天,在该时间段与顺铂联合用药治疗效果最佳.

Differential anti-tumor effects for various regimens of endostar plus cisplatin in ovarian cancer

Objective To find the time window of normalization of tumor vasculature by endostar in tumor-bearing mice with ovarian cancer.Methods The nude murine model of ovarian cancer was established.The vasculature markers α-SMA (alpha-smooth muscle actin) and collagen Ⅳ covered tumor vessels and hypoxic zone following the treatment of endostar were monitored.According to the changes of microvascular morphology and tumor hypoxia zone,the time window was identified.Furthermore the treatment protocols of scheduling dosing of cisplatin plus endostar at different time points were designed.After treatment tumor volume,the parameters of microvascular density (MVD) and PCNA (proliferating cell nuclear antigen) were monitored to evaluate the effects of different protocols.Results At Days 4 and 6 posttreatment,more α-SMA and collagen Ⅳ covered vessels could be observed.The amount of microvasculature expressed α-SMA on days 4 compared with control was ( 15.3 ±5.2) vs (4.3 ±2.1 )/mm2 (P ＜0.01 ) ; at Day 6,the result was ( 16.4 ± 4.6) vs (6.6 ± 2.4 )/mm2 ( P ＜ 0.01 ).The expression of collagen Ⅳ had a similar change.And the numbers of microvasculature expressing collagen Ⅳ was ( 14.7 ± 4.3 ) vs (6.7 ±5.1 )/mm2 at Days 4 and 6 ( P ＜ 0.01 ) ; ( 18.4 ± 5.5 ) vs (7.1 ± 1.7 )/mm2 ( P ＜ 0.01 ).The expression of HIF-1α decreased in hypoxic area.In the rhES + DDP (d4 -6) group,the value of microvessel density (MVD) decreased and the expression of PCNA significantly decreased versus other groups. Conclusion Endostar may normalize the tumor vasculature.And the time window is found at Days 4 -6 post-treatment.During the time of vascular normalization,a combination therapy of endostar plus cisplatin has optimal efficacies.