The therapeutic potential of hepatocyte growth factor to sensitize ovarian cancer cells to cisplatin and paclitaxel in vivo
The therapeutic potential of hepatocyte growth factor to sensitize ovarian cancer cells to cisplatin and paclitaxel in vivo
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DOI：
10.1158/1078-0432.ccr-06-1915
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发表时间：
2007-04-01
影响因子：
11.5
通讯作者：
Di Renzo, Maria Flavia
中科院分区：
文献类型：
--
作者：
Bardella, Chiara;Dettori, Daniela;Di Renzo, Maria Flavia
目的：晚期卵巢癌最初对铂类药物和紫杉烷类药物的联合化疗有反应，但在大多数情况下，会产生耐药性。我们最近发现，在体外，肝细胞生长因子（HGF）增强顺铂（CDDP）和紫杉醇治疗的人卵巢癌细胞系的死亡。本研究解决是否在体内肝细胞生长因子使卵巢癌细胞更敏感，这些chemotherapeutics.Experimental设计：使用慢病毒载体携带的肝细胞生长因子转基因，我们转导SK-OV-3和NIH：OVCAR-3卵巢癌细胞系，以获得稳定的自分泌和旁分泌肝细胞生长因子受体激活。在体外，我们测定了生长，运动，侵袭力，并对CDDP和紫杉醇的HGF分泌的大部分的NSCLC细胞群体的反应。在体内，我们测试了药物与s.c.在免疫受损小鼠中由野生型和HGF分泌细胞形成的肿瘤。将荷瘤小鼠用CDDP（i. p.）和紫杉醇（i. v.），结果：在体外，HGF分泌细胞没有显示出改变的增殖率和存活率，但对CDDP和紫杉醇单独或联合触发的死亡强烈敏感。在体内，我们发现了一个治疗窗口中，自分泌/旁分泌的HGF肿瘤敏感的低剂量的药物，这是无效的自己.Conclusions：这些数据提供了概念的证明，在体内基因治疗与HGF可能是胜任的敏感性卵巢癌细胞的常规化疗。
Purpose: Advanced ovarian cancers are initially responsive to combinatorial chemotherapy with platinum drugs and taxanes but, in most cases, develop drug resistance. We recently showed that, in vitro, hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and paclitaxel. The present study addresses whether in vivo HGF makes ovarian carcinoma cells more responsive to these chemotherapeutics.Experimental Design: Using Lentiviral vectors carrying the HGF transgene, we transduced SK-OV-3 and NIH:OVCAR-3 ovarian carcinoma cell lines to obtain stable autocrine and paracrine HGF receptor activation. In vitro, we assayed growth, motility, invasiveness, and the response to CDDP and paclitaxel of the HGF-secreting bulk unselected cell populations. In vivo, we tested the cytotoxic effects of the drugs versus s.c. tumors formed by the wild-type and HGF-secreting cells in immunocompromised mice. Tumor-bearing mice were treated with CDDP (i.p.) and paclitaxel (i.v.), combined in different schedules and doses.Results: In vitro, HGF-secreting cells did not show altered proliferation rates and survival but were strongly sensitized to the death triggered by CDDP and paclitaxel, alone or in combination. In vivo, we found a therapeutic window in which autocrine/paracrine HGF made tumors sensitive to low doses of the drugs, which were ineffective on their own.Conclusions: These data provide the proof-of-concept that in vivo gene therapy with HGF might be competent in sensitizing ovarian cancer cells to conventional chemotherapy.