Paclitaxel (Taxol) is a promising frontline chemotherapeutic agent for the treatment of human breast and ovarian cancers. The adenoviral type 5 E1A gene has been tested in multiple clinical trials for its anticancer activity. E1A has also been shown to sensitize paclitaxel-induced killing in E1A-expressing cells. Here, we show that E1A can sensitize paclitaxel-induced apoptosis in breast cancer cells in a gene therapy setting by an orthotopic mammary tumor model. We first showed that expression of E1A enhanced in vitro paclitaxel cytotoxicity, as compared to the control cells. We then compared the therapeutic efficacy of paclitaxel between orthotopic tumor models established with vector-transfected MDA-MB-231 (231-Vect) versus 231-E1A stable cells, using tumor weight and apoptotic index (TUNEL assay) as the parameters. We found paclitaxel was more effective in shrinking tumors and inducing apoptosis in tumor models established with stable 231-E1A cells than the control 231-Vect cells. We also tested whether E1A could directly enhance paclitaxel-induced killing in nude mice, by using a nonviral, surface-protected cationic liposome to deliver E1A gene via the mouse tail vein. We compared the therapeutic effects of E1A gene therapy with or without Taxol chemotherapy in the established orthotopic tumor model of animals inoculated with MDA-MB-231 cells, and found that a combination of systemic E1A gene therapy and paclitaxel chemotherapy significantly enhanced the therapeutic efficacy and dramatically repressed tumor growth (P < .01). In addition, survival rates were significantly higher in animals treated with combination therapy than in the therapeutic control groups (both P < .0001). Thus, the E1A gene therapy indeed enhances the sensitivity of tumor cells to chemotherapy in a gene therapy setting and, the current study provides preclinical data to support combination therapy between E1A gene and chemotherapy for future clinical trials.

中文翻译：

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通过非病毒介导的原位异种移植人类乳腺癌中E1A基因的全身递送，增强了紫杉醇的细胞毒性并延长了动物的存活率。

紫杉醇（紫杉醇）是用于治疗人类乳腺癌和卵巢癌的有前途的一线化学治疗剂。腺病毒5型E1A基因已通过多项临床试验测试其抗癌活性。E1A也已显示出对紫杉醇诱导的E1A表达细胞杀伤的敏感性。在这里，我们显示，E1A可以通过原位乳腺肿瘤模型在基因治疗中敏化紫杉醇诱导的乳腺癌细胞凋亡。我们首先显示，与对照细胞相比，E1A的表达增强了体外紫杉醇的细胞毒性。然后，我们以肿瘤重量和凋亡指数（TUNEL法）为参数，比较了用载体转染的MDA-MB-231（231-Vect）与231-E1A稳定细胞建立的原位肿瘤模型之间紫杉醇的治疗效果。我们发现在稳定的231-E1A细胞建立的肿瘤模型中，紫杉醇比对照231-Vect细胞在缩小肿瘤和诱导细胞凋亡方面更有效。我们还测试了E1A是否可以通过使用非病毒，表面保护的阳离子脂质体通过小鼠尾静脉递送E1A基因来直接增强紫杉醇对裸鼠的杀伤作用。我们在建立的MDA-MB-231细胞原位肿瘤动物模型中比较了E1A基因疗法与有无紫杉醇化疗的治疗效果，发现全身E1A基因疗法与紫杉醇化疗的结合显着增强了治疗效果，显着抑制肿瘤生长（P <.01）。此外，联合治疗的动物的存活率显着高于治疗对照组（均P <.0001）。因此，在基因治疗的背景下，E1A基因治疗确实增强了肿瘤细胞对化学疗法的敏感性，并且当前研究提供了临床前数据，以支持E1A基因与化学疗法之间的联合治疗，以用于未来的临床试验。