Division of Gastrointestinal Surgery and Surgical Oncology, Department of Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon-shi, Ehime 791-0295, Japan.
Int J Oncol. 2011 Jan;38(1):33-9.
We assessed the effects of direct injection of docetaxel-loaded immuno-(trastuzumab)-liposomes (IDL) on a xenograft mouse tumor model to determine potential clinical applications of intratumoral tailored chemotherapy against Her2/neu-overexpressing gastric cancer. The NCI-N87 Her2/neu overexpressing gastric cancer cell line xenograft mouse model was treated with IDL or docetaxel-loaded liposomes (DL). The ratio of the tumor volume of the treatment:control was determined. In addition, docetaxel pharmacokinetics in tumors were measured using high-performance liquid chromatography, and the cell viability and cell cycle distribution of Her2/neu positive cells were determined by flow cytometric analysis. The IDL group showed a significantly higher distribution of docetaxel in the N87 xenograft tumor tissues and superior antitumor efficacy compared to crude administration of docetaxel and/or trastuzumab and DL. The number of viable Her2/neu positive cells decreased following treatment with either free trastuzumab or IDL. On day 7 after treatment, a decrease in the G0/G1 phase of the cell cycle was observed in the DL and IDL groups compared to the control group. No local adverse effects were observed. These results suggest that intratumoral administration of IDL maintains a high concentration of docetaxel within the tumor leading to a safe and effective regional cancer therapeutic strategy. In addition to the inherent cytotoxic effect of trastuzumab, conjugation of trastuzumab to a liposome further enhanced the retention of docetaxel within the tumors. These data suggest that immuno-liposome mediated delivery of drugs is a promising new therapeutic option for patients with advanced gastric cancer that overexpress Her2/neu.
我们评估了载多西紫杉醇免疫(曲妥珠单抗)脂质体(IDL)直接注射对 Her2/neu 过表达胃癌荷瘤鼠模型的影响,以确定针对 Her2/neu 过表达胃癌的瘤内靶向化疗的潜在临床应用。我们用 IDL 或载多西紫杉醇脂质体(DL)处理 NCI-N87 Her2/neu 过表达胃癌细胞系荷瘤鼠模型。用肿瘤体积比来确定治疗效果。此外,我们用高效液相色谱法测量肿瘤内多西紫杉醇的药代动力学,并用流式细胞术分析测定 Her2/neu 阳性细胞的细胞活力和细胞周期分布。IDL 组在 N87 荷瘤肿瘤组织中显示出更高的多西紫杉醇分布,与粗制多西紫杉醇和/或曲妥珠单抗和 DL 的治疗相比,具有更好的抗肿瘤疗效。用游离曲妥珠单抗或 IDL 处理后,Her2/neu 阳性细胞的活细胞数减少。治疗后第 7 天,与对照组相比,DL 和 IDL 组细胞周期的 G0/G1 期减少。未观察到局部不良反应。这些结果表明,瘤内给予 IDL 可使肿瘤内的多西紫杉醇保持高浓度,从而实现安全有效的局部癌症治疗策略。除了曲妥珠单抗的固有细胞毒性作用外,将曲妥珠单抗与脂质体结合进一步增强了多西紫杉醇在肿瘤内的保留。这些数据表明,免疫脂质体介导的药物递送是一种有前途的新治疗选择,可用于治疗 Her2/neu 过表达的晚期胃癌患者。