The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC V6H-3Z6, Canada.
Breast Cancer Res Treat. 2011 Jan;125(1):89-97. doi: 10.1007/s10549-010-0828-9. Epub 2010 Mar 16.
Targeting HER-2 over-expressing breast cancer cells with trastuzumab has resulted in significant improvements in both disease-free and overall survival rates. However, despite a favorable initial response, some cancer cells become resistant and develop into fatal metastatic disease. Here we report that we can specifically target HER-2 over-expressing and trastuzumab-resistant breast cancer cells by using an engineered lentivirus which has trastuzumab bound to its envelope. In vitro, this lentiviral construct mediated both the expression of reporter genes, such as enhanced green fluorescent protein (EGFP) and firefly luciferase, as well as the therapeutic gene, herpes thymidine kinase (hTK), in HER-2 over-expressing cells. Subsequent application of the pro-drug ganciclovir selectively killed breast cancer cells in which lentivirus mediated expression of hTK. In vivo, we successfully targeted the expression of firefly luciferase to trastuzumab-resistant breast cancer tumors established in nude mice. Furthermore, we found that systemic administration of trastuzumab-bound lentivirus led to expression of EGFP in circulating trastuzumab-resistant breast cancer cells. In conclusion, HER-2 over-expressing breast cancer cells resistant to trastuzumab can be targeted for selective gene expression and destruction by viruses with envelope-proteins engineered to bind to this antibody.
曲妥珠单抗靶向 HER-2 过表达的乳腺癌细胞已显著提高了无病生存率和总生存率。然而，尽管初始反应良好，一些癌细胞仍会产生耐药性，并发展为致命的转移性疾病。在这里，我们报告说，我们可以通过使用一种工程化的慢病毒来特异性地靶向 HER-2 过表达和曲妥珠单抗耐药的乳腺癌细胞，该慢病毒将曲妥珠单抗结合到其包膜上。在体外，这种慢病毒构建体介导了报告基因的表达，如增强型绿色荧光蛋白（EGFP）和萤火虫荧光素酶，以及治疗基因，单纯疱疹胸苷激酶（hTK），在 HER-2 过表达的细胞中。随后应用前药更昔洛韦选择性地杀死了慢病毒介导 hTK 表达的乳腺癌细胞。在体内，我们成功地将萤火虫荧光素酶的表达靶向到裸鼠中建立的曲妥珠单抗耐药乳腺癌肿瘤。此外，我们发现系统给予结合曲妥珠单抗的慢病毒会导致循环中曲妥珠单抗耐药乳腺癌细胞表达 EGFP。总之，曲妥珠单抗耐药的 HER-2 过表达乳腺癌细胞可以通过工程化包膜蛋白结合该抗体的病毒进行靶向性的基因表达和破坏。
