Department of Genetic Therapy, Sidney Kimmel Cancer Center, San Diego, California, USA.
Mol Ther. 2010 May;18(5):921-8. doi: 10.1038/mt.2010.5. Epub 2010 Feb 23.
To target chemotherapy to tumor vascular endothelial cells (TVECs), we created the AdTie2RprCDFib(knob-RGD+) vector by inserting into an AdEasy adenoviral vector (Ad) backbone: (i) the cytosine deaminase (CD) gene driven by the Tie2 receptor promoter (Tie2Rpr) into the E1 region of Ad; (ii) mutations that reduce binding of the fiber knob to the Coxsackie adenovirus receptor (CAR); and (iii) the RGD peptide into the H1 loop of fiber for binding to the alpha(V)beta(3) integrin receptors on TVECs. To reduce uptake of the AdTie2RprCDFib(knob-RGD+) by reticuloendothelial (RE) and liver cells, we intravenously (i.v.) injected Hetastarch and low-dose Ad (one million vector particles (VPs)) prior to i.v. injection of a therapeutic dose (one billion VPs) of the AdTie2RprCDFib(knob-RGD+) vector. This treatment induced regressions of N202 breast cancer and B16 melanoma without toxicity to normal tissues. We showed that the tumor regression was induced by infection of the TVECs and not by the infection of tumor cells by the AdTie2RprCDFib(knob-RGD+) vector.
为了将化疗靶向肿瘤血管内皮细胞（TVECs），我们通过将以下部分插入 AdEasy 腺病毒载体（Ad）骨架来创建 AdTie2RprCDFib(knob-RGD+) 载体：（i）受 Tie2 受体启动子（Tie2Rpr）驱动的胞嘧啶脱氨酶（CD）基因插入到 Ad 的 E1 区；（ii）突变降低了纤维旋钮与柯萨奇腺病毒受体（CAR）的结合；以及（iii）RGD 肽插入纤维的 H1 环中，以与 TVECs 上的α(V)β(3)整合素受体结合。为了减少 AdTie2RprCDFib(knob-RGD+) 被网状内皮（RE）和肝细胞摄取，我们在静脉内（i.v.）注射 Hestastarch 和低剂量的 Ad（一百万病毒颗粒（VP）），然后静脉内注射治疗剂量（十亿 VP）的 AdTie2RprCDFib(knob-RGD+) 载体。这种治疗方法诱导了 N202 乳腺癌和 B16 黑色素瘤的消退，而对正常组织没有毒性。我们表明，肿瘤消退是由 TVECs 的感染引起的，而不是由 AdTie2RprCDFib(knob-RGD+) 载体感染肿瘤细胞引起的。
