Genetic replacement of the adenovirus shaft fiber reduces liver tropism in ovarian cancer gene therapy
Genetic replacement of the adenovirus shaft fiber reduces liver tropism in ovarian cancer gene therapy
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DOI：
10.1089/10430340460745829
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发表时间：
2004-05-01
影响因子：
4.2
通讯作者：
Curiel, DT
中科院分区：
文献类型：
--
作者：
Breidenbach, M;Rein, DT;Curiel, DT
改变腺病毒（Ads）天然嗜性的方法有利于提高其功效和安全性。肝嗜性对于人体潜在临床毒性很重要。Ad 5/3嵌合体，其中Ad 5球被Ad 3球取代，如Ad 5/3luc 1，最近已显示增加卵巢癌细胞系和原发性肿瘤细胞的感染性，其表达低水平的柯萨奇-腺病毒受体（CAR），而不增加肝细胞的感染性。一种新的策略，以解决肝脏摄取的问题，并提高肿瘤/肝脏的比例是遗传替代的Ad纤维轴。Ad5。Ad3.SH.luc1是一种基于Ad 5的载体，含有来自Ad血清型3的纤维轴，但含有来自Ad血清型5的纤维球。比较Ad 5的肿瘤/肝脏。Ad3。SH. luc 1和Ad 5/3luc 1在体内，我们在小鼠中建立了三种不同的卵巢癌肿瘤和治疗模型，模拟腹腔内和静脉内施用肿瘤。Ad5。Ad3。SH.在所有测试的模型中，LUC 1显示出所有病毒中最低的肝嗜性。所有病毒的静脉内给药与腹膜内给药相比导致更高的肿瘤转导率。Ad 5纤维轴的遗传缩短显著增加相对肿瘤/肝脏基因转移。这可以提高有效的肿瘤剂量并减少副作用，从而提高治疗剂的生物利用度。
Approaches to alter the native tropism of adenoviruses ( Ads) are beneficial to increase their efficacy and safety profile. Liver tropism is important with regard to potential clinical toxicity in humans. Ad5/3 chimeras in which the Ad5 knob is substituted by the Ad3 knob, such as Ad5/3luc1, have been recently shown to increase infectivity of ovarian cancer cell lines and primary tumor cells, which express low levels of the coxsackie-adenovirus receptor ( CAR), without increasing infectivity of liver cells. A novel strategy to address the problem of liver uptake and improve the tumor/liver ratio is genetic replacement of the Ad fiber shaft. Ad5. Ad3.SH.luc1 is an Ad5-based vector that contains the fiber shaft from Ad serotype 3 but the fiber knob from Ad serotype 5. To compare tumor/liver of Ad5. Ad3. SH. luc1 and Ad5/ 3luc1 in vivo, we created three different tumor and treatment models of ovarian cancer in mice, simulating intraperitoneal and intravenous administration of tumors. Ad5. Ad3. SH. luc1 displayed the lowest liver tropism of all viruses in all models tested. Intravenous administration of all viruses resulted in higher tumor transduction rates compared to intraperitoneal administration. Genetic shortening of the Ad5 fiber shaft significantly increases relative tumor/liver gene transfer. This could improve the effective tumor dose and reduce side effects, thereby increasing the bioavailability of therapeutic agents.