Experimental treatment of ovarian cancers by adenovirus vectors combining receptor targeting and selective expression of tumor necrosis factor.
Experimental treatment of ovarian cancers by adenovirus vectors combining receptor targeting and selective expression of tumor necrosis factor.
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DOI：
10.3892/ijo.31.4.813
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发表时间：
2007-10
影响因子：
5.2
通讯作者：
S. Murugesan;Masaki Akiyama;D. Einfeld;T. Wickham;C. King
中科院分区：
文献类型：
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作者：
S. Murugesan;Masaki Akiyama;D. Einfeld;T. Wickham;C. King
卵巢癌是女性中第四大常见癌症，现有治疗方法无法常规治愈。癌症治疗的一种新策略是通过腺病毒载体将TNF α选择性递送至肿瘤。我们已经测试了对腺病毒载体的两种修饰的组合，所述腺病毒载体被设计为限制递送至肿瘤、衣壳修饰和表达控制。为了靶向在肿瘤中高度表达而在腹膜上皮层中稀疏表达的α（v）β（3/5）整联蛋白受体，我们修饰了衣壳纤维和五邻体基底以去除天然受体结合，并在纤维结中掺入了RGD-4C基序（Ad.PB*F*RGD）。该载体在体外和体内测试的所有α（v）β（3/5）阳性卵巢癌细胞中表现出有效的基因转移。重要的是，Ad.PB*F*RGD载体能够抑制卵巢肿瘤结节，并避免感染腹膜内给药后排列在腹膜内空间的正常间皮细胞。为了进一步提高选择性，将不同的启动子整合到衣壳修饰的载体中以赋予hTNF α治疗基因的表达。我们分析了组成型（CMV或RSV）和潜在的肿瘤选择性启动子（MUC-1，E2 F或hTERT）的疗效，选择性和安全性。含有MUC-1启动子的表达TNF的Ad.PB*F*RGD载体在两种卵巢癌异种移植模型（Caov 3和Igr-ov 1）中显示出抗肿瘤活性，几乎没有毒性或全身TNF的证据。这些数据表明，衣壳修饰和表达的转录调控的组合是开发新的卵巢癌治疗的有前途的策略。
Ovarian cancer is the fourth most common cancer among women and existing treatment is not routinely curative. One new strategy for cancer therapy is the selective delivery of TNFalpha to tumors via adenovirus vectors. We have tested the combination of two modifications to adenovirus vectors designed to limit delivery to tumors, capsid modification and expression control. To target alpha(v)beta(3/5) integrin receptors that are highly expressed in tumor and sparsely expressed in the epithelial layer of peritoneum, we modified the capsid fiber and penton base to remove native receptor binding and incorporated an RGD-4C motif in the fiber knob (Ad.PB*F*RGD). This vector exhibits effective gene transfer in all of the alpha(v)beta(3/5)-positive ovarian cancer cells tested in vitro and in vivo. Importantly, the Ad.PB*F*RGD vector is able to transduce ovarian tumor nodules and avoid infecting the normal mesothelial cells that line the intraperitoneal space following intraperitoneal administration. To further increase selectivity, different promoters were incorporated into the capsid-modified vector to confer the expression of the hTNFalpha therapeutic gene. We analyzed both constitutive (CMV or RSV) and potentially tumor selective promoters (MUC-1, E2F or hTERT) in terms of efficacy, selectivity and safety. TNF-expressing Ad.PB*F*RGD vectors containing the MUC-1 promoter showed anti-tumor activity in two ovarian cancer xenograft models (Caov3 and Igr-ov1) with little evidence of toxicity or systemic TNF. The data indicate that combination of capsid modification and transcriptional regulation of expression is a promising strategy for development of a new ovarian cancer treatment.