Oncolytic Virotherapy as a Novel Strategy for Pancreatic Cancer
Oncolytic Virotherapy as a Novel Strategy for Pancreatic Cancer
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DOI：
10.1097/00006676-200404000-00022
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发表时间：
2004-04
期刊：
影响因子：
2.9
通讯作者：
M. Sunamura;H. Hamada;F. Motoi;M. Oonuma;H. Abe;Y. Saitoh;T. Hoshida;Shigeru Ottomo;N. Omura;S. Matsuno
中科院分区：
文献类型：
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作者：
M. Sunamura;H. Hamada;F. Motoi;M. Oonuma;H. Abe;Y. Saitoh;T. Hoshida;Shigeru Ottomo;N. Omura;S. Matsuno
摘要：我们已经开发出一种新的基因治疗，靶向胰腺癌的基因改变，在肿瘤细胞中使用溶瘤复制选择性腺病毒。E1 B-55 kDa缺失型腺病毒（AxE 1AdB）可以在TP 53缺陷的人癌细胞中选择性复制，但不能在具有功能性TP 53的细胞中复制。连续注射AxE 1AdB可明显抑制重症联合免疫缺陷病小鼠胰腺肿瘤的生长。此外，AxE 1AdB显示出作为病毒载体增强基因表达的能力。据报道，尿嘧啶磷酸核糖转移酶（UPRT）克服了5-FU耐药性。因此，在腹膜内播散性肿瘤模型中评价了表达UPRT的复制选择性腺病毒（AxE 1AdB-UPRT）的治疗优势。5-FU和AxE 1 AdB-UPRT的联合治疗显着降低了扩散的肿瘤负荷，而不会对正常组织造成毒性。我们还阐明了AxE 1AdB通过保留的E1 A区域抑制肿瘤血管生成的过程：腺病毒E1 A蛋白与pRB结合，迫使静止细胞进入S期。我们构建了一个双突变体，复制选择性腺病毒（AxdAdB-3），其中包含E1 A区RB结合基序的突变和大E1 B-55 kDa的缺失。AxdAdB-3在体外迅速诱导癌细胞死亡，并在体内显示出有效的抗肿瘤作用。这些结果强烈表明，AxdAdB-3具有比以前认为的更广泛的治疗潜力，因为大多数胰腺癌在TP 53和RB通路中都存在异常。
Abstract: We have developed a novel gene therapy that targets genetic alterations in pancreatic cancer using oncolytic replication–selective adenoviruses in tumor cells. E1B-55kDa-deleted adenovirus (AxE1AdB) can selectively replicate in TP53-deficient human cancer cells but not cells with functional TP53. Consecutive injection with AxE1AdB markedly inhibited the growth of human pancreatic tumors in severe combined immunodeficiency disease mice. Furthermore, AxE1AdB displayed the ability to enhance gene expression as a virus vector. It is reported that uracil phosphoribosyl transferase (UPRT) overcomes 5-FU resistance. The therapeutic advantage of a replication-selective adenovirus that expresses UPRT (AxE1AdB-UPRT) was thus evaluated in an intraperitoneum-disseminated tumor model. Combined treatment with 5-FU and AxE1AdB-UPRT dramatically reduced the disseminated tumor burden without causing toxicity in normal tissues. We also clarified the process of AxE1AdB-inhibited tumor angiogenesis through the preserved E1A region: an adenoviral E1A protein binds to pRB, forcing the quiescent cell into the S phase. We constructed a double-mutant, replication-selective adenovirus (AxdAdB-3) containing a mutation in the RB-binding motif of the E1A region and a deletion of large E1B-55kDa. AxdAdB-3 swiftly induced cancer cell death in vitro and showed a potent antitumor effect in vivo. These results strongly suggest that AxdAdB-3 possesses a wider therapeutic potential than previously believed, given that most pancreatic cancers have abnormalities in both the TP53 and RB pathways.