基于环氧合酶-2启动子的条件性复制腺病毒增强胰腺癌感染性

Infectivity enhanced, cyclooxygenase-2 promoter-based conditionally replicative adenovirus for pancreatic cancer.

作者信息

Yamamoto Masato, Davydova Julia, Wang Minghui, Siegal Gene P, Krasnykh Victor, Vickers Selwyn M, Curiel David T

机构信息

Division of Human Gene Therapy, University of Alabama at Birmingham, BMR2-408, 901 19th Street South, Birmingham, Alabama 35294-2172, USA.

出版信息

Gastroenterology. 2003 Oct;125(4):1203-18. doi: 10.1016/s0016-5085(03)01196-x.

DOI:10.1016/s0016-5085(03)01196-x

PMID:14517802

Abstract

BACKGROUND AND AIMS

Pancreatic cancer is one of the most aggressive human malignancies. Conditionally replicative adenoviruses (CRAds) have shown some promise in the treatment of cancers. However, to date, their application for pancreatic cancer has met several obstacles: one is lack of a good control element to regulate replication, and the other is relatively low adenoviral infectivity. Thus, we constructed infectivity enhanced cyclooxygenase (COX)-2 promoter-based CRAds to develop a safe and effective therapeutic modality.

METHODS

The CRAds were designed to achieve COX-2 promoter-controlled E1 expression for regulated replication (COX-2 CRAds). The infectivity-enhanced CRAds also have an RGD-4C motif in the adenoviral fiber-knob region. The selectivity and efficacy of these constructs were analyzed with cell lines in vitro. The in vivo therapeutic effect and viral replication were analyzed with a xenograft model. Pathology of the major organs and E1 RNA levels in the liver were also studied after systemic administration.

RESULTS

The COX-2 CRAds showed a selective cytocidal effect in vitro in COX-2-positive cells and killed most of the pancreatic cancer cells. In vivo, intratumoral administration of the infectivity-enhanced COX-2 CRAds (10(9) particles) showed a strong antitumor effect comparable to wild-type virus, whereas the COX-2 CRAds without infectivity enhancement showed a limited effect. Viral replication was confirmed in the xenograft tumors. Systemic administration did not cause any detectable toxicity; the E1 RNA level in the liver after COX-2 CRAd administration was minimal.

CONCLUSIONS

Infectivity-enhanced COX-2 CRAd is a promising agent for the treatment of pancreatic cancer.

摘要

背景与目的

胰腺癌是最具侵袭性的人类恶性肿瘤之一。条件性复制腺病毒（CRAds）在癌症治疗中已显示出一定前景。然而，迄今为止，它们在胰腺癌治疗中的应用遇到了几个障碍：一是缺乏良好的调控元件来调节复制，二是腺病毒感染性相对较低。因此，我们构建了基于感染性增强的环氧合酶（COX）-2启动子的CRAds，以开发一种安全有效的治疗方式。

方法

设计CRAds以实现COX-2启动子控制的E1表达，用于调控复制（COX-2 CRAds）。感染性增强的CRAds在腺病毒纤维钮区域还具有RGD-4C基序。用体外细胞系分析这些构建体的选择性和功效。用异种移植模型分析体内治疗效果和病毒复制。全身给药后还研究了主要器官的病理学和肝脏中的E1 RNA水平。

结果

COX-2 CRAds在体外对COX-2阳性细胞显示出选择性杀细胞作用，并杀死了大多数胰腺癌细胞。在体内，瘤内注射感染性增强的COX-2 CRAds（10^9个颗粒）显示出与野生型病毒相当的强大抗肿瘤作用，而未增强感染性的COX-2 CRAds显示出有限的作用。在异种移植肿瘤中证实了病毒复制。全身给药未引起任何可检测到的毒性；COX-2 CRAd给药后肝脏中的E1 RNA水平极低。