Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
Clin Cancer Res. 2011 Feb 1;17(3):538-49. doi: 10.1158/1078-0432.CCR-10-1628. Epub 2010 Nov 29.
Current treatments for ovarian cancer have limited therapeutic outcomes due to advanced stage of the disease at diagnosis. Among new therapies, conditionally replicating adenoviruses (CRAds), designed to selectively lyse cancer cells, hold promise. In clinical trials, CRAds exhibited limited efficacy thus far. Second-generation CRAds are being developed to express a therapeutic protein to enhance antitumor efficacy. One attractive target in the tumor microenvironment is the matrix metalloproteinases (MMPs) that degrade the extracellular matrix, and are upregulated in ovarian cancer. Tissue inhibitor of metalloproteinase 2 (TIMP2) is an endogenous inhibitor of MMPs. The present study developed and evaluated a novel CRAd (Ad5/3-CXCR4-TIMP2) for ovarian cancer therapy.
A targeted CRAd, Ad5/3-CXCR4-TIMP2 was developed using the CXCR4 promoter for enhanced replication, and expressing the TIMP2 transgene. The efficacy of this armed CRAd was determined in both established human ovarian cancer cell lines and in primary ovarian tumor samples.
Ad5/3-CXCR4-TIMP2 mediated expression of functional TIMP2, as demonstrated by the inhibition of MMP activity. In addition, arming with TIMP2 did not inhibit viral replication or oncolytic potency, as the TIMP2-armed viruses showed enhanced killing of cancer cells when compared to the unarmed viruses. We also examined viral replication in primary ovarian cancer tissues obtained from patients with stage III and IV ovarian cancer. In four of the five tumor samples, Ad5/3-CXCR4-TIMP2 revealed a 21- to 89-fold increase in replication when compared to the Ad5/3 virus.
Results support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of patients with advanced ovarian cancer.
由于诊断时疾病已处于晚期，目前针对卵巢癌的治疗方法疗效有限。在新的治疗方法中，条件复制型腺病毒（CRAds）有望选择性裂解癌细胞。在临床试验中，CRAds 的疗效迄今为止有限。第二代 CRAds 正在被开发以表达治疗性蛋白来增强抗肿瘤疗效。肿瘤微环境中的一个有吸引力的靶标是基质金属蛋白酶（MMPs），它们降解细胞外基质，在卵巢癌中上调。组织金属蛋白酶抑制剂 2（TIMP2）是 MMPs 的内源性抑制剂。本研究开发并评估了一种用于卵巢癌治疗的新型 CRAd（Ad5/3-CXCR4-TIMP2）。
使用 CXCR4 启动子开发靶向 CRAd（Ad5/3-CXCR4-TIMP2），以增强复制，并表达 TIMP2 转基因。在已建立的人卵巢癌细胞系和原发性卵巢肿瘤样本中，确定了这种武装 CRAd 的疗效。
Ad5/3-CXCR4-TIMP2 介导功能性 TIMP2 的表达，如 MMP 活性的抑制所证明。此外，用 TIMP2 武装不会抑制病毒复制或溶瘤效力，因为与无武装病毒相比，TIMP2 武装的病毒对癌细胞的杀伤作用增强。我们还检查了从 III 期和 IV 期卵巢癌患者获得的原发性卵巢癌组织中的病毒复制。在五个肿瘤样本中的四个中，与 Ad5/3 病毒相比，Ad5/3-CXCR4-TIMP2 的复制增加了 21 至 89 倍。
结果支持将 Ad5/3-CXCR4-TIMP2 用于治疗晚期卵巢癌患者的转化潜力。
