Department of Obstetrics and Gynecology, University of Düsseldorf Medical Center, Düsseldorf, Germany.
Gynecol Oncol. 2011 Oct;123(1):138-46. doi: 10.1016/j.ygyno.2011.06.007. Epub 2011 Jul 13.
Multidrug resistance gene 1 (MDR1) mediated resistance to chemotherapeutic agents is a major obstacle for the therapy of various cancer types. The use of conditionally replicating adenoviruses (CRAds) is dependent on molecular differences between tumor cells and non tumor cells. Transcriptional targeting of CRAd replication is an effective way to control replication regulation. The aim of this study was to evaluate the effect of a MDR1 targeted fiber-modified CRAd against chemotherapy resistant ovarian cancer.
MDR1 expression was evaluated in chemotherapy naïve and pretreated ovarian cancer cells and various control cells. We constructed 2 variants of a fiber-modified CRAd, Ad5/3MDR1E1 and Ad5/3MDR1E1∆24 containing the MDR1 promoter to control viral replication via the E1A gene. The MDR promoter activity and cell killing efficacy were evaluated in vitro. Orthotopic murine models of peritoneally disseminated ovarian cancer were utilized to evaluate the preclinical efficacy of MDR targeted CRAds in vivo. To evaluate the liver toxicity of MDR1 targeted CRAds, we compared Ad5/3MDR1E1 with Ad5/3∆24, a CRAd that replicates in cancer cells inactive in the Rb/p16 pathway by use of an in vivo hepatotoxicity model.
We demonstrate efficient oncolysis of Ad5/3MDR1E1 in both chemotherapy resistant ovarian cancer cell lines and in primary tumor cells from pretreated patients as well as therapeutic efficacy in an orthotopic mouse model. Ad5/3MDR1E1 demonstrated significantly decreased liver toxicity compared to other 5/3-fiber modified control vectors examined.
In summary, Ad5/3MDR1E1 is an efficient and safe gene therapy approach for specific targeting of chemotherapy resistant cancer cells.
多药耐药基因 1（MDR1）介导的对化疗药物的耐药性是各种癌症类型治疗的主要障碍。条件复制型腺病毒（CRAds）的使用依赖于肿瘤细胞与非肿瘤细胞之间的分子差异。CRAd 复制的转录靶向是控制复制调节的有效方法。本研究旨在评估针对化疗耐药卵巢癌的 MDR1 靶向纤维修饰型 CRAd 的疗效。
评估了化疗初治和预处理的卵巢癌细胞以及各种对照细胞中的 MDR1 表达。我们构建了两种纤维修饰型 CRAd 的变体，Ad5/3MDR1E1 和 Ad5/3MDR1E1∆24，它们含有 MDR1 启动子，通过 E1A 基因控制病毒复制。在体外评估了 MDR 启动子活性和细胞杀伤效力。利用腹膜播散性卵巢癌的原位小鼠模型评估了 MDR 靶向 CRAd 在体内的临床前疗效。为了评估 MDR1 靶向 CRAd 的肝毒性，我们比较了 Ad5/3MDR1E1 和 Ad5/3∆24，后者是一种通过使用体内肝毒性模型在 Rb/p16 途径失活的癌细胞中复制的 CRAd。
我们证明了 Ad5/3MDR1E1 在化疗耐药卵巢癌细胞系以及预处理患者的原发性肿瘤细胞中均能有效进行肿瘤溶解，并且在原位小鼠模型中具有治疗效果。与其他 5/3 纤维修饰对照载体相比，Ad5/3MDR1E1 显示出明显降低的肝毒性。
总之，Ad5/3MDR1E1 是一种针对化疗耐药癌细胞的高效、安全的基因治疗方法。
