Alonso Marta M, Cascallo Manel, Gomez-Manzano Candelaria, Jiang Hong, Bekele B Nebiyou, Perez-Gimenez Anna, Lang Frederick F, Piao Yuji, Alemany Ramon, Fueyo Juan
Brain Tumor Center, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Res. 2007 Sep 1;67(17):8255-63. doi: 10.1158/0008-5472.CAN-06-4675.
During 2007, approximately 200,000 people in the United States will be diagnosed with brain tumors. Gliomas account for 77% of primary malignant brain tumors, and the prognosis has hardly changed in the past 20 years, with only 30% of patients with malignant glioma surviving 5 years after diagnosis. Oncolytic adenoviruses are promising therapies for the treatment of gliomas. Here, report the antiglioma activity of the tumor-selective ICOVIR-5 adenovirus, which encompasses an early 1A adenoviral (E1A) deletion in the retinoblastoma (Rb) protein-binding region, substitution of the E1A promoter for E2F-responsive elements, and an RGD-4C peptide motif inserted into the adenoviral fiber to enhance adenoviral tropism. Mechanistic studies showed a dramatic addiction of ICOVIR-5 to the E2F1 oncogene in vitro and in vivo. This addiction was mediated by the occupancy of the ectopic adenoviral E2F1-responsive elements by the endogenous E2F1 protein resulting in high level of E1A expression in cancer cells and potent antiglioma effect. Importantly, we showed for the first time the ability of oncolytic adenoviruses to enhance E2F transcriptional activity in vivo, and we provided direct evidence of the interaction of the E2F1 protein with native and ectopic adenovirus promoters. Restoration of Rb function led to the association of Rb/E2F1 repressor complexes with ICOVIR-5 ectopic E2F1 promoter and subsequent down-modulation of E1A, dramatically impairing adenoviral replication. In xenografted mice, intratumoral injection of ICOVIR-5 resulted in a significant improvement of the median survival (P < 0.0001), and furthermore, led to 37% of long-term survivors free of disease. The antitumor activity of ICOVIR-5 suggests that it has the potential to be an effective agent in the treatment of gliomas.
2007年期间，美国约有20万人将被诊断患有脑肿瘤。神经胶质瘤占原发性恶性脑肿瘤的77%，在过去20年中其预后几乎没有变化，只有30%的恶性神经胶质瘤患者在诊断后能存活5年。溶瘤腺病毒是治疗神经胶质瘤的有前景的疗法。在此，我们报道肿瘤选择性ICOVIR-5腺病毒的抗神经胶质瘤活性，该病毒在视网膜母细胞瘤（Rb）蛋白结合区域存在早期1A腺病毒（E1A）缺失，用E2F反应元件取代E1A启动子，并在腺病毒纤维中插入RGD-4C肽基序以增强腺病毒嗜性。机制研究表明，ICOVIR-5在体外和体内对E2F1癌基因有显著依赖性。这种依赖性是由内源性E2F1蛋白占据异位腺病毒E2F1反应元件介导的，导致癌细胞中E1A高水平表达和强大的抗神经胶质瘤作用。重要的是，我们首次展示了溶瘤腺病毒在体内增强E2F转录活性的能力，并提供了E2F1蛋白与天然和异位腺病毒启动子相互作用的直接证据。Rb功能的恢复导致Rb/E2F1阻遏复合物与ICOVIR-5异位E2F1启动子结合，随后E1A下调，显著损害腺病毒复制。在异种移植小鼠中，瘤内注射ICOVIR-5导致中位生存期显著改善（P < 0.0001），此外，还导致37%的长期存活者无疾病。ICOVIR-5的抗肿瘤活性表明它有潜力成为治疗神经胶质瘤的有效药物。
