Gomez-Manzano Candelaria, Yung W K Alfred, Alemany Ramon, Fueyo Juan
Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Neurology. 2004 Aug 10;63(3):418-26. doi: 10.1212/01.wnl.0000133302.15022.7f.
Oncolytic or tumor-selective adenoviruses are constructed as novel antiglioma therapies. After infection, the invading genetic adenoviral material is activated within the host cell. E1A and E1B adenoviral proteins are expressed immediately. E1A protein interacts with cell cycle regulatory proteins, such as retinoblastoma (Rb), driving the cell into the S phase and ensuing viral replication. The action of E1A stimulates the cellular p53 tumor suppressor system, which results in growth arrest or apoptosis, and halts adenovirus replication. However, adenoviral E1B interacts with p53 protein, preventing the DNA replication process from being abrogated by the induction of p53-mediated apoptosis. It was subsequently hypothesized that mutant adenoviruses that were unable to express wild-type E1A or E1B proteins could not replicate in normal cells with functional Rb or p53 pathways but instead would replicate and kill glioma cells that had defects in the regulation of these tumor suppressor pathways. Mutant E1B adenoviruses have already entered the clinical setting as an experimental treatment for patients with malignant gliomas. Mutant E1A adenoviruses are now in preclinical development as antiglioma therapy. In this review, the authors describe the mechanisms underlying the production of oncolytic adenoviruses, preclinical and clinical experiences with specific oncolytic adenoviruses, and the possibilities of combining mutant oncolytic adenoviruses with gene therapy or conventional therapies for managing malignant gliomas.
溶瘤性或肿瘤选择性腺病毒被构建为新型抗胶质瘤疗法。感染后，入侵的腺病毒遗传物质在宿主细胞内被激活。E1A和E1B腺病毒蛋白立即表达。E1A蛋白与细胞周期调节蛋白相互作用，如视网膜母细胞瘤（Rb），促使细胞进入S期并随后进行病毒复制。E1A的作用刺激细胞p53肿瘤抑制系统，导致生长停滞或凋亡，并停止腺病毒复制。然而，腺病毒E1B与p53蛋白相互作用，防止DNA复制过程因p53介导的凋亡诱导而被废除。随后有人推测，无法表达野生型E1A或E1B蛋白的突变腺病毒不能在具有功能性Rb或p53途径的正常细胞中复制，而是会在这些肿瘤抑制途径调节存在缺陷的胶质瘤细胞中复制并杀死它们。突变型E1B腺病毒已作为恶性胶质瘤患者的实验性治疗方法进入临床应用。突变型E1A腺病毒目前正处于作为抗胶质瘤疗法的临床前开发阶段。在这篇综述中，作者描述了溶瘤腺病毒产生的潜在机制、特定溶瘤腺病毒的临床前和临床经验以及将突变型溶瘤腺病毒与基因疗法或传统疗法联合用于治疗恶性胶质瘤的可能性。
