Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer
Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer
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DOI：
10.1038/sj.onc.1204094
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发表时间：
2000-12-27
期刊：
影响因子：
8
通讯作者：
Kirn, D
中科院分区：
文献类型：
--
作者：
Kirn, D
任何癌症治疗的临床效用都是由其抗肿瘤效力和癌细胞与正常细胞之间的治疗指数来确定的。转移性实体瘤的化疗通常由于治疗指数不足和/或抗肿瘤效力不足而失败。虽然标准药物针对癌细胞内各种不同的结构，但几乎所有的药物都被认为是通过诱导细胞凋亡来杀死癌细胞的。因此，即使联合使用多种高剂量化疗药物，也会产生抗凋亡克隆。因此，新的治疗方法不仅必须比现有的治疗方法具有更强的效力和更强的选择性，而且还应该具有新的作用机制，不会与现有的治疗方法产生交叉耐药性（即疗效不应完全依赖于癌细胞的凋亡诱导）。复制选择性溶瘤病毒（病毒治疗）似乎具有这些特点。病毒进化为感染细胞、复制、诱导细胞死亡、释放病毒颗粒，最终在人体组织中传播。肿瘤组织中的复制导致肿瘤部位的输入剂量放大，而正常组织中缺乏复制可导致有效清除并降低毒性（图1）。肿瘤组织内的选择性复制理论上可以显著提高这些药物的治疗指数。此外，病毒通过一些独特的机制杀死细胞。除了在复制周期结束时直接裂解外，病毒还可以通过表达有毒蛋白、诱导炎症细胞因子和t细胞介导的免疫以及增强细胞对其作用的敏感性来杀死细胞。因此，由于癌细胞中经典凋亡途径的激活不是唯一的杀伤模式，因此与标准化疗或放疗的交叉耐药发生的可能性要小得多。分子生物学和遗传学的革命性进展已经导致了对(1)病毒的复制和致病性以及(2)致癌作用的基本理解。这些进步使得新的药物被设计来提高它们的安全性和/或抗肿瘤的效力。在过去的十年中，正在开发的基因工程病毒包括腺病毒、疱疹病毒和牛痘病毒。具有固有肿瘤选择性的病毒已被鉴定，包括呼肠孤病毒、自主细小病毒、新城疫病毒、麻疹病毒株和水疱性口炎病毒（Kirn, 2000a）。这些药物中的每一种在体外和/或体内都显示出肿瘤选择性，其中许多药物遵循肿瘤内、腹腔和/或静脉给药途径。
The clinical utility of any cancer treatment is defined by both its antitumoral potency and its therapeutic index between cancerous and normal cells. Chemotherapy for metastatic solid tumors generally fails due to an insufficient therapeutic index and/or insufficient antitumoral potency. Although standard agents target a variety of different structures within cancer cells, almost all of them are thought to kill cancer cells through the induction of apoptosis. As a result, apoptosis-resistant clones develop following standard therapies, even if numerous high-dose chemotherapeutic agents are used in combination. Novel therapeutic approaches must therefore have not only greater potency and greater selectivity than currently available treatments, they should also have novel mechanisms of action that will not be subject to cross-resistance with existing approaches (ie efficacy should not be exclusively dependent on apoptosis induction in cancer cells).Replication-selective oncolytic viruses (virotherapy) appear to have these characteristics. Viruses have evolved to infect cells, replicate, induce cell death, release of viral particles, and finally to spread in human tissues. Replication in tumor tissue leads to amplification of the input dose at the tumor site, while a lack of replication in normal tissues can result in efficient clearance and reduced toxicity (Figure 1). Selective replication within tumor tissue can theoretically increase the therapeutic index of these agents dramatically. In addition, viruses kill cells by a number of unique mechanisms. In addition to direct lysis at the conclusion of the replicative cycle, viruses can kill cells through expression of toxic proteins, induction of both inflammatory cytokines and T-cell-mediated immunity, and enhancement of cellular-sensitivity to their effects. Therefore, since activation of classical apoptosis pathways in the cancer cell is not the exclusive mode of killing, cross-resistance with standard chemotherapeutics or radiotherapy is much less likely to occur. Revolutionary advances in molecular biology and genetics have led to a fundamental understanding of both (1) the replication and pathogenicity of viruses and (2) carcinogenesis. These advances have allowed novel agents to be engineered to enhance their safety and/or their antitumoral potency. Over the past decade, genetically-engineered viruses in development have included adenoviruses, herpesviruses and vaccinia. Viruses with inherent tumor-selectivity have been characterized and include reovirus, autonomous parvoviruses, Newcastle disease virus, measles virus strains and vesicular stomatitis virus (Kirn, 2000a). Each of these agents has shown tumor selectivity in vitro and/or in vivo, with many of these agents following intratumoral, intraperitoneal and/or intravenous routes of administration.