Cancer Research：脊髓灰质炎病毒可破坏小鼠成神经细胞瘤
脊髓灰质炎病毒（poliovirus）虽然是引起某种儿童疾病的罪魁祸首，但可治疗另一种儿童疾病——成神经细胞瘤（neuroblastoma）。3月15日《Cancer Research》杂志
一篇文章报道，Stony Brook大学研究人员利用一种无毒性的poliovirus，有效去除了小鼠的成神经细胞瘤，即便此小鼠曾经接种过抵御poliovirus的疫苗。
poliovirus破坏被其感染的细胞，复制出的病毒颗粒从细胞中释放后，再攻击周围细胞。研究人员利用了病毒的这一特点，在感染过脊髓灰质炎病毒的成神经细胞瘤模型小鼠体内直接注射毒力已经被削弱的poliovirus，结果病毒破坏了所有12只小鼠体内的肿瘤，180天后有两只小鼠的肿瘤复发。
病毒自身没有在任何一只小鼠体内引起副作用。研究人员说，病毒颗粒进入血流后会被poliovirus疫苗产生的抗体消灭，如果应用于人类，可能会成为一种安全有效的治疗致癌症的措施。
“一种无毒的poliovirus，是寻找能够杀灭肿瘤但不会伤害患者的一个重要步骤，” Hidemi Toyoda博士说，“我们有效地驯服了一种在几十年前对儿童有致死性的病毒polio，并用其一个重要天性治疗了一种在当代有致死性的疾病。”
奇怪的是，研究人员还发现poliovirus能够有效杀灭小鼠体内新出现的肿瘤。成神经细胞瘤是四大常见儿童实体肿瘤之一，化疗后经常复发。“成神经细胞瘤很难治愈，化疗不利于日后健康，与传统疗法相结合，一种poliovirus治疗能减少儿童接受化疗和放疗的次数，降低副作用。”
为了检测poliovirus治疗癌症的效果，研究人员首先要获得一种安全形式的病毒。Eckard Wimmer博士曾经利用poliovirus的基本化学成分合成出poliovirus，并在合成poliovirus的基础上，利用病毒RNA基因组非spacer region区（一个相当重要的功能区）中的一个核苷酸取代spacer region区的一个核苷酸，得到高度减弱的病毒。文章高级作者Jeronimo Cello评价此工程为给病毒上了双保险。“如果spacer region区一直被阻断，遗传工程poliovirus就不能产生自身的神经剧毒（neurovirulent）拷贝，”Cello说，“万一调节基因元件丢失了，病毒也不会复制。”
为了检测病毒破坏成神经细胞瘤的能力，研究人员建立了一个携带人类CD155基因（CD155编码允许poliovirus进入细胞的受体）的成神经细胞瘤转基因小鼠模型。然后给小鼠接种抵抗poliovirus的疫苗。
因为大多数人都接受过抵抗poliovirus的疫苗免疫，Toyoda与其同事想知道是否这种免疫会妨碍病毒治疗肿瘤。通过直接将病毒注射到小鼠的肿瘤中，研究人员证明病毒能够找到靶标并绕过疫苗产生的抗体。
不仅npoliovirus有破坏肿瘤的能力，病毒治疗法似乎能够抑制癌症复发，破坏继发性移植瘤，大概是由于抗肿瘤免疫反应增强。因为poliovirus来自于免疫系统，研究人员不能确定免疫反应的发生机制。“动物用于抵抗成神经细胞瘤的免疫力某种程度上说还是一个谜，是我们将来希望研究的部分。鉴于成神经细胞瘤复发频繁，这是一个令人鼓舞的发现。”
部分英文原文：
Cancer Research 67, 2857-2864, March 15, 2007. doi: 10.1158/0008-5472.CAN-06-3713
Experimental Therapeutics, Molecular Targets, and Chemical Biology
Oncolytic Treatment and Cure of Neuroblastoma by a Novel Attenuated Poliovirus in a Novel Poliovirus-Susceptible Animal Model
Hidemi Toyoda, Jiang Yin, Steffen Mueller, Eckard Wimmer and Jeronimo Cello
Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, New York
Requests for reprints: Eckard Wimmer, Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY 11794-5222. E-mail: ewimmer@ms.cc.sunysb.edu .
Abstract
Neuroblastoma is one of the most common solid tumors in children. Treatment is of limited utility for high-risk neuroblastoma and prognosis is poor. Resistance of neuroblastoma to conventional therapies has prompted us to search for a novel therapeutic approach based on genetically modified polioviruses. Poliovirus targets motor neurons leading to irreversible paralysis. Neurovirulence can be attenuated by point mutations or by exchange of genetic elements between different picornaviruses. We have developed a novel and stable attenuated poliovirus, replicating in neuroblastoma cells, by engineering an indigenous replication element (cre), copied from a genome-internal site, into the 5'-nontranslated genomic region (mono-crePV). An additional host range mutation (A133G) conferred replication in mouse neuroblastoma cells (Neuro-2aCD155) expressing CD155, the poliovirus receptor. Crossing immunocompetent transgenic mice susceptible to poliovirus (CD155 tg mice) with A/J mice generated CD155 tgA/J mice, which we immunized against poliovirus. Neuro-2aCD155 cells were then transplanted into these animals, leading to lethal tumors. Despite preexisting high titers of anti-poliovirus antibodies, established lethal s.c. Neuro-2aCD155 tumors in CD155 tgA/J mice were eliminated by intratumoral administrations of A133Gmono-crePV. No signs of paralysis were observed. Interestingly, no tumor growth was observed in mice cured of neuroblastoma that were reinoculated s.c. with Neuro-2aCD155. This result indicates that the destruction of neuroblastoma cells by A133Gmono-crePV may lead to a robust antitumor immune response. We suggest that our novel attenuated oncolytic poliovirus is a promising candidate for effective oncolytic treatment of human neuroblastoma or other cancer even in the presence of present or induced antipolio immunity. [Cancer Res 2007;67(6):2857–64]
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