脊髓灰質(zhì)炎病毒（poliovirus）雖然是引起某種兒童疾病的罪魁禍首，但可治療另一種兒童疾病——成神經(jīng)細胞瘤（neuroblastoma）,。3月15日《Cancer Research》雜志
一篇文章報道,，Stony Brook大學(xué)研究人員利用一種無毒性的poliovirus,，有效去除了小鼠的成神經(jīng)細胞瘤，即便此小鼠曾經(jīng)接種過抵御poliovirus的疫苗,。
poliovirus破壞被其感染的細胞,，復(fù)制出的病毒顆粒從細胞中釋放后，再攻擊周圍細胞,。研究人員利用了病毒的這一特點,，在感染過脊髓灰質(zhì)炎病毒的成神經(jīng)細胞瘤模型小鼠體內(nèi)直接注射毒力已經(jīng)被削弱的poliovirus，結(jié)果病毒破壞了所有12只小鼠體內(nèi)的腫瘤,，180天后有兩只小鼠的腫瘤復(fù)發(fā),。
病毒自身沒有在任何一只小鼠體內(nèi)引起副作用。研究人員說,，病毒顆粒進入血流后會被poliovirus疫苗產(chǎn)生的抗體消滅,，如果應(yīng)用于人類，可能會成為一種安全有效的治療致癌癥的措施,。
“一種無毒的poliovirus,，是尋找能夠殺滅腫瘤但不會傷害患者的一個重要步驟，” Hidemi Toyoda博士說,，“我們有效地馴服了一種在幾十年前對兒童有致死性的病毒polio,，并用其一個重要天性治療了一種在當代有致死性的疾病,。”
奇怪的是，研究人員還發(fā)現(xiàn)poliovirus能夠有效殺滅小鼠體內(nèi)新出現(xiàn)的腫瘤,。成神經(jīng)細胞瘤是四大常見兒童實體腫瘤之一,，化療后經(jīng)常復(fù)發(fā)。“成神經(jīng)細胞瘤很難治愈,，化療不利于日后健康,，與傳統(tǒng)療法相結(jié)合，一種poliovirus治療能減少兒童接受化療和放療的次數(shù),，降低副作用,。”
為了檢測poliovirus治療癌癥的效果，研究人員首先要獲得一種安全形式的病毒,。Eckard Wimmer博士曾經(jīng)利用poliovirus的基本化學(xué)成分合成出poliovirus,，并在合成poliovirus的基礎(chǔ)上，利用病毒RNA基因組非spacer region區(qū)（一個相當重要的功能區(qū)）中的一個核苷酸取代spacer region區(qū)的一個核苷酸,，得到高度減弱的病毒,。文章高級作者Jeronimo Cello評價此工程為給病毒上了雙保險。“如果spacer region區(qū)一直被阻斷,，遺傳工程poliovirus就不能產(chǎn)生自身的神經(jīng)劇毒（neurovirulent）拷貝,，”Cello說，“萬一調(diào)節(jié)基因元件丟失了,，病毒也不會復(fù)制,。”
為了檢測病毒破壞成神經(jīng)細胞瘤的能力，研究人員建立了一個攜帶人類CD155基因（CD155編碼允許poliovirus進入細胞的受體）的成神經(jīng)細胞瘤轉(zhuǎn)基因小鼠模型,。然后給小鼠接種抵抗poliovirus的疫苗,。
因為大多數(shù)人都接受過抵抗poliovirus的疫苗免疫，Toyoda與其同事想知道是否這種免疫會妨礙病毒治療腫瘤,。通過直接將病毒注射到小鼠的腫瘤中,，研究人員證明病毒能夠找到靶標并繞過疫苗產(chǎn)生的抗體。
不僅npoliovirus有破壞腫瘤的能力,，病毒治療法似乎能夠抑制癌癥復(fù)發(fā),，破壞繼發(fā)性移植瘤，大概是由于抗腫瘤免疫反應(yīng)增強,。因為poliovirus來自于免疫系統(tǒng),，研究人員不能確定免疫反應(yīng)的發(fā)生機制。“動物用于抵抗成神經(jīng)細胞瘤的免疫力某種程度上說還是一個謎,，是我們將來希望研究的部分,。鑒于成神經(jīng)細胞瘤復(fù)發(fā)頻繁，這是一個令人鼓舞的發(fā)現(xiàn),。”
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: [email protected] .
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]
