J Virol：重组病毒或成为前列腺癌新型疗法

近日，刊登在国际著名病毒学杂志Journal of Virology上的一篇研究报告中，来自弗吉尼亚理工学院的研究者通过研究揭示了，一种重组的新城鸡瘟病毒（A recombinant Newcastle disease virus）可以杀死包括耐药性癌细胞在内的所有种类的前列腺癌细胞，而且可以使得正常细胞不被损伤。

研究者表示，基于这种病毒的疗法或许可以避免前列腺癌激素疗法以及化疗所引发的副作用，这种重组化的修饰病毒可以在临床前动物模型中进行检测，并且有可能应用于I期人类临床试验。

新城鸡瘟病毒可以杀死鸡，但是对人类无任何影响，其是一种溶瘤病毒，可以杀灭肿瘤。这种病毒在一系列人类癌症临床试验中表现出较好的结果。然而需要注射大量的病毒才可以达到较为理想的治疗效果，因为在试验中，病毒有可能到达肿瘤的量并不够不足以发挥功能。

研究者通过修饰病毒的融合蛋白来解决这种问题，融合蛋白可以将病毒的外膜融合进细胞膜，使得病毒可以进入宿主细胞，这些融合蛋白可以被一系列不同的细胞蛋白酶类激活，这些蛋白酶类可以按照一定方式来修饰融合蛋白，以便于融合蛋白可以仅仅被前列腺特异性抗原所裂开。这就大大降低了病毒的拖把概率，因为修饰后的病毒仅仅可以和前列腺癌细胞进行作用，这样一来就降低了疗法中所用的病毒量。

修饰后的新城鸡瘟病毒在治疗其它癌症方面也具有较为明显的优势，首先，其针对前列腺癌细胞的特异性意味着其不会攻击正常细胞，这样就避免了一般化疗所引发的副作用。第二，这将为激素耐受的病人提供一种新的疗法，而不会带来副作用。

大约在6个男性中就会有1人被诊断为前列腺癌，而且36人中就有1人死于该疾病。对激素疗法耐受的前列腺癌患者，如果癌症发生转移，其生存中值只有40个月，如果癌症没有转移也只有68个月。

原文链接：

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Prostate Specific Antigen Retargeted Recombinant Newcastle Disease Virus for Prostate Cancer Virotherapy

Oncolytic virus (OV) therapies of cancer are based on the use of replication competent, tumor selective viruses with limited toxicity. Newcastle disease virus (NDV), an avian paramyxovirus, is a promising OV and is inherently tumor selective and cytotoxic only to tumor cells. Replication is restricted in normal cells. Despite encouraging Phase I/II clinical trials with NDV, further refinements for tumor specific targeting are needed to enhance its therapeutic index. Systemically delivered NDV fails to reach solid tumors in therapeutic concentration and also spreads poorly within the tumors due to barriers including complement, innate immunity and extracellular matrix. Overcoming these hurdles is paramount to realize the exceptional oncolytic efficacy of NDV. We engineered the F protein of NDV and generated a recombinant NDV (rNDV), whose F protein is cleavable exclusively by prostate specific antigen (PSA). The rNDV replicated efficiently and specifically in prostate cancer (CaP) cells and three-dimensional prostaspheres but failed to replicate in the absence of PSA. Induction of intracellular PSA production by a synthetic androgen analog (R1881) enhanced fusogenicity in androgen responsive CaP cells. Further, PSA-cleavable rNDV caused specific lysis of androgen independent and androgen responsive/non-responsive CaP cells and prostaspheres with an EC50 ranging from 0.01 to 0.1 multiplicity of infection. PSA retargeted NDV efficiently lysed prostasphere tumor mimics, suggesting efficacy in vivo. Also, PSA-cleavable NDV failed to replicate in chicken embryos, indicating no pathogenicity to chickens. Prostate specific antigen targeting is likely to enhance the therapeutic index of rNDV owing to tumor restricted replication and enhanced fusogenicity.

来源：生物谷