Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses
Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses
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DOI：
10.1016/j.virol.2004.08.039
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发表时间：
2004-12-05
期刊：
影响因子：
3.7
通讯作者：
Lyles, DS
中科院分区：
文献类型：
--
作者：
Ahmed, M;Cramer, SD;Lyles, DS
水泡性口炎病毒（VSV）具有诱导细胞凋亡的能力，是一种具有吸引力的肿瘤治疗病毒。以前的研究表明，VSV选择性地感染肿瘤细胞，因为它们的抗病毒反应缺陷使它们比正常细胞更容易受到VSV感染。我们在前列腺肿瘤系统中通过比较LNCaP和PC-3前列腺肿瘤细胞与来自患者前列腺切除术标本的良性人前列腺上皮细胞来验证这一假设。我们比较了含有野生型（wt）M蛋白（rwt）和等基因M蛋白突变体病毒（rM 51 R-M）的重组病毒的细胞杀伤能力，该病毒在感染的细胞中诱导干扰素（IFN），并应显示出对肿瘤细胞更大的选择性。我们的结果表明，在单循环感染实验中，LNCaP细胞对野生型和突变型病毒的杀伤敏感，而PC-3细胞对VSV诱导的细胞杀伤具有高度抗性。LNCaP和良性前列腺细胞对这两种病毒的敏感性相似，表明正常前列腺细胞对VSV的杀伤并不具有固有的抗性。在每种细胞系中，rM 51 R-M病毒诱导的凋亡水平与rwt病毒相似，表明M蛋白在这些细胞中VSV诱导的凋亡中不起显著作用。在多周期感染实验中，LNCaP细胞比良性前列腺上皮细胞对rM 51 R-M病毒诱导的细胞杀伤更敏感，但不是rwt病毒。两种病毒在裸鼠瘤内和静脉内接种后在体内减少LNCaP肿瘤体积方面同样有效，而PC-3肿瘤对VSV治疗具有抗性。用rM 51 R-M病毒处理的小鼠中没有一只死于病毒感染，而用rwt病毒处理的小鼠中有50-71%死于病毒感染。同样，当通过更敏感的鼻内途径接种时，rM 51 R-M病毒的致病性低于其来源的rwt病毒。这些结果表明，M蛋白突变体病毒是前列腺肿瘤治疗的溶瘤病毒的上级候选者，但未来使用VSV的策略将需要测试个体肿瘤对病毒感染的易感性。(C)2004年爱思唯尔公司All rights reserved.
Because of its potent ability to induce apoptosis, vesicular stomatitis virus (VSV) is an attractive candidate as an oncolytic virus for tumor therapy. Previous studies have suggested that VSV selectively infects tumor cells due to defects in their antiviral responses making them more susceptible to VSV infection than normal cells. We tested this hypothesis in the prostate tumor system by comparing LNCaP and PC-3 prostate tumor cells to benign human prostatic epithelial cells from patient prostatectomy specimens. We compared the cell killing ability of a recombinant virus containing a wild-type (wt) M protein (rwt) and an isogenic M protein mutant virus (rM51R-M) that induces interferon (IFN) in infected cells and should display a greater selectivity for tumor cells. Our results showed that in single-cycle infection experiments, LNCaP cells were sensitive to killing by both wt and mutant viruses, while PC-3 cells were highly resistant to VSV-induced cell killing. LNCaP and benign prostate cells were similarly susceptible to both viruses, indicating that normal prostate cells are not inherently resistant to killing by VSV. In each of the cell lines, the rM51R-M virus induced similar levels of apoptosis to rwt virus, showing that the M protein does not play a significant role in apoptosis induction by VSV in these cells. In multiple-cycle infection experiments, LNCaP cells were more sensitive than benign prostatic epithelial cells to virus-induced cell killing by rM51R-M virus, but not rwt virus. Both viruses were equally effective at reducing LNCaP tumor volume in vivo following intratumoral and intravenous inoculation in nude mice, while PC-3 tumors were resistant to VSV treatment. None of the mice treated with rM51R-M virus died as a result of virus infection, while 50-71% of mice treated with rwt virus succumbed to virus infection. Similarly, when inoculated by the more sensitive intranasal route, the rM51R-M virus was less pathogenic than the rwt virus from which it was derived. These results indicate that M protein mutant viruses are superior candidates as oncolytic viruses for therapies of prostate tumors, but future strategies for use of VSV will require testing individual tumors for their susceptibility to virus infection. (C) 2004 Elsevier Inc. All rights reserved.