Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells.
Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells.
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溶瘤单纯疱疹病毒载体和紫杉烷类药物协同作用，促进前列腺癌细胞的杀伤。
DOI：
10.1038/cgt.2009.10
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发表时间：
2009-07
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
作者：
基因工程化的溶瘤单纯疱疹病毒-1（HSV-1）载体选择性地在肿瘤细胞中复制，导致直接杀伤而不伤害正常细胞。使用溶瘤HSV载体的一个临床限制是其减弱的生长。我们假设，适当选择的化疗药物与溶瘤HSV的组合可能是一种有效的手段，以促进增强前列腺癌细胞杀死在体外和体内。在这里，我们已经确定了G47Δ与微管稳定紫杉烷类药物多西他赛和紫杉醇协同作用，以增强前列腺癌细胞的体外杀伤。体内有效性研究表明，当与多西他赛联合使用时，G47Δ可降低至少10倍。免疫印迹分析显示，紫杉醇诱导的磷酸化特异性有丝分裂标志物op 18/stathmin或组蛋白-H3的积累被G47Δ显著减少，这与增强的细胞凋亡相关，需要活跃的病毒复制。此外，细胞周期分析表明，在G47Δ存在的情况下，大多数在有丝分裂中停滞的4 N细胞是MPM-2阴性的，表明细胞过早退出有丝分裂。这些发现表明，G47Δ可能部分作用于有丝分裂阻断的细胞以增强细胞死亡，这可能是体内观察到的增强的抗肿瘤功效的原因。
Genetically engineered oncolytic herpes simplex virus-1 (HSV-1) vectors selectively replicate in tumor cells causing direct killing whereas sparing normal cells. One clinical limitation of using oncolytic HSV vectors is their attenuated growth. We hypothesized that the appropriately chosen chemotherapeutic agent combined with an oncolytic HSV could be an effective means to promote augmented prostate cancer cell killing both in vitro and in vivo. Here we have identified that G47Δ synergizes with the microtubule-stabilizing taxane agents docetaxel and paclitaxel to enhance the in vitro killing of prostate cancer cells. In vivo efficacy studies show that when combined with docetaxel, G47Δ could be reduced at least 10-fold. Immunoblot analysis revealed that docetaxel-induced accumulation of the phospho-specific mitotic markers op18/stathmin or histone-H3 was markedly reduced by G47Δ, which correlated with enhanced apoptosis and required active viral replication. Furthermore, cell-cycle analysis demonstrated that in the presence of G47Δ, the majority of 4N cells arrested in mitosis were MPM-2-negative, indicative of cells exiting mitosis prematurely. These findings suggest that G47Δ may act in part, on mitotically blocked cells to enhance cell death, which may account for the enhanced antitumor efficacy observed in vivo.
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影响因子：
6.4
作者：
Varghese, S;Rabkin, SD;Martuza, RL
通讯作者：
Martuza, RL
影响因子：
82.9
作者：
MINETA, T;RABKIN, SD;MARTUZA, RL
通讯作者：
MARTUZA, RL
影响因子：
3.7
作者：
Ehmann, GL;McLean, TI;Bachenheimer, SL
通讯作者：
Bachenheimer, SL
影响因子：
4.2
作者：
Walker, JR;McGeagh, KG;Martuza, RL
通讯作者：
Martuza, RL
影响因子：
5.4
作者：
He, B;Chou, J;Roizman, B
通讯作者：
Roizman, B