高热通过热休克蛋白途径增强溶瘤单纯疱疹病毒对胰腺癌的杀伤作用。

Hyperthermia potentiates oncolytic herpes viral killing of pancreatic cancer through a heat shock protein pathway.

机构信息

Division of Surgical Oncology, Hartford Hospital, Hartford, CT, USA.

出版信息

Surgery. 2010 Aug;148(2):325-34. doi: 10.1016/j.surg.2010.05.005.

DOI:10.1016/j.surg.2010.05.005

PMID:20633729

Abstract

BACKGROUND

Oncolytic herpes simplex virus-1 (HSV-1) is designed to specifically infect, replicate in, and lyse cancer cells. This study investigates a novel therapeutic regimen, combining the effects of NV1066 (a recombinant HSV-1) and hyperthermia in the treatment of pancreatic cancer.

METHODS

NV1066 is an attenuated HSV-1 that replicates in cells resistant to apoptosis. Heat shock protein 72 (Hsp72) is a member of a family of proteins that is upregulated after hyperthermic insult, lending cellular protection by inhibiting apoptosis. In these experiments, we test the hypothesis that increased Hsp72 expression in response to hyperthermia enhances anti-apoptotic mechanisms, thereby increasing viral replication and tumor cell kill. Hs 700T pancreatic cancer cells were treated with hyperthermia alone (42 degrees C), NV1066 alone, and combination therapy. Cell survival and viral growth were measured. The effect of siRNA-directed Hsp72 knockdown was also measured.

RESULTS

Combining hyperthermia and viral treatment produced a synergistic effect on cell kill. Viral growth increased greater than 6-fold in the presence of hyperthermia (P < .05). Hyperthermia alone showed minimal cytotoxic activity against Hs 700T cells, while NV1066 infection resulted in approximately 50% cell kill. The combination of hyperthermia and viral infection significantly increased cell kill to approximately 80% (P < .01). Hsp72 knockdown attenuated this synergistic effect.

CONCLUSION

Hyperthermia enhances NV1066 replication, thereby potentiating the viral oncolytic response against pancreatic cancer cells. This finding has potential clinical application in the use of heated perfusion or permissive hyperthermia for delivery of oncolytic viral therapies.

摘要

背景

溶瘤单纯疱疹病毒-1（HSV-1）旨在特异性感染、复制和裂解癌细胞。本研究探讨了一种新的治疗方案，即联合 NV1066（一种重组 HSV-1）和高热治疗胰腺癌。

方法

NV1066 是一种复制细胞对凋亡有抗性的减毒 HSV-1。热休克蛋白 72（Hsp72）是热休克蛋白家族的一员，在受到高热刺激后上调，通过抑制细胞凋亡来提供细胞保护。在这些实验中，我们检验了这样一个假设，即热应激诱导的 Hsp72 表达增加增强了抗凋亡机制，从而增加了病毒复制和肿瘤细胞杀伤。我们用单纯热疗（42℃）、NV1066 单独治疗和联合治疗来处理 Hs 700T 胰腺癌细胞。测量细胞存活和病毒生长情况。还测量了 siRNA 介导的 Hsp72 敲低的效果。

结果

热疗和病毒治疗联合对细胞杀伤产生协同作用。热疗存在时，病毒生长增加了 6 倍以上（P<0.05）。单纯热疗对 Hs 700T 细胞的细胞毒性作用很小，而 NV1066 感染导致约 50%的细胞杀伤。热疗和病毒感染的联合显著增加了约 80%的细胞杀伤（P<0.01）。Hsp72 敲低削弱了这种协同作用。