Brief Article
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World J Gastroenterol. Aug 21, 2013; 19(31): 5138-5143
Published online Aug 21, 2013. doi: 10.3748/wjg.v19.i31.5138
Preclinical evaluation of herpes simplex virus armed with granulocyte-macrophage colony-stimulating factor in pancreatic carcinoma
Hao Liu, Shou-Jun Yuan, Ying-Tai Chen, Yi-Bin Xie, Liang Cui, Wei-Zhi Yang, De-Xuan Yang, Yan-Tao Tian
Hao Liu, Ying-Tai Chen, Yi-Bin Xie, Yan-Tao Tian, Liang-Cui, Department of Abdominal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China
Shou-Jun Yuan, De-Xuan Yang, Pharmacological and Toxicological Laboratory, Institute of Radiation Medicine Medical, Beijing 100850, China
Wei-Zhi Yang, Radiobiology Laboratory, Cancer Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100021, China
Author contributions: Liu H, Yuan SJ, Yang WZ and Tian YT conceived and led the study; Liu H, Chen YT and Yang DX carried out the statistical analysis; Liu H, Chen YT, Xie YB, Cui L and Tian YT drafted and revised the manuscript; and all authors reviewed and approved the manuscript.
Correspondence to: Yan-Tao Tian, MD, Professor, Department of Abdominal Surgery, Cancer Hospital, Chinese Academy of Medical Science, Peking Union Medical College, 17 Nan-li, Pan Jia Yuan, Chaoyang District, Beijing 100021, China. tyt67@163.com
Telephone: +86-10-87787120 Fax: +86-10-67730386
Received: May 1, 2013
Revised: June 28, 2013
Accepted: July 17, 2013
Published online: August 21, 2013
Processing time: 110 Days and 6.4 Hours
Abstract

AIM: To investigate the therapeutic efficacy and mechanisms of action of oncolytic-herpes-simplex-virus encoding granulocyte-macrophage colony-stimulating factor (HSVGM-CSF) in pancreatic carcinoma.

METHODS: Tumor blocks were homogenized in a sterile grinder in saline. The homogenate was injected into the right armpit of each mouse. After vaccination, the mice were randomly assigned into four groups: a control group, a high dose HSVGM-CSF group [1 × 107 plaque forming units (pfu)/tumor], a medium dose HSVGM-CSF group (5 × 106 pfu/tumor) and a low dose HSVGM-CSF group (5 × 105 pfu/tumor). After initiation of drug administration, body weights and tumor diameters were measured every 3 d. Fifteen days later, after decapitation of the animal by cervical dislocation, each tumor was isolated, weighed and stored in 10% formaldehyde solution. The drug effectiveness was evaluated according to the weight, volume and relative volume change of each tumor. Furthermore, GM-CSF protein levels in serum were assayed by enzyme-linked immunosorbent assays at 1, 2, 3 and 4 d after injection of HSVGM-CSF.

RESULTS: Injection of the recombinant mouse HSV encoding GM-CSF resulted in a significant reduction in tumor growth compared to the control group, and dose-dependent effects were observed: the relative tumor proliferation rates of the low dose, medium dose and high dose groups on 15 d after injection were 45.5%, 55.2% and 65.5%, respectively. The inhibition rates of the tumor weights of the low, middle, and high dose groups were 41.4%, 46.7% and 50.5%, respectively. Furthermore, the production of GM-CSF was significantly increased in the mice infected with HSVGM-CSF. The increase in the GM-CSF level was more pronounced in the high dose group compared to the other two dose groups.

CONCLUSION: Our study provides the first evidence that HSVGM-CSF could inhibit the growth of pancreatic cancer. The enhanced GM-CSF expression might be responsible for the phenomenon.

Keywords: Pancreatic carcinoma; Gene therapy; Animal test; Herpes-simplex-virus encoding granulocyte-macrophage colony-stimulating factor

Core tip: Herpes-simplex-virus encoding granulocyte-macrophage colony-stimulating factor (HSVGM-CSF) is an engineered oncolytic virus. The key features of HSVGM-CSF include the deletion of both copies of γ134.5 and the ICP47 gene as well as interruption of the ICP6 gene and insertion of the therapeutic gene GM-CSF. Our study provides the first evidence that HSVGM-CSF could inhibit the growth of pancreatic cancer in a dose-dependent manner. Enhanced GM-CSF expression might be responsible for the phenomenon.