Published online Aug 21, 2013. doi: 10.3748/wjg.v19.i31.5138
Revised: June 28, 2013
Accepted: July 17, 2013
Published online: August 21, 2013
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.
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.