Department of Abdominal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.
World J Gastroenterol. 2013 Aug 21;19(31):5138-43. doi: 10.3748/wjg.v19.i31.5138.
To investigate the therapeutic efficacy and mechanisms of action of oncolytic-herpes-simplex-virus encoding granulocyte-macrophage colony-stimulating factor (HSV(GM-CSF)) in pancreatic carcinoma.
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 HSV(GM-CSF) group [1 × 10⁷ plaque forming units (pfu)/tumor], a medium dose HSV(GM-CSF) group (5 × 10⁶ pfu/tumor) and a low dose HSV(GM-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 HSV(GM-CSF).
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 HSV(GM-CSF). The increase in the GM-CSF level was more pronounced in the high dose group compared to the other two dose groups.
Our study provides the first evidence that HSV(GM-CSF) could inhibit the growth of pancreatic cancer. The enhanced GM-CSF expression might be responsible for the phenomenon.
研究编码粒细胞-巨噬细胞集落刺激因子（HSV（GM-CSF））的溶瘤单纯疱疹病毒在胰腺癌中的治疗效果和作用机制。
将肿瘤块在无菌研磨机中用生理盐水匀浆。匀浆注射到每只小鼠的右腋窝。接种后，将小鼠随机分为四组：对照组、高剂量 HSV（GM-CSF）组[1×10⁷ 空斑形成单位（pfu）/肿瘤]、中剂量 HSV（GM-CSF）组（5×10⁶ pfu/肿瘤）和低剂量 HSV（GM-CSF）组（5×10⁵ pfu/肿瘤）。给药开始后，每 3 天测量一次体重和肿瘤直径。15 天后，通过颈椎脱位处死动物后，每个肿瘤均被分离、称重并储存在 10%甲醛溶液中。根据每个肿瘤的重量、体积和相对体积变化评估药物疗效。此外，在注射 HSV（GM-CSF）后 1、2、3 和 4 天，通过酶联免疫吸附试验测定血清中的 GM-CSF 蛋白水平。
与对照组相比，注射重组鼠 HSV 编码 GM-CSF 可显著抑制肿瘤生长，且具有剂量依赖性：注射后 15 天，低、中、高剂量组的相对肿瘤增殖率分别为 45.5%、55.2%和 65.5%。低、中、高剂量组的肿瘤重量抑制率分别为 41.4%、46.7%和 50.5%。此外，感染 HSV（GM-CSF）的小鼠 GM-CSF 的产生显著增加。与其他两个剂量组相比，高剂量组 GM-CSF 水平的增加更为明显。
本研究首次提供了 HSV（GM-CSF）可抑制胰腺癌生长的证据。增强的 GM-CSF 表达可能是导致这种现象的原因。
