Xu Maolei, Zhou Ling, Zhang Peng, Lu Yong, Ge Chiyu, Yao Wenjun, Xing Yun, Xiao Wen, Dong Yuankai, Wu Jie, Cao Rongyue, Li Taiming
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, People's Republic of China,
Tumour Biol. 2013 Oct;34(5):3173-82. doi: 10.1007/s13277-013-0887-8. Epub 2013 Jun 15.
Angiogenesis inhibitors combined with other anticancer drugs have been shown to inhibit tumor growth in animal models and some of them were recently used in clinical trials. In the present study, a whole hepatocellular carcinoma cell lysate based vaccine with diphtheria toxin (DT) and two tandem repeats of microbial HSP70 peptide epitope 407-426 (2 mHSP70407-426, M2) as adjuvant, which was called HDM, was combined with a whole human umbilical vein endothelial cell (HUVEC) vaccine to develop a combination treatment regimen. This combination treatment regimen was named HUVEC-HDM, which was supposed to enhance its antitumor efficiency. HUVEC-HDM was administrated subcutaneously in both prophylactic and therapeutic procedures. Compared to either single vaccine, HUVEC-HDM induced a more significant inhibition on the growth and metastasis of H22 hepatocellular carcinoma in mice and prolonged the survival of tumor-bearing mice. Besides, HUVEC-HDM immunization elicited strong humoral and cellular immune responses targeting tumor cell as well as tumor angiogenesis, which could be responsible for the enhanced antitumor effect. Moreover, histochemistry analysis showed that HUVEC-HDM induced large areas of continuous necrosis within tumors, correlating well with the extent of tumor inhibition. These results not only highlight the superiority of the combined HUVEC-HDM treatment regimen, but also support the translation of such approaches into the clinic for the treatment of patients with hepatocellular carcinoma.
血管生成抑制剂与其他抗癌药物联合使用已在动物模型中显示出抑制肿瘤生长的效果，其中一些最近已用于临床试验。在本研究中，一种以白喉毒素（DT）和微生物热休克蛋白70肽表位407 - 426的两个串联重复序列（2 mHSP70407 - 426，M2）作为佐剂的全肝癌细胞裂解物疫苗（称为HDM）与全人脐静脉内皮细胞（HUVEC）疫苗联合，以开发一种联合治疗方案。这种联合治疗方案被命名为HUVEC - HDM，旨在提高其抗肿瘤效率。HUVEC - HDM在预防和治疗过程中均通过皮下注射给药。与单一疫苗相比，HUVEC - HDM对小鼠H22肝癌的生长和转移具有更显著的抑制作用，并延长了荷瘤小鼠的生存期。此外，HUVEC - HDM免疫引发了针对肿瘤细胞以及肿瘤血管生成的强烈体液免疫和细胞免疫反应，这可能是抗肿瘤效果增强的原因。此外，组织化学分析表明，HUVEC - HDM在肿瘤内诱导了大面积的连续性坏死，与肿瘤抑制程度密切相关。这些结果不仅突出了联合HUVEC - HDM治疗方案的优越性，也支持将这种方法转化到临床用于治疗肝癌患者。
