Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China.
J Transl Med. 2011 Apr 11;9:39. doi: 10.1186/1479-5876-9-39.
Gene therapy is a promising therapeutic approach for cancer. Targeted expression of desired therapeutic proteins within the tumor is the best approach to reduce toxicity and improve survival. This study is to establish a more effective and less toxic gene therapy of cancer.
Combined gene therapy strategy with recombinant adenovirus expressing horseradish peroxidase (HRP) mediated by human telomerase reverse transcriptase (hTERT) promoter (AdhTERTHRP) and murine interleukin-12 (mIL-12) under the control of Cytomegalovirus (CMV) promoter (AdCMVmIL-12) was developed and evaluated against Lewis lung carcinoma (LLC) both in vivo and in vitro. The mechanism of action and systemic toxicities were also investigated.
The combination of AdhTERTHRP/indole-3-acetic acid (IAA) treatment and AdCMVmIL-12 resulted in significant tumor growth inhibition and survival improvement compared with AdhTERTHRP/IAA alone (tumor volume, 427.4 ± 48.7 mm3 vs 581.9 ± 46.9 mm3, p = 0.005 on day 15; median overall survival (OS), 51 d vs 33 d) or AdCMVmIL-12 alone (tumor volume, 362.2 ± 33.8 mm3 vs 494.4 ± 70.2 mm3, p = 0.046 on day 12; median OS, 51 d vs 36 d). The combination treatment stimulated more CD4+ and CD8+ T lymphocyte infiltration in tumors, compared with either AdCMVmIL-12 alone (1.3-fold increase for CD4+ T cells and 1.2-fold increase for CD8+ T cells, P < 0.01) or AdhTERTHRP alone (2.1-fold increase for CD4+ T cells and 2.2-fold increase for CD8+ T cells, P < 0.01). The apoptotic cells in combination group were significantly increased in comparison with AdCMVmIL-12 alone group (2.8-fold increase, P < 0.01) or AdhTERTHRP alone group (1.6-fold increase, P < 0.01). No significant systematic toxicities were observed.
Combination gene therapy with AdhTERTHRP/IAA and AdCMVmIL-12 could significantly inhibit tumor growth and improve host survival in LLC model, without significant systemic adverse effects.
基因治疗是癌症治疗的一种很有前途的方法。在肿瘤内靶向表达所需的治疗性蛋白是降低毒性和提高存活率的最佳方法。本研究旨在建立一种更有效、毒性更低的癌症基因治疗方法。
采用携带人端粒酶逆转录酶（hTERT）启动子的重组腺病毒（AdhTERTHRP）和受巨细胞病毒（CMV）启动子调控的小鼠白细胞介素-12（mIL-12）（AdCMVmIL-12）的联合基因治疗策略，对Lewis 肺癌（LLC）进行体内和体外评估。还研究了其作用机制和全身毒性。
与 AdhTERTHRP/IAA 单独治疗或 AdCMVmIL-12 单独治疗相比，AdhTERTHRP/吲哚乙酸（IAA）治疗联合 AdCMVmIL-12 治疗显著抑制肿瘤生长，提高生存（肿瘤体积，15 天 427.4±48.7mm3 与 581.9±46.9mm3，p=0.005；中位总生存期（OS），51 天与 33 天）或 AdCMVmIL-12 单独治疗（肿瘤体积，12 天 362.2±33.8mm3 与 494.4±70.2mm3，p=0.046；中位 OS，51 天与 36 天）。与 AdCMVmIL-12 单独治疗（CD4+T 细胞增加 1.3 倍，CD8+T 细胞增加 1.2 倍，P<0.01）或 AdhTERTHRP 单独治疗（CD4+T 细胞增加 2.1 倍，CD8+T 细胞增加 2.2 倍，P<0.01）相比，联合治疗组肿瘤中 CD4+和 CD8+T 淋巴细胞浸润明显增加。与 AdCMVmIL-12 单独治疗组（增加 2.8 倍，P<0.01）或 AdhTERTHRP 单独治疗组（增加 1.6 倍，P<0.01）相比，联合治疗组凋亡细胞明显增加。未观察到明显的系统毒性。
AdhTERTHRP/IAA 和 AdCMVmIL-12 的联合基因治疗可显著抑制 LLC 模型的肿瘤生长，提高宿主存活率，无明显全身不良反应。
