Ma Hong, Zhang Yunjia, Wang Hailong, Han Chuanhui, Lei Runhong, Zhang Lei, Yang Zuye, Rao Ling, Qing Hong, Xiang Jim, Deng Yulin
School of Life Science, Beijing Institute of Technology, Haidian District, Beijing 100081, China.
Int J Mol Sci. 2013 Dec 19;15(1):1-14. doi: 10.3390/ijms15010001.
The effect of chemotherapy drug Mitomycin C (MMC) in combination with recombinant adeno-associated virus II (rAAV2) in cancer therapy was investigated, and the mechanism of MMC affecting rAAV2's bioactivity was also studied. The combination effect was evaluated by the level of GFP and TNF expression in a human glioma cell line, and the mechanism of MMC effects on rAAV mediated gene expression was investigated by AAV transduction related signal molecules. C57 and BALB/c nude mice were injected with rAAV-EGFP or rAAV-TNF alone, or mixed with MMC, to evaluate the effect of MMC on AAV-mediated gene expression and tumor suppression. MMC was shown to improve the infection activity of rAAV2 both in vitro and in vivo. Enhancement was found to be independent of initial rAAV2 receptor binding stage or subsequent second-strand synthesis of target DNA, but was related to cell cycle retardation followed by blocked genome degradation. In vivo injection of MMC combined with rAAV2 into the tumors of the animals resulted in significant suppression of tumor growth. It was thus demonstrated for the first time that MMC could enhance the expression level of the target gene mediated by rAAV2. The combination of rAAV2 and MMC may be a promising strategy in cancer therapy.
研究了化疗药物丝裂霉素C（MMC）与重组腺相关病毒II（rAAV2）联合用于癌症治疗的效果，并研究了MMC影响rAAV2生物活性的机制。通过人胶质瘤细胞系中绿色荧光蛋白（GFP）和肿瘤坏死因子（TNF）的表达水平评估联合效果，并通过AAV转导相关信号分子研究MMC对rAAV介导的基因表达的影响机制。给C57和BALB/c裸鼠单独注射rAAV-EGFP或rAAV-TNF，或与MMC混合注射，以评估MMC对AAV介导的基因表达和肿瘤抑制的作用。结果表明，MMC在体外和体内均能提高rAAV2的感染活性。发现增强作用与初始rAAV2受体结合阶段或随后的靶DNA第二链合成无关，但与细胞周期阻滞及随后的基因组降解受阻有关。在动物肿瘤中体内注射MMC与rAAV2的组合导致肿瘤生长显著受到抑制。因此首次证明MMC可提高rAAV2介导的靶基因表达水平。rAAV2与MMC的联合可能是癌症治疗中一种有前景的策略。
