PLos One：刘新垣等靶向前列腺癌的基因-病毒特异性治疗获进展

4月11日，PLos One在线发表了中科院生化与细胞所刘新垣院士研究组关于“靶向前列腺癌的基因-病毒特异性治疗”（Cancer Targeting-Gene-ViroTherapy specific for Prostate Cancer, CTGVT-PCa）策略的最新研究成果。

前列腺癌是男性泌尿生殖系统肿瘤中最重要的一种，据估计，2010年美国有191533例前列腺癌新发病例和26329例死亡病例，超过肺癌，居男性癌症之首。我国前列腺癌的发病率远较欧美国家低，但最近趋势也较严重，应该深切关注。

丁苗同学的研究是对原来CTGVT的一种修饰，她所构建的“Ad-DD3-E1A-WPRE-E1B(Δ55)-gene”是以前列腺癌特异性启动子DD3驱动前列腺特异性抗癌基因PTEN的表达，所以对前列腺癌具有较强的特异杀伤，比对肝癌或其它癌症的杀伤能力更大，是前列腺癌特异性抗癌策略，故名为CTGVT-PCa（prostate cancer）。此外，还加入了对RNA起稳定作用的WPRE，提高E1A的表达量，提高对前列腺癌的杀伤力，所以对前列腺癌取得了较好的抗癌效果。

CTGVT是将抗癌基因加入到溶瘤病毒（oncolytic virus，OV）中构建而成，故也叫OV-gene治疗。过去OV与gene都是分开研究的，只有CTGVT才把二者结合起来了，OV是一种能靶向癌症并能在癌细胞中复制的溶瘤病毒载体，此载体能在癌细胞复制数百倍，则插入其中的抗癌基因也随之复制数百倍，故抗癌效果要增大数十倍，所以CTGVT是一种很好，很有前景的抗癌策略，目前也得到国际上的认可，而丁苗同学的工作又对此作了改进，构造了前列腺癌特异的抗癌策略（即CTGVT-PCa）。

该课题得到了国家重点基础研究发展计划（973计划）、国家自然科学基金项目、中国科学院知识创新工程重要方向项目、上海市科委项目和浙江理工大学的经费支持。

doi:10.1371/journal.pone.0035153
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Prostate Cancer-Specific and Potent Antitumor Effect of a DD3-Controlled Oncolytic Virus Harboring the PTEN Gene

Miao Ding, Xin Cao, Hai-neng Xu, Jun-kai Fan, Hong-ling Huang, Dong-qin Yang1, Yu-hua Li, Jian Wang, Runsheng Li, Xin-Yuan Liu

Prostate cancer is a major health problem for men in Western societies. Here we report a Prostate Cancer-Specific Targeting Gene-Viro-Therapy (CTGVT-PCa), in which PTEN was inserted into a DD3-controlled oncolytic viral vector (OV) to form Ad.DD3.E1A.E1B(Δ55)-(PTEN) or, briefly, Ad.DD3.D55-PTEN. The woodchuck post-transcriptional element (WPRE) was also introduced at the downstream of the E1A coding sequence, resulting in much higher expression of the E1A gene. DD3 is one of the most prostate cancer-specific genes and has been used as a clinical bio-diagnostic marker. PTEN is frequently inactivated in primary prostate cancers, which is crucial for prostate cancer progression. Therefore, the Ad.DD3.D55-PTEN has prostate cancer specific and potent antitumor effect. The tumor growth rate was almost completely inhibited with the final tumor volume after Ad.DD3.D55-PTEN treatment less than the initial volume at the beginning of Ad.DD3.D55-PTEN treatment, which shows the powerful antitumor effect of Ad.DD3.D55-PTEN on prostate cancer tumor growth. The CTGVT-PCa construct reported here killed all of the prostate cancer cell lines tested, such as DU145, 22RV1 and CL1, but had a reduced or no killing effect on all the non-prostate cancer cell lines tested. The mechanism of action of Ad.DD3.D55-PTEN was due to the induction of apoptosis, as detected by TUNEL assays and flow cytometry. The apoptosis was mediated by mitochondria-dependent and -independent pathways, as determined by caspase assays and mitochondrial membrane potential.