日本研究人员成功地利用人工酶作为“剪刀”,切断了引发宫颈癌的人乳头瘤病毒的DNA,从而遏制了其增殖。这一技术有望应用于治疗由DNA病毒引起的疾病。
宫颈癌是女性最常见的恶性肿瘤,人乳头瘤病毒是引发宫颈癌的主要原因。人乳头瘤病毒是一种球形DNA病毒,所谓DNA病毒是核酸为单链或双链DNA的一种病毒,广泛存在于人、脊椎动物、昆虫体内以及多种传代细胞系中,它无法单独繁殖,必须寄生在活细胞内。
日本冈山大学的一个研究小组人工合成出一种“限制性核酸内切酶”,可以将糖分子与磷酸之间的键结“剪断”,从而将双链DNA“切断”。将这种人工酶植入人类细胞,它就与人乳头瘤病毒的DNA结合在一起,在特定部位将其切断,让病毒的增殖水平降低到通常水平的4%左右。
研究负责人世良贵史说:“即使病毒侵入人体,只要不增殖就不会发病。使用这种人工酶,即使是新型病毒,只要弄清DNA排列的一部分,就可以将其切断,从而容易作为抗病毒药物使用。”
相关论文已经刊登在美国《科学公共图书馆—综合卷》上(PLOS ONE)。(生物谷Bioon.com)
doi:10.1371/journal.pone.0002917
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Systemic Therapy for Cervical Cancer with Potentially Regulatable Oncolytic Adenoviruses
Anna Kanerva, Sergio Lavilla-Alonso,Mari Raki, Lotta Kangasniemi, Gerd J. Bauerschmitz, Koichi Takayama, Ari Ristimaki, Renee A-Desmond, Akseli Hemminki.
Clinical trials have confirmed the safety of selectively oncolytic adenoviruses for treatment of advanced cancers. However, increasingly effective viruses could result in more toxicity and therefore it would be useful if replication could be abrogated if necessary. We analyzed viruses containing the cyclooxygenase-2 (Cox-2) or vascular endothelial growth factor (VEGF) promoter for controlling replication. Anti-inflammatory agents can lower Cox-2 protein levels and therefore we hypothesized that also the promoter might be affected. As Cox-2 modulates expression of VEGF, also the VEGF promoter might be controllable. First, we evaluated the effect of anti-inflammatory agents on promoter activity or adenovirus infectivity in vitro. Further, we analyzed the oncolytic potency of the viruses in vitro and in vivo with and without the reagents. Moreover, the effect of on virus replication was analyzed. We found that RGD-4C or Ad5/3 modified fibers improved the oncolytic potency of the viruses in vitro and in vivo. We found that both promoters could be downregulated with dexamethasone, sodium salicylate, or salicylic acid. Oncolytic efficacy correlated with the promoter activity and in vitro virus production could be abrogated with the substances. In vivo, we saw good therapeutic efficacy of the viruses in a model of intravenous therapy of metastatic cervical cancer, but the inhibitory effect of dexamethasone was not strong enough to provide significant differences in a complex in vivo environment. Our results suggest that anti-inflammatory drugs may affect the replication of adenovirus, which might be relevant in case of replication associated side effects.