Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
J Leukoc Biol. 2011 Mar;89(3):351-7. doi: 10.1189/jlb.0410216. Epub 2010 Nov 17.
The 2009 outbreak of pandemic H1N1 influenza, increased drug resistance, and the significant delay in obtaining adequate numbers of vaccine doses have heightened awareness of the need to develop new antiviral drugs that can be used prophylactically or therapeutically. Previously, we showed that the experimental anti-tumor drug DMXAA potently induced IFN-β but relatively low TNF-α expression in vitro. This study confirms these findings in vivo and demonstrates further that DMXAA induces potent antiviral activity in vitro and in vivo. In vitro, DMXAA protected RAW 264.7 macrophage-like cells from VSV-induced cytotoxicity and moreover, inhibited replication of influenza, including the Tamiflu®-resistant H1N1 influenza A/Br strain, in MDCK cells. In vivo, DMXAA protected WT C57BL/6J but not IFN-β(-/-) mice from lethality induced by the mouse-adapted H1N1 PR8 influenza strain when administered before or after infection. Protection was accompanied by mitigation of weight loss, increased IFN-β mRNA and protein levels in the lung, and significant inhibition of viral replication in vivo early after DMXAA treatment. Collectively, this study provides data to support the use of DMXAA as a novel antiviral agent.
2009 年大流行的 H1N1 流感、不断增加的药物耐药性以及获得足够数量疫苗的显著延迟，都使人们更加意识到需要开发新的抗病毒药物，这些药物可以用于预防或治疗。此前，我们发现实验性抗肿瘤药物 DMXAA 可在体外强烈诱导 IFN-β，但相对较低的 TNF-α表达。本研究在体内证实了这些发现，并进一步表明 DMXAA 在体外和体内均具有强大的抗病毒活性。在体外，DMXAA 可保护 RAW 264.7 样巨噬细胞免受 VSV 诱导的细胞毒性，此外，DMXAA 还可抑制包括达菲®耐药的 H1N1 流感 A/Br 株在内的流感病毒在 MDCK 细胞中的复制。在体内，DMXAA 可保护 WT C57BL/6J 但不能保护 IFN-β(-/-) 小鼠免受经小鼠适应的 H1N1 PR8 流感株感染后的致死性，无论在感染前或感染后给药。保护作用伴随着体重减轻的缓解、肺中 IFN-β mRNA 和蛋白水平的增加以及 DMXAA 治疗后早期体内病毒复制的显著抑制。总的来说，这项研究提供了支持将 DMXAA 用作新型抗病毒药物的数据。
