Influence of method of systemic administration of adenovirus on virus-mediated toxicity: focus on mortality, virus distribution, and drug metabolism.
Influence of method of systemic administration of adenovirus on virus-mediated toxicity: focus on mortality, virus distribution, and drug metabolism.
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DOI：
10.1016/j.vascn.2008.07.003
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发表时间：
2008-11
影响因子：
1.9
通讯作者：
Croyle MA
中科院分区：
文献类型：
--
作者：
Boquet MP;Wonganan P;Dekker JD;Croyle MA
尾静脉注射2×1012病毒颗粒/公斤(VP/kg)或更高剂量的重组人腺病毒5型(HAdV-5)对大鼠有明显的毒性和致死性。当通过外科植入的颈静脉导管给予5.7×1012VP/kg剂量时，未观察到这种情况。在这里，我们评估了HAdV-5被引入体循环的方式如何影响治疗后0.25、1和4天的大鼠的生物分布、转基因表达、毒性和死亡率。经颈静脉插管或直接尾静脉注射表达β-半乳糖苷酶或生理盐水的HAdV-55.7×1012VP/kg。所有动物在颈静脉给药后存活。尾静脉注射HAdV5使死亡率增加到42%(p≤0.0 1)。所有死亡均发生在4小时内。在病毒感染的前24小时内，经颈静脉注射的动物在肝脏和脾中的转基因表达水平显著高于尾静脉注射的动物，并且在这些组织和肾脏和肺中的病毒基因组显著多于经尾静脉注射的动物(p≤0.01)。此后，两组之间没有显著差异。死亡动物的样本含有更高水平的病毒基因组，死亡时血清转氨酶平均升高4倍。在整个研究过程中，两种给药方法在肝脏细胞色素P450表达和活性的变化方面没有显著差异。这些发现表明，在大鼠和可能的其他动物模型上注射病毒后，在早期时间点评估毒性数据和其他参数时，应仔细考虑全身注射的方法。
Doses of 2 × 1012 virus particles/kilogram (vp/kg) and higher of recombinant human adenovirus serotype 5 (HAdV-5) given via the tail vein induce significant toxicity and mortality in the rat. This was not observed when doses of 5.7 × 1012 vp/kg were given through a surgically implanted jugular catheter. Here we assess how the manner by which HAdV-5 is introduced into the systemic circulation affects biodistribution, transgene expression, toxicity and mortality 0.25, 1, and 4 days after treatment in the rat. Animals were given 5.7 × 1012 vp/kg of HAdV-5 expressing beta-galactosidase or saline through a jugular catheter or by direct tail-vein injection. All animals survived after jugular vein dosing. Tail-vein injection of HAdV-5 increased the mortality rate to 42% (p ≤ 0.01). All deaths occurred within 4 hours. Animals dosed through the jugular vein had significantly higher levels of transgene expression in the liver and spleen and significantly more viral genomes in these tissues and kidney and lung within the first 24 hours of viral infection compared to those dosed by tail-vein injection (p ≤ 0.01). There was no significant difference between the groups thereafter. Samples from animals that died contained even higher levels of viral genomes and serum transaminases were elevated on average by a factor of 4 at the time of death. There was no significant difference between the two dosing methods with respect to changes in hepatic cytochrome P450 expression and activity throughout the study. These findings suggest that the method of systemic administration should be carefully considered when assessing toxicity data and other parameters at early time points after virus administration in the rat and possibly other animal models.