Identifying the safety profile of a novel infectivity-enhanced conditionally replicative adenovirus, Ad5-Δ24-RGD, in anticipation of a phase I trial for recurrent ovarian cancer
Identifying the safety profile of a novel infectivity-enhanced conditionally replicative adenovirus, Ad5-Δ24-RGD, in anticipation of a phase I trial for recurrent ovarian cancer
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DOI：
10.1016/j.ajog.2006.12.016
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发表时间：
2007-04-01
影响因子：
9.8
通讯作者：
Alvarez, Ronald D.
中科院分区：
文献类型：
--
作者：
Page, John G.;Tian, Baohong;Alvarez, Ronald D.
目的：本研究的目的是评估向性修饰的感染性增强的条件复制型腺病毒Ad 5-Delta 24-精氨酸-甘氨酸-天冬氨酸（RGD）的生物分布和毒性。用5 × 10（8）至5 × 10（11）个颗粒/kg的Ad 5-Delta 24- 3对棉鼠队列进行连续3天的静脉内或腹腔内给药。在第8、17或56天处死。对于生物分布研究，使用定量聚合酶链反应分析评价了14个器官部位的组织样本和血清样本中是否存在病毒。对于毒性实验，从超过30个器官部位和血清样品的组织样品获得的评估载体相关的组织或实验室effects.RESULTS：Ad 5-Delta 24-RGD注意到在测试样品中，在第8和17天的动物，静脉内和腹腔内治疗与清除第56天。在腹膜内给药动物的血液和肝脏标本中观察到载体拷贝数较低。在接受Ad 5-Delta 24-RGD腹腔内治疗的大鼠中观察到轻度腹膜炎组织病理学发现;病理学发现并未随剂量、时间的推移或与接受Ad 5-Delta 24治疗的动物中观察到的结果相比发生显着变化。结论：这些研究为计划的卵巢癌临床试验提供了有关Ad 5-Delta 24-RGD剂量和预期毒性的重要见解。
OBJECTIVE: The purpose of this study was to evaluate the biodistribution and toxicity of the tropism-modified infectivity-enhanced conditionally replicative adenovirus, Ad5-Delta 24-arginine-glycine-aspartate (RGD).STUDY DESIGN: Cohorts of cotton rats were treated intravenously or intraperitoneally for 3 consecutive days with 5 x 10(8) to 5 x 10(11) particles/kg of Ad5-Delta 24-RGD or controls and killed on day 8, 17, or 56. For biodistribution studies, tissue samples from 14 organ sites and serum samples were evaluated for the presence of virus with the use of quantitative polymerase chain reaction analysis. For toxicity experiments, tissue samples from more than 30 organ sites and serum samples were obtained for the assessment of vector-related tissue or laboratory effects.RESULTS: Ad5-Delta 24-RGD was noted in tested samples at days 8 and 17 in animals that were treated intravenously and intraperitoneally with clearance by day 56. There were lower copies of vector noted in the blood and liver specimens of intraperitoneally treated animals. Mild peritonitis histopathologic findings were noted in rats that were treated intraperitoneally with Ad5-Delta 24-RGD; pathologic findings did not vary significantly with dose, over time, or in comparison to that noted in animals that were treated with Ad5-Delta 24.CONCLUSION: These studies provide critical insights regarding Ad5-Delta 24-RGD dosing and anticipated toxicity for a planned clinical trial for ovarian cancer.