Preclinical toxicology of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for prostate cancer.
Preclinical toxicology of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for prostate cancer.
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DOI：
10.1038/mto.2015.6
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Siddiqui F
中科院分区：
文献类型：
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作者：
Freytag SO;Zhang Y;Siddiqui F
本研究的目的是在临床前模型中检查溶瘤腺病毒介导的细胞毒性和白细胞介素12（IL-12）基因治疗的联合毒性，以支持未来的I期试验。120只C57 BL/6雄性小鼠接受前列腺内注射生理盐水（n = 24）或表达两种自杀基因和小鼠IL-12的溶瘤腺病毒（Ad 5-yCD/mutTKSR 39 rep-mIL 12）（n = 96）。以1.3 × 106、1.3 × 107、1.3 × 108 vp/kg三个剂量水平给予腺病毒，随后给予5-氟胞嘧啶（5-FC）和更昔洛韦（GCV）前体药物治疗2周。没有过早死亡。在研究的78天活体阶段，动物的每日观察未发现任何明显的临床问题。最高腺病毒剂量组中的动物在第3天表现出淋巴细胞减少症和转氨酶升高，两者均在第17天消退。除前列腺和精囊轻度炎症外，主要器官的组织病理学基本无异常。前列腺和血清中的IL-12和干扰素-γ水平在第3天达到峰值，到第17天检测不到或恢复到基线水平。在任何时间点，任何组的血清中均未检测到腺病毒DNA。结果表明，表达两个自杀基因和IL-12的溶瘤腺病毒的局部给药耐受性良好，并支持将这种研究方法转移到人体试验中。
The purpose of this study was to examine the toxicity of combining oncolytic adenovirus-mediated cytotoxic and interleukin 12 (IL-12) gene therapy in a preclinical model to support future phase 1 trials. One hundred and twenty C57BL/6 male mice received an intraprostatic injection of saline (n = 24) or an oncolytic adenovirus (Ad5-yCD/mutTKSR39rep-mIL12) expressing two suicide genes and mouse IL-12 (n = 96). The adenovirus was administered at three dose levels (1.3 × 106, 1.3 × 107, 1.3 × 108 vp/kg) followed by 2 weeks of 5-flurocytosine (5-FC) and gancliclovir (GCV) prodrug therapy. There were no premature deaths. Daily observations of animals did not reveal any obvious clinical problems throughout the 78-day in-life phase of the study. Animals in the highest adenovirus dose group exhibited lymphopenia and transaminitis on day 3, both of which resolved by day 17. Except for mild inflammation of the prostate and seminal vesicles, histopathology of major organs was largely unremarkable. IL-12 and interferon-gamma levels in prostate and serum peaked on day 3 and were either undetectable or returned to baseline levels by day 17. No adenoviral DNA was detected in serum in any group at any time point. The results demonstrate that local administration of an oncolytic adenovirus expressing two suicide genes and IL-12 is well tolerated and support moving this investigational approach into human trials.