Department of Comparative Biomedical Sciences, LSU School of Veterinary Medicine, Baton Rouge, LA, USA.
Cancer Gene Ther. 2011 Apr;18(4):265-74. doi: 10.1038/cgt.2010.77. Epub 2011 Jan 14.
This study's goal was to assess the safety of tumor-targeted interleukin-12 (ttIL-12) when administered by electrogenetherapy in C3H/HeJ mice by identifying an initial safe dose for human dose escalation schemes, toxicity target organs, markers of toxicity, and toxicity reversibility. Tumor-free mice receiving two doses of 0.45% NaCl, 1 μg ttIL-12 DNA in 0.45% NaCl or 5 μg ttIL-12 DNA in 0.45% NaCl, 10 days apart combined with low-intensity electroporation were compared with non-treatment controls over time. All mice had blood cell counts, serum chemistry profiles, plasma interleukin-12 and IFNγ determinations, necropsy and multi-organ histopathology. Mild treatment-associated changes included electroporation-associated muscle changes that resolved by 30 days; decreased total white blood cell counts and infectious disease in the 5 μg ttIL-12 group, but not in the 1 μg group, and liver changes in ttIL-12 groups that correlated with alanine transaminase levels and resolved by 30 days. Dystrophic cardiac calcification seen in older, 5 μg ttIL-12-treated mice was the only serious toxicity. Based on these results and the lack of any effect on wound healing when combined with surgery, low-intensity electrogenetherapy with ttIL-12 appears to be safe and well tolerated.
本研究旨在通过确定用于人体剂量递增方案的初始安全剂量、毒性靶器官、毒性标志物和毒性可逆性，评估电基因治疗中肿瘤靶向白细胞介素-12（ttIL-12）的安全性。无肿瘤的 C3H/HeJ 小鼠接受两次间隔 10 天的 0.45%NaCl、0.45%NaCl 中 1μg ttIL-12 DNA 或 0.45%NaCl 中 5μg ttIL-12 DNA 联合低强度电穿孔治疗，并与未治疗对照组进行比较。所有小鼠均进行血细胞计数、血清化学谱、血浆白细胞介素-12 和 IFNγ测定、尸检和多器官组织病理学检查。轻度治疗相关变化包括电穿孔相关的肌肉变化，这些变化在 30 天内得到解决；5μg ttIL-12 组的总白细胞计数和传染病减少，但 1μg 组没有，ttIL-12 组的肝脏变化与丙氨酸转氨酶水平相关，并在 30 天内得到解决。在较老的 5μg ttIL-12 治疗小鼠中观察到的营养不良性心脏钙化是唯一的严重毒性。基于这些结果以及与手术联合使用时对伤口愈合没有任何影响，低强度电基因治疗联合 ttIL-12 似乎是安全且耐受良好的。
