Heller Loree, Merkler Kathleen, Westover Jeffrey, Cruz Yolmari, Coppola Domenico, Benson Kaaron, Daud Adil, Heller Richard
Department of Medical Microbiology and Immunology, University of South Florida, Tampa 33612, USA.
Clin Cancer Res. 2006 May 15;12(10):3177-83. doi: 10.1158/1078-0432.CCR-05-2727.
Interleukin-12 (IL-12) has potential as an immunotherapeutic agent for the treatment of cancer but is unfortunately associated with toxicity. Delivery of a plasmid encoding IL-12 with electroporation induces an antitumor effect in the B16 mouse melanoma model without serious side effects. To translate this observation to the clinic, an evaluation of toxicity was done in the mouse model.
Weight change, tumor response, blood chemistry and hematology values, and serum IL-12 levels were evaluated. Multiple tissues were analyzed histopathologically.
A pronounced reduction in tumor volume, including a large percentage of complete regressions, was observed after electrically mediated gene therapy. No significant increases in serum IL-12 levels were detected. Tumor-bearing mice showed an increased number of atypical hematology values when compared with normal naive controls. Statistically significant differences in chemistry and hematology values were observed sporadically in most of the standard chemistry and hematology categories in all groups. The only histopathologic abnormality specific to the animals receiving both plasmid and electroporation was inflammation associated with the kidney at the last time point.
In general, mice that received both plasmid and electroporation showed the least abnormal histopathologic findings and were found to be in the best health, reflecting the reduced burden of disease. No significant toxic effects due to the IL-12 gene therapy were observed.
白细胞介素-12（IL-12）作为一种癌症免疫治疗药物具有潜力，但遗憾的是它与毒性相关。通过电穿孔递送编码IL-12的质粒在B16小鼠黑色素瘤模型中诱导了抗肿瘤作用，且无严重副作用。为了将这一观察结果转化到临床，在小鼠模型中进行了毒性评估。
评估体重变化、肿瘤反应、血液生化和血液学值以及血清IL-12水平。对多个组织进行组织病理学分析。
电介导基因治疗后观察到肿瘤体积显著减小，包括很大比例的完全消退。未检测到血清IL-12水平显著升高。与正常未处理对照组相比，荷瘤小鼠出现非典型血液学值的数量增加。在所有组的大多数标准生化和血液学类别中偶尔观察到生化和血液学值的统计学显著差异。接受质粒和电穿孔的动物唯一特有的组织病理学异常是在最后一个时间点与肾脏相关的炎症。
总体而言，接受质粒和电穿孔的小鼠组织病理学异常发现最少，且健康状况最佳，这反映了疾病负担的减轻。未观察到IL-12基因治疗产生的显著毒性作用。
