Mazzolini G, Qian C, Xie X, Sun Y, Lasarte J J, Drozdzik M, Prieto J
Department of Medicine, School of Medicine and Clinica Universitaria, University of Navarra, Pamplona, Spain.
Cancer Gene Ther. 1999 Nov-Dec;6(6):514-22. doi: 10.1038/sj.cgt.7700072.
Interleukin-12 (IL-12) has been shown to possess potent immunoregulatory and antitumoral effects. We have evaluated the anti-oncogenic potential and the mechanisms of the antitumoral effect of in vivo adenovirus-mediated transfer of IL-12 gene in a murine model of colon cancer. AdCMVIL-12 was constructed to permit coordinated production of p40 and p35 subunits of IL-12 gene to obtain the maximum IL-12 bioactivity. Infection of murine colon cancer CT-26 cells in vitro with AdCMVIL-12 resulted in the production of high levels of IL-12. In vivo gene therapy of colon cancer nodules by intratumoral injection of AdCMVIL-12 induced a local increase in IL-12 and interferon-gamma levels and a complete regression of the tumor in 26 of 34 (76%) mice. Tumor disappeared between days 7 and 10 after vector administration. The antitumoral effect was mediated by CD8+ T cells and was associated with the generation of cytotoxic T lymphocytes against colon cancer cells. Animals that eliminated the tumor were protected against a second administration of neoplastic cells. Treatment with AdCMVIL-12 of one tumor nodule also caused regression of established tumors at distant sites. These data demonstrate that AdCMVIL-12 is a useful therapeutic tool for established colon cancer in mice and should be considered for application in humans.
白细胞介素-12（IL-12）已被证明具有强大的免疫调节和抗肿瘤作用。我们在结肠癌小鼠模型中评估了体内腺病毒介导的IL-12基因转移的抗癌潜力和抗肿瘤作用机制。构建了AdCMVIL-12以协调产生IL-12基因的p40和p35亚基，从而获得最大的IL-12生物活性。用AdCMVIL-12体外感染小鼠结肠癌CT-26细胞可导致高水平的IL-12产生。通过瘤内注射AdCMVIL-12对结肠癌结节进行体内基因治疗可诱导局部IL-12和干扰素-γ水平升高，34只小鼠中有26只（76%）的肿瘤完全消退。在载体给药后第7至10天肿瘤消失。抗肿瘤作用由CD8 + T细胞介导，并且与针对结肠癌细胞的细胞毒性T淋巴细胞的产生有关。消除肿瘤的动物对再次给予肿瘤细胞具有抵抗力。用AdCMVIL-12治疗一个肿瘤结节也会导致远处已形成肿瘤的消退。这些数据表明，AdCMVIL-12是治疗小鼠已形成结肠癌的有用治疗工具，应考虑应用于人类。
