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Therapy of cancer by cytokines mediated by gene therapy approach

机译：基因疗法介导的细胞因子对癌症的治疗

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Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in patients with this strategy had limited efficacy. Therefore, improvement of gene transfer vector system is necessary. A hybrid viral vector, consisting of SFV replicon with either murine IL-12 or reporter LacZ gene, was constructed. This hybrid vector showed specificity and high level of expression in HCC both in vitro and in vivo. In a rat orthotropic liver tumor model, treatment of established tumors by the hybrid vector with mIL-12 gene resulted in a strong anti-tumor activity without accompanying toxicity. Subsequently, a helper-dependent adenovirus vectors containing a mifepristone (RU486) inducible system was constructed for controlled and liver-specific expression of human interleukin 12 (hIL-12) (HD-Ad/RUhIL-12) and mouse IL-12 (mIL-12) (HD-Ad/RUmIL-12). Data showed that high and sustained serum levels of hIL-12 could be attained by continuing administration of RU486 every 12 or 24 h. Repetitive induction of ML-12 could be obtained over, at least, a period of 48 weeks after a single injection of HD-Ad/RUhIL-12. Treatment of liver metastases with of HD-Ad/RUmIL-12 plus RU846 resulted in complete tumor regression in all animals. Then, different cytokine genes were inserted into conditional replicative adenoviruses vectors (also called oncolytic adenovirus). Replication of adenovirus in tumor cells would kill tumor cells and release viruses, which infect surrounding tumor cells. The combination of cytopathic effect by oncolytic adenovirus and biological effect of transgene would exert strong antitumor activity. These new types of vectors may provide a potent and safe tool for cancer gene therapy.
机译：基因治疗提供了一种新的癌症治疗方法。已经使用编码免疫刺激性细胞因子的基因转移在消除动物癌症方面取得了显著成功。但是，采用这种策略的患者的临床试验疗效有限。因此，有必要改进基因转移载体系统。构建了由SFV复制子与鼠IL-12或报告基因LacZ基因组成的杂种病毒载体。该杂合载体在体外和体内均显示出在HCC中的特异性和高水平的表达。在大鼠正交异性肝肿瘤模型中，用mIL-12基因的杂种载体处理已建立的肿瘤可产生强大的抗肿瘤活性，而不会产生毒性。随后，构建了包含米非司酮（RU486）诱导系统的依赖辅助的腺病毒载体，用于人白介素12（hIL-12）（HD-Ad / RUhIL-12）和小鼠IL-12（mIL）的受控和肝脏特异性表达-12）（HD-Ad / RUmIL-12）。数据显示，通过每12或24小时连续施用RU486可以达到高水平和持续的hIL-12血清水平。单次注射HD-Ad / RUhIL-12后至少48周内即可获得ML-12的重复诱导。 HD-Ad / RUmIL-12加RU846治疗肝转移导致所有动物的肿瘤完全消退。然后，将不同的细胞因子基因插入条件复制腺病毒载体（也称为溶瘤腺病毒）中。腺病毒在肿瘤细胞中复制会杀死肿瘤细胞并释放病毒，从而感染周围的肿瘤细胞。溶瘤腺病毒的细胞病变作用与转基因的生物学作用相结合，将具有很强的抗肿瘤活性。这些新型载体可能为癌症基因治疗提供有效而安全的工具。

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