Interferon-α gene therapy for cancer: retroviral transduction of fibroblasts and particle-mediated transfection of tumor cells are both effective strategies for gene delivery in murine tumor models
Interferon-α gene therapy for cancer: retroviral transduction of fibroblasts and particle-mediated transfection of tumor cells are both effective strategies for gene delivery in murine tumor models
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癌症的干扰素-α基因治疗：成纤维细胞的逆转录病毒转导和肿瘤细胞的颗粒介导的转染都是小鼠肿瘤模型中基因传递的有效策略
作者：
T. Tüting;A. Gambotto;J. Baar;I. Davis;W. Storkus;PJ Zavodny;S. Narula;H. Tahara;P. Robbins;M. Lotze
将干扰素-α基因稳定地导入肿瘤细胞，可以消除肿瘤的形成，并诱导抗肿瘤免疫。然而，适合于临床应用的干扰素-α基因治疗癌症的策略尚未见报道。在这项研究中，我们研究了两种基因传递系统：逆转录病毒转导成纤维细胞和粒子介导的肿瘤细胞转染法，它们能够在小鼠肿瘤模型中介导局部高水平的旁分泌产生具有生物活性的干扰素-α。尽管干扰素-α具有抗增殖作用，但仍有可能获得稳定的逆转录病毒产生细胞系，并转导多种小鼠肿瘤细胞，包括同基因成纤维细胞，稳定分泌2,000-5 000 U(40-100 ng)小鼠干扰素-α/10 6细胞/24 h，在建立的模型中转导肿瘤细胞降低致瘤性，并在几种小鼠肿瘤模型系统中诱导抗肿瘤免疫。重要的是，逆转录病毒转导的同基因成纤维细胞携带干扰素-α基因能够抑制低免疫原性TS/A小鼠乳腺癌的建立，并诱导抗肿瘤免疫。用基因枪将基因枪介导入肿瘤细胞，在最初的24 h内可产生高达20000α的干扰素- /106细胞，并且在抑制TS/A腺癌的形成和诱导抗肿瘤免疫方面同样有效。这些结果表明，逆转录病毒转导自体成纤维细胞可以作为干扰素-α基因治疗肿瘤的一种有效的基因输送方法。粒子介导的新分离的肿瘤细胞转染法可能是一种具有临床吸引力的非病毒基因传递的替代方法。这两种策略都绕过了常规建立绝大多数人类癌症的原代肿瘤细胞系的困难。
Stable transfection of tumor cells with IFN-α genes has been shown to result in abrogation of tumor establishment and induction of antitumor immunity. However, strategies suitable for the clinical application of IFN-α gene therapy for cancer have not been reported. In this study, we investigated two gene delivery systems capable of mediating the local paracrine production of high levels of biologically active IFN-α in murine tumor models: retroviral transduction of fibroblasts and particle-mediated transfection of tumor cells. In spite of the antiproliferative effects of IFN-α, it was possible to obtain stable retroviral producer cell lines and transduce a variety of murine tumor cells including syngeneic fibroblasts to stably secrete 2000–5000 U (40–100 ng) murine IFN-α/106 cells/24 h. IFN-α transduction of tumor cells abrogated tumorigenicity in establishment models and induced antitumor immunity in several murine tumor model systems. Importantly, IFN-α gene delivery using retrovirally transduced syngeneic fibroblasts was capable of suppressing the establishment of the poorly immunogenic TS/A mouse mammary adenocarcinoma and induced antitumor immunity. Particle-mediated transient transfection of tumor cells using the gene gun led to the production of up to 20000 U IFN-α/106 cells during the first 24 h and proved to be equally effective in suppressing establishment of TS/A adenocarcinoma and inducing antitumor immunity. These results suggest that retroviral transduction of autologous fibroblasts can serve as an effective gene delivery method for IFN-α gene therapy of cancer. Particle-mediated transfection of freshly isolated tumor cells may represent a clinically attractive alternative approach for nonviral gene delivery. Both strategies circumvent the difficulties in routinely establishing primary tumor cell lines from the vast majority of human cancers.
DOI：
10.1073/pnas.90.18.8392
发表时间：
1993-09-15
影响因子：
11.1
作者：
PEAR, WS;NOLAN, GP;BALTIMORE, D
通讯作者：
BALTIMORE, D
影响因子：
11.2
作者：
J. Meko;J. Yim;K. Tsung;J. Norton
通讯作者：
J. Meko;J. Yim;K. Tsung;J. Norton