Santodonato L, Ferrantini M, Palombo F, Aurisicchio L, Delmastro P, La Monica N, Di Marco S, Ciliberto G, Du M X, Taylor M W, Belardelli F
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Cancer Gene Ther. 2001 Jan;8(1):63-72. doi: 10.1038/sj.cgt.7700274.
Recent studies have shown that gene therapy with type I interferon (IFN) in an adenovirus vector is a powerful tool to suppress the growth of human tumors transplanted in immune-deficient mice. However, in these studies the host immune-mediated effects, which may be important in mediating the long-term control of tumor growth by these cytokines, was not studied. In this paper, we evaluate the antitumor efficacy of different adenoviral vectors containing mouse IFN-alpha genes (i.e., a first-generation replication-defective vector containing IFN-alpha1 and two different second-generation vectors containing IFN-alpha2) in immunocompetent DBA/2 mice transplanted with highly metastatic Friend leukemic cells resistant in vitro to type I IFN. We found that injection of all the different adenovirus vectors containing mouse IFN-alpha( genes resulted in a marked antitumor response in mice transplanted either subcutaneously or intravenously with IFN-resistant Friend leukemic cells compared to tumor-bearing animals inoculated with a control vector. Tumor growth inhibition after injection of IFN-adenovirus vectors was associated with a prolonged presence of high IFN levels in the sera of the injected mice. Suppression of metastatic tumor growth was also observed after a single injection of the IFN--adenovirus recombinant vectors, whereas a comparable antitumor response generally required several injections of high doses of IFN. Altogether, these results demonstrate that IFN--adenoviral vectors can efficiently inhibit metastatic tumor growth by host-mediated mechanisms and suggest that adenovirus-mediated IFN-alpha gene therapy may represent an attractive alternative to the conventional clinical use of this cytokine, which generally requires multiple injections of high IFN doses for a prolonged period of time.
最近的研究表明，用腺病毒载体进行I型干扰素（IFN）基因治疗是抑制移植到免疫缺陷小鼠体内的人类肿瘤生长的有力工具。然而，在这些研究中，宿主免疫介导的效应（这在介导这些细胞因子对肿瘤生长的长期控制中可能很重要）并未得到研究。在本文中，我们评估了不同的含有小鼠IFN-α基因的腺病毒载体（即，一种含有IFN-α1的第一代复制缺陷型载体和两种不同的含有IFN-α2的第二代载体）对移植了在体外对I型干扰素耐药的高转移性Friend白血病细胞的免疫活性DBA/2小鼠的抗肿瘤疗效。我们发现，与接种对照载体的荷瘤动物相比，注射所有不同的含有小鼠IFN-α基因的腺病毒载体，均导致皮下或静脉注射IFN耐药的Friend白血病细胞的小鼠出现明显的抗肿瘤反应。注射IFN-腺病毒载体后肿瘤生长受到抑制，这与注射小鼠血清中长时间存在高IFN水平有关。单次注射IFN-腺病毒重组载体后也观察到转移性肿瘤生长受到抑制，而类似的抗肿瘤反应通常需要多次注射高剂量的IFN。总之，这些结果表明，IFN-腺病毒载体可通过宿主介导的机制有效抑制转移性肿瘤生长，并表明腺病毒介导的IFN-α基因治疗可能是这种细胞因子传统临床应用的一种有吸引力的替代方法，传统临床应用通常需要长时间多次注射高剂量的IFN。
