¹Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy

²IRBM, Rome, Italy

³Department of Biology, Indiana University, Bloomington, Indiana, 47401

Correspondence to: Filippo Belardelli , Laboratory of Virology, Istituto Superiore di Sanità Viale Regina Elena 299, 00161 Rome, Italy. E-mail: belard@iss.it

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- genes (i.e., a first-generation replication-defective vector containing IFN-1 and two different second-generation vectors containing IFN-2) 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- 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- 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. Cancer Gene Therapy (2001) 8, 63-72

Tumor; IFN-; adenoviral vectors; gene therapy; mice