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ORIGINAL RESEARCH ARTICLE

The Role of Interferon- in a Successful Murine Tumor Therapy

Timothy A. Steele^*,1 and Christopher C. Hauser

^* Department of Microbiology, Osteopathic Medical Center, Des Moines University, Des Moines, Iowa 50312; and Department of Health Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201

To whom requests for reprints should be addressed at ¹ Department of Microbiology, Osteopathic Medical Center, Des Moines University, 3200 Grand Avenue, Des Moines, IA 50312. E-mail: timothy.steele{at}dmu.edu

Combination therapy using reovirus type 3 and the chemo-therapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is sufficient to cure approximately 80% of EL-4 lymphoma tumor–bearing BD2F1 male mice. Cured animals can be challenged with the EL-4 tumor, in the absence of the therapy, to yield 100% survival, whereas those challenged with heterologous tumor produce 0% survival. These results strongly suggest that a host-immune response is responsible for the observed therapeutic effect. Reovirus, a double-stranded RNA virus, is an efficient inducer of type I interferon. In an effort to determine the role of virus in this therapy, we substituted interferon- (IFN-) for reovirus in the therapy. Doses of IFN- from 1000–10,000 U were capable of replacing reovirus to produce cure rates similar to reovirus. Spleen cells isolated from therapy-treated animals demonstrated high levels of cytotoxicity against the natural killer cell–sensitive cell line YAC-1, but not against EL-4 tumor. In vitro stimulation of isolated spleen cells by IFN- resulted in a high level of natural killer cell activity, but no cytotoxicity against the EL-4 tumor. A significant antiproliferative effect against the EL-4 tumor in cell culture was demonstrated by IFN-. Finally, therapy-treated, tumor-bearing mice that were injected with anti–IFN- + -ß antibodies had similar survival levels as control mice, indicating that other cytokines might also play a role in promoting tumor killing. These investigations suggest that IFN- may be a mediator of antitumor activity in the reovirus therapy system.

Key Words: reovirus • interferon- • immunotherapy • 1,3-bis(2-chloroethyl)-1-nitrosourea • EL-4 lymphoma