¹Department of Physiological Chemistry, Molecular Virology Section, Faculty of Medical Sciences, Groningen University Institute for Drug Exploration, University of Groningen, Groningen, The Netherlands

²Department of Medical Oncology, Molecular Virology Section, Faculty of Medical Sciences, Groningen University Institute for Drug Exploration, University of Groningen, Groningen, The Netherlands

³Department of Medical Microbiology, Molecular Virology Section, Faculty of Medical Sciences, Groningen University Institute for Drug Exploration, University of Groningen, Groningen, The Netherlands

Correspondence to: A H Klimp, Department of Physiological Chemistry, Faculty of Medical Sciences, Groningen University Institute for Drug Exploration, University of Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands

In this study we determined the in vivo localization of recombinant proteins expressed by intraperitoneally (i.p.) injected recombinant Semliki Forest virus (SFV) particles. Subsequently, we investigated the influence of i.p. administered SFV particles encoding recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF) on intraperitoneal recruitment and activation of cells. Finally, the therapeutic effect of SFV-GM-CSF treatment on an i.p. growing ovarian tumor was determined. Intraperitoneal injections of recombinant SFV particles encoding the reporter protein luciferase resulted in a high level of luciferase activity in cells of the peritoneal lining and tumor cells in the peritoneal cavity. Low levels of luciferase activity were found in liver, spleen and lungs. Injection of SFV-GM-CSF particles resulted in a slight increase in the number of peritoneal macrophages and in a significant increase in the number of neutrophils. In contrast to multiple i.p. injections with commercially available recombinant GM-CSF, i.p. injected SFV-GM-CSF particles activated the macrophages to tumor cytotoxicity. Although treatment of tumor-bearing mice with SFV-GM-CSF particles did not result in prolonged survival, tumor growth was inhibited for 2 weeks. Our findings indicate that macrophage-activating cytokines expressed by the efficient and safe recombinant SFV system when administered i.p. may provide an immunotherapeutic treatment modality additional to current chemotherapeutic treatment of intraperitoneally growing cancers. Gene Therapy (2001) 8, 300-307.

Semliki Forest virus; gene therapy; granulocyte-macrophage colony-stimulating factor; tumor cytotoxicity; intraperitoneal