G-CSF prevents the suppression of bone marrow hematopoiesis induced by IL-12 and augments its antitumor activity in a melanoma model in mice

Background: IL-12 has been successfully used in experimental tumor therapy. However, administration of this cytokine induces dose-dependent suppression of hematopoiesis that could potentially limit its use in clinical trials. We decided to examine whether the myelosuppressive activity of IL-12 could be corrected by the administration of G-CSF. Materials and methods: In the initial experiments the influence of IL-12 and/or G-CSF on bone marrow and spleen GM-CFC was evaluated. To examine whether G-CSF could influence the antitumor activity of IL-12 the combination therapy with these agents was carried out starting on day seven following inoculation of melanoma MmB16 cells into the footpads of B6D2F(1) mice. To obtain insight into the mechanism of the observed augmented antitumor activity of the combination therapy with IL-12 and G-CSF, the influence of these cytokines on macrophage activity (cytotoxicity and nitric oxide release) was analyzed. Results: In accord with our expectations, the application of G-CSF partially prevented the suppression of bone marrow myelopoiesis in IL-12-treated mice. Unexpectedly, G-CSF also showed potentiation of antitumor effects of lL-12 in this melanoma model. The augmented antitumor activity of combined IL-12/G-CSF immunotherapy could result from the enhanced stimulation of macrophage NO production and cytotoxicity. Conclusion: The simultaneous administration of IL-12 and G-CSF partially prevented suppression of bone marrow myelopoiesis ir. IL-12-treated mice. Moreover, treatment with these cytokines also results in potentiated antitumor effects in a murine melanoma model.