Inhibition of tumor‐induced angiogenesis by the administration of recombinant interferon‐γ followed by a synthetic lipid‐a subunit analogue (GLA‐60)

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Abstract
The effect of the administration of recombinant interferon‐γ. (rlFN‐γ) and a synthetic lipid A subunit analog (GLA‐60) on angiogenesis induced by B16‐BL6 melanoma was examined in syngeneic C57BLJ.6 mice. Intravenous administration of rlFN‐γ followed by GLA‐60 (referred to as rIFN‐γ/GLA‐60) induced endogenous production of tumor necrosis factor (TNF). This treatment on day 3 after tumor inoculation caused a marked decrease in the number of vessels oriented towards the tumor mass (angiogenic response) and tumor size over a period of 9 days. In contrast, neither rlFN‐γ nor GLA‐60 alone, nor GLA‐60/ rIFN‐γ (reverse sequence of administration), which is unable to induce the production of TNF in the serum, had any effect. Sera induced by the treatment with rIFN‐γJ.GLA‐60, and recombinant TNF, inhibited the in vitro growth of lung endothelial cells which is considered to be one of the essential events in tumor neovascularization. Multiple i.v. treatments with rIFN‐γ/ GLA‐60 on days 5, 8 and 11 after s.c. implantation of tumor, significantly inhibited primary tumor growth by the amputation time (day 20) and lung metastasis of BI6‐BL6 cells on day 34, while other treatment modalities had no such effect. Our results indicate that inhibition of lung‐tumor metastasis by rlFN‐γ/GLA‐60 treatment may be partly due to the inhibition of tumor‐associated angiogenesis.