Differential growth inhibition of cerebral metastases by anti-angiogenic compounds

Abstract

Background: The formation of brain metastases is intrinsically linked to concomitant angiogenesis. The purpose of the present study was to investigate the combined effects of interleukin-12 (IL-12) and EMD121974 on the growth and distribution of melanoma brain metastases since both substances may interact with important steps in the cascade of brain metastases formation.

Materials and methods: Brain metastases were induced by either stereotactic implantation of cells to the brain parenchyma or by injection of the melanoma cells into the internal carotid artery to mimic hematogenous metastatic spread in mice. Naive or IL-12-overexpressing murine K1735 melanoma cells were used either alone or in combination with intraperitoneal anti-integrin treatment using EMD121974.

Results: Solid melanoma metastases were more susceptible to daily low-dose treatment of EMD121974 than multiple hematogenous metastases. Interleukin-12 had a profound effect on both types of brain metastases. After 21 days, a marked reduction of vascularity was observed in both tumor types.

Conclusion: The combination of endogenous IL-12 production with integrin blockade resulted in additive effects for murine hematogenous brain metastases but not for focal brain metastases.

Keywords: Brain metastases; EMD121974; brain tumor; cilengitide; interleukin-12; melanoma.