Using an orthotopic intracerebral model, we investigated whether systemic treatment with DC101, a
monoclonal antibody against
vascular endothelial growth factor receptor (VEGFR)-2, could inhibit angiogenesis and the growth of human
glioblastoma cells in severe combined immunodeficient mice. Intraperitoneal treatment with DC101, control
IgG, or PBS was initiated either on day 0 or, in another series, on day 6 after
tumor cell implantation, and animals were killed approximately 2 weeks after
tumor cell injection.
Tumor volumes in animals treated with DC101 were reduced by 59 and 81% compared with
IgG and PBS controls, respectively (P < 0.001), when treatment was initiated immediately, and similar results were obtained when treatment started on day 6. Microvessel density in
tumors of DC101-treated animals was reduced by at least 40% compared with animals treated with control
IgG or PBS (P < 0.01). We observed a reduction in
tumor cell proliferation and an increase in apoptosis in DC101-treated animals (P < 0.001). However, in mice treated with DC101, we also noticed a striking increase in the number and total area of small satellite
tumors clustered around, but distinct from, the primary. These satellites usually contained central vessel cores, and
tumor cells often had migrated over long distances along the host vasculature to eventually reach the surface and spread leptomeningeally. We conclude that systemic antagonization of
VEGFR-2 can inhibit
glioblastoma neovascularization and growth but can lead to increased cooption of preexistent cerebral blood vessels. Therefore, a combination of different treatment modalities which also include anti-invasive
therapy may be needed for an effective
therapy against
glioblastoma, and the use of an antibody against
VEGFR-2 may be one effective component.