Tumour control by whole brain irradiation of anti-VEGF-treated mice bearing intracerebral glioma

Abstract

Aim of the study Tumour angiogenesis and invasion are key features of glioblastoma multiforme (GBM). Angiogenesis inhibitors increase progression-free survival (PFS) of recurrent GBM patients. VEGF inhibition controls the bulk tumour growth by inhibition of angiogenesis, but does not inhibit the invasive tumour component. We investigated if invasive tumour growth can be controlled by combining anti-VEGF treatment with irradiation of tumour plus surrounding brain in an orthotopic murine model for GBM. Methods and materials GBM cell line U251-NG2 was inoculated through a guide screw in the right frontal lobe of 53 athymic nude mice. Pegaptanib (a slow-releasing aptamer against VEGF) was injected in the tumour bed either or not followed by irradiation treatment with implanted I-125 seeds. Pegaptanib and/or irradiation were compared with sham-treated controls, resulting in four groups of 10–15 mice each. After 6 weeks of treatment, histological analysis was performed on all brains. Results VEGF inhibition by locally deposited pegaptanib decreased tumour blood vessel density, and increased tumour hypoxia. Pegaptanib treatment still allowed the formation of tumour satellites. Irradiation decreased tumour size and suppressed formation of satellites. Combined pegaptanib plus irradiation further increased PFS. Tumour size directly correlated with PFS. Concluding statement The anti-tumour effects of local VEGF inhibition are partially circumvented by the formation of invasive tumour satellites. Additional irradiation is effective in slowing down proliferation of these invasive tumour components.