Therapeutic synergy of TNP-470 and ionizing radiation: effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multiforme xenografts.

摘要: We examined the effect on tumor growth, vessel morphology, and expression of angiogenic factors combining radiotherapy antiangiogenesis in human glioblastoma line U87 grown flank or intracranially nude mouse. The antiangiogenic agent TNP-470 was given 6.7 mg/kg s.c. daily day 1-7 starting 1 week after transplantation. Irradiation (IR), 10 Gy x 1, administered 7. A series tumors were excised 8 48 h end treatment. vascular morphology evaluated CD31 immunostained cryosections by electron microscopy, pattern (mRNA protein) quantitatively analyzed phosphorimaging Northern blots Western blots. Significant inhibition growth relative to untreated controls achieved monotherapy with both (P < 0.001) IR 0.001). significant enhancement this obtained 0.05). saw no either alone addition survival mice intracranial tumors. immunostaining showed acute endothelial swelling luminal protrusion irradiated vessels but never pretreated TNP-470, not controls. density (Chalkley point counts) unchanged therapy. In TNP-470-treated tumors, we observed a distinct broadening basement membrane an approximately 400-700-nm-thick electron-dense yet uncharacterized fibrillar material. treated +/- also had significantly increased mRNA angiopoietin-1, whereas angiopoietin-2, factor basic fibroblast treatments. conclusion, enhanced ionizing IR, our findings strongly indicate that microvascular damage is effectively prevented concurrent up-regulation angiopoietin-1 seems play role protective mechanism, which as fully elucidated.