How Does Antiangiogenic Therapy Affect Brain Tumor Response to
How Does Antiangiogenic Therapy Affect Brain Tumor Response to
Original article: Winkler F et al . (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6: 553-563
Tumor vessels have structural and functional abnormalities, which impair tissue oxygenation and drug delivery, and may induce resistance to therapy. Glioblastoma multiforme is an extreme example. Antiangiogenic therapy has been combined with radiotherapy with mixed results: additive or synergistic tumor growth delay, or reduced response. It is not clear which order of administration is most effective.
To determine how best to combine antiangiogenic therapy and radiotherapy by characterizing the time course of vascular changes, tumor hypoxia and response to γ-radiation following vascular normalization by VEGFR2 blockade.
Male nude mice bearing U87 glioma tumors in the cerebral cortex received either DC101 VEGFR2-specific antibody (40 mg/kg intraperitoneally on days 0, 3 and 6) or γ radiation given to the upper part of the brain (three 7 Gy fractions, given daily at 4.6 Gy/min), or a combination, whereby radiotherapy was started 9 or 2 days before, or 1, 4 or 7 days after the first DC101 injection. To block angiopoietin-1/Tie2 receptor signaling, animals were injected either intraperitoneally, with 20 mg/kg anti-mouse Tie2 blocking antibody, or stereotactically into the tumor with 125 nmol of the Tie2 blocking peptide NLLMAAS. To inhibit matrix metalloproteinases (MMP), mice were injected intraperitoneally with 150 µg of the nonspecific MMP inhibitor GM6001. All agents were given 30 min following DC101 or control antibody.
Tumor growth delay, defined as the time taken for tumors to double in diameter.
DC101 produced an insignificant delay in tumor growth, but radiation significantly delayed growth by about 12.5 days. When DC101 was combined with radiotherapy in a suboptimal regimen no more than additive effects were observed. However, administering radiotherapy 4-6 days after DC101 treatment synergistically delayed tumor growth. This coincided with the time of maximum tumor oxygenation (days 5-8). Similarly, vessel coverage by pericytes increased markedly between days 2 and 5, and fell again by day 8, peaking on day 2, when the diameter of tumor vessels had decreased significantly. Extensive vascular regression had occurred by day 8, when pericyte coverage had fallen to the control level. At the time of peak pericyte coverage, only two molecules were upregulated more than 3-fold, human angiopoietin-1 (4.8-fold) and human ephrin B2 (3.8-fold). Increased deposition of angiopoetin-1 protein in proximity to its receptor Tie2 on endothelial cells was observed on days 2 and 5. In the presence of Tie2 blockade, DC101 did not increase vascular pericyte coverage, or decrease mean vascular diameter, and reduction in tumor hypoxia at day 5 after DC101 therapy was decreased. DC101 reduced basement membrane thickness on days 2 and 5; coadministration of an MMP inhibitor completely abolished this effect.
VEGFR blockade temporarily normalizes tumor vessel walls, leading to improved vascular function and tumor oxygenation, thus enhancing response to radiotherapy.
Original article: Winkler F et al . (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6: 553-563
Tumor vessels have structural and functional abnormalities, which impair tissue oxygenation and drug delivery, and may induce resistance to therapy. Glioblastoma multiforme is an extreme example. Antiangiogenic therapy has been combined with radiotherapy with mixed results: additive or synergistic tumor growth delay, or reduced response. It is not clear which order of administration is most effective.
To determine how best to combine antiangiogenic therapy and radiotherapy by characterizing the time course of vascular changes, tumor hypoxia and response to γ-radiation following vascular normalization by VEGFR2 blockade.
Male nude mice bearing U87 glioma tumors in the cerebral cortex received either DC101 VEGFR2-specific antibody (40 mg/kg intraperitoneally on days 0, 3 and 6) or γ radiation given to the upper part of the brain (three 7 Gy fractions, given daily at 4.6 Gy/min), or a combination, whereby radiotherapy was started 9 or 2 days before, or 1, 4 or 7 days after the first DC101 injection. To block angiopoietin-1/Tie2 receptor signaling, animals were injected either intraperitoneally, with 20 mg/kg anti-mouse Tie2 blocking antibody, or stereotactically into the tumor with 125 nmol of the Tie2 blocking peptide NLLMAAS. To inhibit matrix metalloproteinases (MMP), mice were injected intraperitoneally with 150 µg of the nonspecific MMP inhibitor GM6001. All agents were given 30 min following DC101 or control antibody.
Tumor growth delay, defined as the time taken for tumors to double in diameter.
DC101 produced an insignificant delay in tumor growth, but radiation significantly delayed growth by about 12.5 days. When DC101 was combined with radiotherapy in a suboptimal regimen no more than additive effects were observed. However, administering radiotherapy 4-6 days after DC101 treatment synergistically delayed tumor growth. This coincided with the time of maximum tumor oxygenation (days 5-8). Similarly, vessel coverage by pericytes increased markedly between days 2 and 5, and fell again by day 8, peaking on day 2, when the diameter of tumor vessels had decreased significantly. Extensive vascular regression had occurred by day 8, when pericyte coverage had fallen to the control level. At the time of peak pericyte coverage, only two molecules were upregulated more than 3-fold, human angiopoietin-1 (4.8-fold) and human ephrin B2 (3.8-fold). Increased deposition of angiopoetin-1 protein in proximity to its receptor Tie2 on endothelial cells was observed on days 2 and 5. In the presence of Tie2 blockade, DC101 did not increase vascular pericyte coverage, or decrease mean vascular diameter, and reduction in tumor hypoxia at day 5 after DC101 therapy was decreased. DC101 reduced basement membrane thickness on days 2 and 5; coadministration of an MMP inhibitor completely abolished this effect.
VEGFR blockade temporarily normalizes tumor vessel walls, leading to improved vascular function and tumor oxygenation, thus enhancing response to radiotherapy.