The Addition of AG-013736 to Fractionated Radiation Improves Tumor Response without Functionally Normalizing the Tumor Vasculature

Abstract

Although antiangiogenic strategies have proven highly promising in preclinical studies and some recent clinical trials, generally only combinations with cytotoxic therapies have shown clinical effectiveness. An ongoing question has been whether conventional therapies are enhanced or compromised by antiangiogenic agents. The present studies were designed to determine the pathophysiologic consequences of both single and combined treatments using fractionated radiotherapy plus AG-013736, a receptor tyrosine kinase inhibitor that preferentially inhibits vascular endothelial growth factor receptors. DU145 human prostate xenograft tumors were treated with (a) vehicle alone, (b) AG-013736, (c) 5 Â 2 Gy/wk radiotherapy fractions, or (d) the combination. Automated image processing of immunohistochemical images was used to determine total and perfused blood vessel spacing, overall hypoxia, pericyte/collagen coverage, proliferation, and apoptosis. Combination therapy produced an increased tumor response compared with either monotherapy alone. Vascular density progressively declined in concert with slightly increased A-smooth muscle actin-positive pericyte coverage and increased overall tumor hypoxia (compared with controls). Although functional vessel endothelial apoptosis was selectively increased, reductions in total and perfused vessels were generally proportionate, suggesting that functional vasculature was not specifically targeted by combination therapy. These results argue against either an AG-013736-or a combination treatment-induced functional normalization of the tumor vasculature. Vascular ablation was mirrored by the increased appearance of dissociated pericytes and empty type IV collagen sleeves. Despite the progressive decrease in tumor oxygenation over 3 weeks of treatment, combination therapy remained effective and tumor progression was minimal. [Cancer Res 2007;67(20):9921-8]

Long-term interferon-α treatment suppresses tumor growth but promotes metastasis capacity in hepatocellular carcinoma

“…Hypoxia develops due to the excessive oxygen consumption through the increased metabolic activity associated with rapidly proliferating tumor cells (Bristow and Hill 2008;Liao and Johnson 2007). Most studies suggest that the increased tumor hypoxia by anti-angiogenesis therapy appears to be due to the impaired oxygen supply created by the collapse of the neovasculature after the loss of endothelial cells or pericytes (Franco et al 2006;Chang et al 2007;Bix et al 2006;Fenton and Paoni 2007;Fenton et al 2004). Besides the direct eVect on the tumor vasculature, antiangiogenesis agents also indirectly suppress tumor cell proliferation (Fenton et al 2004;Roberts et al 2005;Murphy et al 2006), resulting from less blood supply.…”

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

“…On the other hand, some data [48] showed that axitinib significantly increased tumor hypoxia with a potential detrimental effect.…”

“…Fenton and Paoni [48] evaluated how sequencing of axitinib and fractionated RT could affect results. The study showed a benefit of adding axitinib to fractionated RT regarding tumor growth delay and tumor vasculature, but it failed to demonstrate the better sequence of treatment modalities.…”

Targeting integrins in malignant glioma

“…Consistent with a cytotoxic effect of radiotherapy on angiogenic vessels, concomitant administration of antiangiogenic drugs decreases endothelial cell survival. Anti-VEGF antibodies (e.g., bevacizumab) [16], VEGFR inhibitors (e.g., AG-013736) [17], mTOR inhibitors (e.g., RAD001) [18], and integrin inhibition (cilengitide) [19] sensitize angiogenic endothelial cells to ionizing radiation-induced death, thereby enhancing tumor vascular damage induced by radiotherapy and improving therapeutic response [20]. Irradiation of glioma cells increases their expression of alphaVbeta3 integrin [21], thus integrin inhibition will further synergize with radiation therapy.…”