Mechanism of Reoxygenation after Antiangiogenic Therapy Using SU5416 and Its Importance for Guiding Combined Antitumor Therapy

Abstract

Emerging preclinical studies support the concept of a transient ''normalization'' of tumor vasculature during the early stage of antiangiogenic treatment, with possible beneficial effects on associated radiotherapy or chemotherapy. One key issue in this area of research is to determine whether this feature is common to all antiangiogenic drugs and whether the phenomenon occurs in all types of tumors. In the present study, we characterized the evolution of the tumor oxygenation (in transplantable liver tumor and FSAII tumor models) after administration of SU5416, an antagonist of the vascular endothelial growth factor receptor. SU5416 induced an early increase in tumor oxygenation [measured by electronic paramagnetic resonance (EPR)], which did not correlate with remodeling of the tumor vasculature (assessed by CD31 labeling using immunohistochemistry) or with tumor perfusion (measured by dynamic contrast enhanced-magnetic resonance imaging). Inhibition of mitochondrial respiration (measured by EPR) was responsible for this early reoxygenation. Consistent with these unique findings in the tumor microenvironment, we found that SU5416 potentiated tumor response to radiotherapy but not to chemotherapy. In addition to the fact that the characterization of the tumor oxygenation is essential to enable correct application of combined therapies, our results show that the long-term inhibition of oxygen consumption is a potential novel target in this class of compounds.

Low-field paramagnetic resonance imaging of tumor oxygenation and glycolytic activity in mice

“…Recently, transient improvement in tumor pO 2 by antiangiogenesis drugs has been getting increasing attention to improve radiotherapy efficacy (43). A combination of pO 2 maps obtained by EPRI and perfusion-weighted images by MRI will contribute to a better understanding of tumor oxygen status and its relationship with other blood flow and metabolic profiles, making it possible for a more detailed planning of combination therapy of anticancer drugs and radiation.…”

The Acidic Tumor Microenvironment Promotes the Reconversion of Nitrite into Nitric Oxide: Towards a New and Safe Radiosensitizing Strategy

“…Electronic paramagnetic resonance (EPR) oximetry, using charcoal (CX0670-1; EM Science) as the oxygensensitive probe, was used to evaluate tumor and muscle oxygenation as previously described (33). EPR spectra were recorded using an EPR spectrometer (Magnettech) with a low frequence microwave bridge operating at 1.2 GHz and extended loop resonator.…”

“…The suspension was drawn into glass capillary tubes; cytotoxicity was concomitantly evaluated with a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay (34). All spectra were recorded on a Bruker EMX EPR spectrometer operating at 9 GHz, as previously described (33). The probe was calibrated at various O 2 concentrations between 100% nitrogen and air so that the line width measurements were related to O 2 concentration at any value.…”

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

“…As discussed below, many studies testing the effects of antiangiogenic drugs have shown a presence of a "normalization window"-a time period beginning with the appearance of a normalized vascular phenotype (typically within 1 -2 days of starting treatment), and ending when features of normalization are lost Winkler et al 2004;Jain 2005b;Batchelor et al 2007;Kamoun et al 2009 Xian et al 2006;McCarty et al 2007;Mazzone et al 2009. c This is controversial given recent reports of increased metastasis after antiangiogenic therapy in certain animal models (Ebos et al 2009;Paez-Ribes et al 2009 Gorski et al 1999;Hansen-Algenstaedt et al 2000;Lee et al 2000;Kozin et al 2001;Ader et al 2003;Winkler et al 2004;Ansiaux et al 2005Ansiaux et al , 2006Pore et al 2006a;Dings et al 2007;Kashiwagi et al 2008;Batra et al 2009;Cerniglia et al 2009;Tsukada et al 2009;McGee et al 2010. g Teicher et al 1995a,b;Wildiers et al 2003;Segers et al 2006;Dickson et al 2007a,b,c;Bhattacharya et al 2008Bhattacharya et al , 2009Zhou et al 2008;Juan et al 2009;Zhou and Gallo 2009;J Liu, S Liao, B Diop-Frimpong, et al, unpubl. data. section, we discuss the key molecules implicated in tumor vessel biology with a focus on their role in regulating vascular normalization.…”

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