Acute hypoxia (transient cycles of hypoxia-reoxygenation) is known to occur in solid tumors and is generally believed to be caused by tumor blood flow instabilities. It was recently demonstrated that T2*-weighted (T2*w) gradient echo (GRE) MRI is a powerful non-invasive method for investigating periodic changes in tumor pO2 and blood flow associated with acute hypoxia. Here, the possible correlation between tumor vessel immaturity, vessel functionality and T2*w GRE signal fluctuations was investigated. Intramuscularly implanted FSa II fibrosarcoma-bearing mice were imaged at 4.7 T. Maps of spontaneous fluctuations of MR signal intensity in tumor tissue during air breathing were obtained using a T2*w GRE sequence. This same sequence was also employed during air-5% CO2 breathing (hypercapnia) and carbogen breathing (hypercapnic hyperoxia) to obtain parametric maps representing vessel maturation and vessel function, respectively. Vascular density, vessel maturation and vessel perfusion were also assessed histologically by using CD31 labeling, alpha-smooth muscle actin immunoreactivity and Hoechst 33242 labeling, respectively. About 50% of the tumor fluctuations occurred in functional tumor regions (responsive to carbogen) and 80% occurred in tumor regions with immature vessels (lack of response to hypercapnia). The proportion of hypercapnia-responsive voxels were found to be twice as great in fluctuating than in non-fluctuating tumor areas (P: 0.22 vs 0.13). Similarly, the proportion of functional voxels was somewhat greater in fluctuating tumor areas (P: 0.54 vs 0.43). The mean values of MR signal changes during hypercapnia (VD) and during carbogen breathing (VF) (significant voxels only) were also larger in fluctuating than in non-fluctuating tumor areas (P < 0.05). This study demonstrated that adequate vessel functionality and advanced vessel maturation could explain at least in part the occurrence of spontaneous T2*w GRE signal fluctuations. Functionality and maturation are not required for signal fluctuations, however, because a large fraction of fluctuations could still occur in non-perfused and/or immature vessels.
We hypothesized that nonsteroidal antiinflammatory drugs (NSAIDs) might enhance tumor radiosensitivity by increasing tumor oxygenation (pO 2 ), via either a decrease in the recruitment of macrophages or from inhibition of mitochondrial respiration. The effect of four NSAIDs (diclofenac, indomethacin, piroxicam, and NS-398) on pO 2 was studied in murine TLT liver tumors and FSaII fibrosarcomas. At the time of maximum pO 2 (t max , 30 minutes after administration), perfusion, oxygen consumption, and radiation sensitivity were studied. Local pO 2 measurements were done using electron paramagnetic resonance. Tumor perfusion and permeability measurements were assessed by dynamic contrast-enhanced magnetic resonance imaging. The oxygen consumption rate of tumor cells after in vivo NSAID administration was measured using high-frequency electron paramagnetic resonance. Tumor-infiltrating macrophage localization was done with immunohistochemistry using CD11b antibody. All the NSAIDs tested caused a rapid increase in pO 2 . At t max , tumor perfusion decreased, indicating that the increase in pO 2 was not caused by an increase in oxygen supply. Also at t max , global oxygen consumption decreased but the amount of tumor-infiltrating macrophages remained unchanged. Our study strongly indicates that the oxygen effect caused by NSAIDs is primarily mediated by an effect on mitochondrial respiration. When irradiation (18 Gy) was applied at t max , the tumor radiosensitivity was enhanced (regrowth delay increased by a factor of 1.7). These results show the potential utility of an acute administration of NSAIDs for radiosensitizing tumors, and shed new light on the mechanisms of NSAID radiosensitization. These results also provide a new rationale for the treatment schedule when combining NSAIDs and radiotherapy. (Cancer Res 2005; 65(17): 7911-6)
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.
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