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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.

Heterogeneities in tumor blood flow are associated with cyclic changes in pO2 or cyclic hypoxia. A major difference from O2 diffusion‐limited or chronic hypoxia is that the tumor vasculature itself may be directly influenced by the fluctuating hypoxic environment, and the reoxygenation phases complicate the usual hypoxia‐induced phenotypic pattern. Here, we determined the cyclic hypoxia‐driven pathways that modulate hypoxia inducible factor (HIF)‐1α abundance in endothelial cells to identify possible therapeutic targets. We found that exposure of endothelial cells to cycles of hypoxia/reoxygenation led to accumulation of HIF‐1α during the hypoxic periods and the phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK) and endothelial nitric oxide synthase (eNOS) during the reoxygenation phases. We identified stimulation of mitochondrial respiration and activation of the phosphoinositide‐3 kinase (PI3K)/Akt pathway during intervening reoxygenation periods as major triggers of the stabilization of HIF‐1α. We also found that the NOS inhibitor nitro‐l‐arginine methyl ester further stimulated the cyclic hypoxia‐driven HIF‐1α accumulation and the associated gain in endothelial cell survival, thereby mirroring the effects of a PI3K/Akt inhibitor. However, combination of both drugs resulted in a net reduction in HIF‐1α and a dramatic in decrease in endothelial cell survival. In conclusion, this study identified cyclic hypoxia, as reported in many tumor types, as a unique biological challenge for endothelial cells that promotes their survival in a HIF‐1α‐dependent manner through phenotypic alterations occurring during the reoxygenation periods. These observations also indicate the potential of combining Akt‐targeting drugs with anti‐angiogenic drugs, in particular those interfering with the NO pathway.

Purpose: We hypothesized that glucocorticoids may enhance tumor radiosensitivity by increasing tumor oxygenation (pO 2 ) through inhibition of mitochondrial respiration. Experimental Design: The effect of three glucocorticoids (hydrocortisone, dexamethasone, and prednisolone) on pO 2 was studied in murine TLT liver tumors and FSaII fibrosarcomas. At the time of maximum pO 2 (t max , 30 min after administration), perfusion, oxygen consumption, and radiation sensitivity were studied. Local pO 2 measurements were done using electron paramagnetic resonance. The oxygen consumption rate of tumor cells after in vivo glucocorticoid administration was measured using high-frequency electron paramagnetic resonance. Tumor perfusion and permeability measurements were assessed by dynamic contrast-enhanced magnetic resonance imaging. Results: All glucocorticoids 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.When irradiation (25 Gy) was applied at t max , the tumor radiosensitivity was enhanced (regrowth delay increased by a factor of 1.7). Conclusion:These results show the potential usefulness of the administration of glucocorticoids before irradiation.Tumor hypoxia is a critical determinant of resistance to radiotherapy and chemotherapy (1, 2). To target this resistance, prodrugs have been developed that are activated in hypoxic regions (3). In addition to this approach, we may also consider that a transient increase in tumor oxygenation may be beneficial if combined with radiotherapy. Indeed, a number of tumor oxygenating treatments have been developed to improve the therapeutic outcome. Mechanistically, tumor hypoxia results from an imbalance between oxygen delivery and oxygen consumption, either of which may be potentially targeted by therapeutic interventions. On one hand, oxygen delivery may be increased by increasing tumor perfusion (4 -7) or by changing the hemoglobin saturation curve (8, 9). On the other hand, tumor hypoxia can be alleviated by decreasing the oxygen consumption. It has been predicted that modification of oxygen consumption is much more efficient at alleviating hypoxia than modification of oxygen delivery (10). Several drugs that inhibit mitochondrial respiration, such as metaiodobenzylguanidine (11), insulin (12, 13), and cyclooxygenase-2 inhibitors (14), have been characterized for their potential to increase tumor oxygenation and thereby enhance radiosensitivity.Here, we hypothesized that glucocorticoids could be other important modulators of tumor oxygenation. The rationale for this hypothesis is that glucocorticoids are known to inhibit oxidative phosphorylation of the respiratory chain, with important effect on respiration rate of cells (15,16). Using two different tumor models, we show that the administration of glucocorticoids (hydrocortisone, prednisolone, and dexamethasone) has a profound effect on tumor oxygenation....

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