Purpose: To examine, using blood oxygen level dependent (BOLD) MRI and EPR oximetry, the changes in oxygenation of intracranial tumors induced by carbogen breathing. Materials and Methods:The 9L and CNS-1 intracranial rat tumor models were imaged at 7T, before and during carbogen breathing, using a multi-echo gradient-echo (GE) sequence to map R 2 *. On a different group of 9L tumors, tissue pO 2 was measured using EPR oximetry with lithium phthalocyanine as the oxygen-sensitive material. Results:The average decline in R 2 * with carbogen breathing was 13 Ϯ 1 s -1 in the CNS-1 tumors and 29 Ϯ 4 s -1 in the 9L tumor. The SI vs. TE decay curves indicate the presence of multiple components in the tumor. Tissue pO 2 in the two 9L tumors measured was 8.6 Ϯ 0.5 and 3.6 Ϯ 0.6 mmHg during air breathing, and rose to 20 Ϯ 7 and 16 Ϯ 4 mmHg (mean Ϯ SE) with carbogen breathing. Significant changes were observed by 10 minutes, but changes in pO 2 and R 2 * continued in some subjects over the entire 40 minutes. Conclusion:EPR results indicate that glial sarcomas may be radiobiologically hypoxic. Both EPR and BOLD data indicate that carbogen breathing increases brain tumor oxygenation. These data support the use of BOLD imaging to monitor changes in oxygenation in brain tumors.

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In the present study, the effects of photodynamic therapy (PDT) with verteporfin on tumor blood flow and tumor regrowth were compared as verteporfin distributed in different compartments within the RIF-1 tumor. Tissue distribution of verteporfin was examined by fluorescence microscopy, and blood flow measurements were taken with a laser Doppler system. It was found that, at 15 min after drug administration, when verteporfin was mainly confined within the vasculature, PDT induced a complete arrest of blood flow by 6 h after treatment. PDT treatment at a longer drug-light interval (3 h), which allowed the drug to diffuse to the tumor interstitium, caused significantly less flow decrease, only to 50% of the initial flow in 6 h. A histological study and Hoechst 33342 staining of functional tumor vasculature confirmed the primary vascular damage and the decrease in tumor perfusion. The regrowth rate of tumors treated with 15-min interval PDT was 64% of that of the control group. However, when tumors were treated with 3-h interval PDT, the regrowth rate was not significantly different from that of the control, indicating that only the 15-min interval PDT caused serious damage to the tumor vascular bed. These results support the hypothesis that temporal pharmacokinetic changes in the distribution of the photosensitizer between the tumor parenchyma and blood vessels can significantly alter the tumor target of PDT.

Relative perfusion, pO2, and bioreduction were measured simultaneously in vivo in tissues in mice by following changes in the intensity and shape of the EPR spectra of nitroxides injected directly into the tissues, using low frequency (1.1 GHz) localized EPR spectroscopy. Using normal and blood flow restricted gastrocnemius muscles it was shown that the decrease of the EPR signals of the nitroxides in tissues was due principally to perfusion, which redistributed the nitroxides. Changes in pO2 were reflected by changes of the linewidth; only a perdeuterated nitroxide with a narrow line was an adequate indicator for this parameter. This technique was applied experimental murine tumors (MTG-B and RIF-1) to determine the perfusion and pO2 in these relatively hypoxic model tumor systems. Using the paramagnetic properties of the nitroxides to enhance T1-weighted MR images, heterogeneity in perfusion in individual tumors was demonstrated

Numerical simulations of oxygen diffusion from the capillaries in tumor tissue were used to predict the capillary oxygen supply within and near hypoxic regions of the RIF-1 tumor. A finite element method to simulate the oxygen distribution from a histology section is presented, along with a method to iteratively estimate capillary oxygen concentrations. Pathological structural data for these simulations came from sections of the tumor stained with hematoxylin and eosin and were used to define the capillary positions and shapes, while overlapping regions of low oxygen concentration were defined by the hypoxia marker pimonidazole. These simulations were used to calculate spatial maps of the oxygen concentration and were tested for their ability to reproduce Eppendorf pO(2) histograms from the same tumor line. This simulation study predicted that capillary oxygen concentrations ranged from zero to above 20 microM, with a dominant peak in the hypoxic regions showing 78% of capillaries with less than 1 microM oxygen concentration, compared to only 12% in the non-hypoxic regions. The results were not highly sensitive to the metabolic oxygen consumption rate, within the range of 2 to 16 microM/s. This numerical method for oxygen capillary simulation is readily adaptable to histology sections and provides a method to examine the heterogeneity of oxygen within the capillaries and throughout the tumor tissue section being examined.