Impact of Hypoxia and the Metabolic Microenvironment on Radiotherapy of Solid Tumors (original) (raw)
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Acta Oncologica, 1995
Tumour oxygenation and bioenergetic status were measured in the same tumour and these results related to radiobiological hypoxia. A C3H mouse mammary carcinoma grown in the feet of CDFl mice was used. Bioenergetic status was assessed by 31P MRS using a SISCO 7 Tesla magnet, oxygen measurements were done by a polarographic electrode and the hypoxic fraction was determined from direct analysis of the radiation dose-response data. During all examinations restrained, non-anaesthetized mice were allowed to breathe either 100% oxygen, carbogen, normal air, carbon monoxide (CO) at 75, 220, or 660 ppm or had blood flow occluded by clamping. Results showed a significant correlation between the radiobiological hypoxic fraction and YO pOz d 5 mmHg under the different treatment conditions, whereas no correlation was found between beta nucleosidetriphosphate/inorganic phosphate (P-NTPIPi) ratio and either the hypoxic fraction or the YO of pOz values d 5 mmHg under the different treatment conditions. In conclusion, oxygen electrode measurements were sensitive to changes in tumour hypoxia whereas the bioenergetic status alone seemed to be a less precise measure of hypoxia in this tumour model. Furthermore, the present study demonstrated that tumour cells in vivo can actually maintain the bioenergetic status during a period of severe hypoxia.
International Journal of Radiation Oncology*Biology*Physics, 1994
Purpose: To determine whether electrode measurements of tumor oxygenation, made in a variety of murine tumor models, correlate with estimates of radiobiological hypoxia in the same tumor systems. Methods and Materials: The tumor models used were a QH mammary carcinoma grown in the feet of CDFl mice; the SCCVII, KHT and RIF-1 tumors grown in the feet or flanks of C3H/Km mice; and the CaNT and SaF tumors grown on the backs of CBA mice. All treatments were performed when tumors were about 200 mm3 in size. Radiobiological hypoxic fractions were determined using either a paired survival curve assay, with survival measured O-24 h after irradiation, or using a clamped tumor control assay, with percent local tumor control estimated 90 days after treatment. Measurements of tumor oxygen partial pressure (~0~) distributions were performed using Eppendorf oxygen electrodes.
Cancer research, 1992
Hypoxia is considered to be a major cause of tumor radioresistance. Reoxygenation of previously hypoxic areas after a priming dose of radiation is associated with an increase in tumor radiosensitivity. In a study of a hypoxic mammary carcinoma, 31P nuclear magnetic resonance spectra showed statistically significant increases in metabolite ratios (phosphocreatine/Pi and nucleotide triphosphate/Pi) after 65 and 32 Gy. The maximum changes in metabolite ratios after 32 Gy occurred at 48 h, although significant changes were detected at 24 h. A corresponding increase in the mean tumor pO2 (polarographic microelectrode measurements) and a decrease in hypoxic cell fraction [changes in paired (clamped versus unclamped) tumor control dose for 50% of tumors] were also shown to occur 48 h after a priming dose of 32 Gy. A significant increase in the mean tumor pO2, phosphocreatine/Pi, and nucleotide triphosphate/Pi, compared to initial values, was noted at 24, 48, and 96 h post 65-Gy radiation. ...
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute to improved treatment strategies. Here, we define two imaging biomarkers that predict differences in tumor response to therapy: (i) partial oxygen pressure (pO2), measured by EPR imaging; and (ii) [1-13C] pyruvate metabolism rate, measured by hyperpolarized 13C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa2, and Su.86.86) were grown in mice. The median pO2 of the mature Hs766t, MiaPaCa2, and Su.86.86 tumors was 9.1 ± 1.7, 11.1 ± 2.2, and 17.6 ± 2.6 mm Hg, and the rate of pyruvate-to-lactate conversion was 2.72 ± 0.48, 2.28 ± 0.26, and 1.98 ± 0.51 per minute, respectively (n = 6, each). These results are in agreement with steady-state data of matabolites quantified by mass spectroscopy and histologic analysis, indicating glycolytic and hypoxia profile in Hs...
Cancer research, 2018
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute to improved treatment strategies. Here we define two imaging biomarkers that predict differences in tumor response to therapy: 1) partial oxygen pressure (pO2), measured by EPR imaging; and 2) [1-13C] pyruvate metabolism rate, measured by hyperpolarized 13C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa-2, and Su.86.86) were grown in mice. The median pO2 of the mature Hs766t, MiaPaCa-2, and Su.86.86 tumors was 9.1±1.7, 11.1±2.2, and 17.6±2.6 mmHg, and the rate of pyruvate-to-lactate conversion was 2.72±0.48, 2.28±0.26, and 1.98±0.51 min-1, respectively (n=6, each). These results are in agreement with steady state data of matabolites quantified by mass spectroscopy and histological analysis indicating glycolytic and hypoxia profile in Hs766t, MiaPaca-2, and ...
Tumors growing in irradiated tissue: Oxygenation, metabolic state, and pH
International Journal of Radiation Oncology*Biology*Physics, 1991
Experimental tumors growing in irradiated tissue have been used to study the biological differences characteristic of locally recurrent tumors. Animal tumors were early generation isotransplants of a spontaneous fibrosarcoma in a C3lWSed mouse, designated FSa-II. Since the hypoxic cell fraction of tumors growing in irradiated tissue is increased, these tumors are assumed to be metaboiicaily deprived with hypoperfusion and acidosis. In thii study we directly measured the oxygen partial pressure (~0~) distribution, metabolic state, and pi-l of tumors growing in an irradiated tumor bed using oxygen sensitive electrodes and "P-NMR. The results confirmed a threefold increase in the number of p0, readings 5 2.5 mml-lg and also showed increased acidosis with a 0.17 unit decrease in pH,,. When tumors growing in pre-irradiated tissue reached-100 mm' in volume, a high frequency of gross and microscopic necrosis and hemorrhage was already observed. Consistent with these observations, the phosphocreatine/inorganic phosphate (PCr/P,) and nucleoside triphosphatelinorganic phosphate (NTP/P,) ratios were significantly lower in the tumors in a pre-irradiated bed compared to tumors in a non-irradiated bed (PWP,: 0.51 vs 0.79, p < 0.05; and NTP/P,: 0.64 vs 0.93, p < 0.05). The longitudinal relaxation time (T,) of Pi was numerically shorter in control tumors (consistent with the better tissue oxygenation), but this did not reach statistical significance (2.09 f .ll set vs 2.25 +-16 see).
A dual hypoxic marker technique for measuring oxygenation change within individual tumors
British Journal of Cancer, 1998
Rodent tumour models have been the 'workhorse' for tumour oxygenation research and for investigating radiobiological hypoxic fraction. Because of the intertumour heterogeneity of blood flow and related parameters, most studies have pooled information derived from several different tumours to establish the statistical significance of specific measurements. But it is the oxygenation status of and its modulation in individual tumours that has important prognostic significance. In that regard, the bioreducible hypoxic marker technique was tested for its potential to quantify oxygenation changes within individual tumours. f-D-lodinated azomycin galactoside (IAZG) and P-Diodinated azomycin xylopyranoside (IAZXP) were each radiolabelled with lodine-125 and iodine-131 for measurements of animal tumour oxygenation. The tumour-blood (T/B) ratio of marker radioactivity in mice after the renal excretion of unbound marker (at 3 h and longer times) had been shown to be proportional to radiobiological hypoxic fraction. When markers labelled with both radioisotopes were administered simultaneously to EMT-6 tumour-bearing scid mice, T/B ratios were found to vary by up to 300% between different tumours, with an average intratumour variation of only-4%. When the markers were administered 2.5-3.0 h apart, changes in T/B ratios of 8-25% were observed in 10 out of 28 (36%) tumours. Changes to both higher and lower hypoxic fraction were observed, suggestive of acute or cycling hypoxia. When 0.8 mg g-1 nicotinamide plus carbogen was administered to increase tumour oxygenation, reductions in T/B ratios (mean AT/B-38%) were observed in all tumours. Similar results were obtained with Dunning rat prostate carcinomas growing in Fischer X Copenhagen rats whose T/B ratios of IAZG and radiobiological hypoxic fractions are significantly lower. These studies suggest that fluctuating hypoxia can account for at least 25% of the total hypoxic fraction in some tumours and that correlations between bioreducible marker avidity and related tumour properties will be optimal when the independent assays are performed over the same time period. This dual hypoxic marker technique should prove useful for investigating both spontaneous and induced oxygenation changes within individual rodent tumours.
European Journal of Cancer, 2001
The first aim of this study was to compare the hypoxia imaging ability of fluorine-18 fluoroerythronitroimidazole ([18F]FETNIM) with that of fluorine-18 fluoromisonimidazole ([18F]FMISO) in murine tumours of different sizes under two different oxygenation conditions. Secondly, we wanted to assess the biodistribution of the markers in normal tissues under similar conditions. Female CDF1 mice with a C3H mammary carcinoma grown on their backs were used. Tumours were size matched and animals breathed either normal air (21% O(2)) or carbogen gas (95% O(2) + 5% CO(2)). The gassing procedure was begun 5 min before the intravenous injection of either [18F]FETNIM or [18F]FMISO and continued until the mice were sacrificed at 120 min. Blood, tumour, muscle, heart, lung, liver, kidney and fat were removed, counted for radioactivity and weighed. The tumour and muscle were frozen and cut with a cryomicrotome into sections. The spatial distribution of radioactivity from the tissue sections was determined with digital autoradiography. Estimation of the necrotic fraction was made on sections from formalin-fixed tumours. Digital autoradiography showed that the whole tumour-to-muscle radioactivity uptake ratios were significantly higher in normal air-breathing mice than in carbogen-treated mice for both [18F]FETNIM (4.9+/-2.6 vs 1.8+/-0.5; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01) and [18F]FMISO (4.4+/-1.0 vs 1.5+/-0.4; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). The carbogen treatment had only slight effects on the biodistribution of either marker in normal tissues. The necrotic fraction determined in tumours did not correlate with the tumour volume or with the tumour-to-muscle radioactivity uptake ratio. This study shows that the uptake of both [18F]FETNIM and [18F]FMISO correlates with the oxygenation status in tumours. In addition, our data show no significant difference in the intratumoral uptake between the two markers. However, significantly higher radioactivity uptake values were measured for [18F]FMISO than for [18F]FETNIM in normal tissues.
Seminars in radiation oncology, 2014
The tumor microenvironment is characterized by hypoxia, low pH, and high interstitial fluid pressure. Hypoxic regions in tumors with low partial pressure of oxygen (pO2) levels can result in resistance to radiotherapy, thus causing local failure. Therefore, it would be desirable to noninvasively measure pO2 levels in the tumor before, during, and after treatment to better customize therapy and follow treatment response. Several techniques used in preclinical and clinical studies to obtain the pO2 status of tissue, such as dynamic contrast-enhanced magnetic resonance imaging, blood oxygen level-dependent imaging, and electron paramagnetic resonance imaging, are reviewed. Furthermore, the ability to hyperpolarize specific metabolic substrates that are isotopically labeled with (13)C coupled with magnetic resonance spectroscopy enables noninvasive imaging of tissue metabolism, such as glycolysis.