Systemic Administration of Hemoglobin Vesicle Elevates Tumor Tissue Oxygen Tension and Modifies Tumor Response to Irradiation (original) (raw)
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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).
Oxygenation of tumors by a hemoglobin solution
Journal of Cancer Research and Clinical Oncology, 1993
Tumor oxygen tensions were measured using a computer-controlled PO 2 microelectrode in two preclinical solid tumor models, the rat 9L gliosarcoma and the rat 13672 mammary carcinoma. Tumor oxygenation profiles were determined under four conditions: (a) during normal air breathing, (b) during carbogen breathing, (c) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with normal air breathing and (d) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with carbogen breathing. Both tumors had severely hypoxic regions under normal airbreathing conditions, Although carbogen breathing increased the oxygenation of the better-oxygenated portions of the tumor, it made no impact on the severely hypoxic tumor regions. Administration of the hemoglobin solution was effective in increasing the oxygenation throughout both tumors under normal air-breathing conditions. The addition of carbogen breathing to administration of the hemoglobin solution eliminated severe hypoxia in the 9L gliosarcoma and markedly reduced the severely hypoxic regions of the 13672 mammary carcinoma. At 24 h after administration of the hemoglobin solution the 13672 mammary carcinoma showed greater hypoxia than before treatment, which was partially corrected with carbogen breathing.
International Journal of Radiation Oncology*Biology*Physics, 1997
Purpose: To determine the influence of adjuvant hyperthermia on the oxygenation status of fractionated irradiated tumors. Methods and Materials: Oxygen partial pressure (PO,) in rat rhabdomyosarcomas (RlH) was measured sequentially at weekly intervals during a fractionated irradiation with 6oCo-y-rays (60 Gyf2W4 weeks) In combination with local hyperthenuia (8 f(HT) at 43"C, 1 h/4 weeks). Tumors were heated twice weekly with a 2459 MHz microwave device at 43"C, 1 h starting 10 min after irradiation. The pOz measurements (pOz-his&graph, Eppendorf, Gemmny) were performed in anesthetized animals during mechanical ventilation and in healottynsmic steady state. AR tumor p0, measurements were correlated to measurements of the arterial oxygen partiai pressure (paOJ de&-mid by a blood gas analyzer. Results: The oxygenation status of RlH tumors decreased continuously from the start of the combined treatment, &&&teasing radiation dose and number of heat fractions. In untreated controls a median tumor PO, of 23 t 2 mmHg (mean ? SEM) was measured. Tumor ~0, decreased to 11% 2 mmHg after 30 Gy + 4 HT (2 weeks), and to 6 IT 2 mmHg after 60 Gy + 8HT (4 weeks). The increase in the frequency of pOz-values below 5 mmHg and the decrease in the range of the pOz histograms [Ap(lOBO)] further indicated that tumor hypoxia increased relatively rapidly from the start of combined treatment. After 60 Gy + 8HT 48 2 5% (mean t SEM) of the pOzvalues recorded were helow 5 mmHg. Conduaions: These fhtdings suggest that adjuvant hyperthermia to radiotherapy induces greater changes in tumor oxygenation than radiation alone [cf. (39)]. This might be of importance for the temporary appheation of byperthermia in the course of a conventional radiation treatment.
Artificial Organs, 2016
Liposome-encapsulated hemoglobin (LEH) with high (h-LEH, P 50 O 2 5 10 mm Hg) or low O 2 affinity (l-LEH, P 50 O 2 5 40 mm Hg) may improve O 2 delivery to sensitize tumor tissues for radiotherapy. A total of 10 mL/ kg of h-LEH, l-LEH, red blood cells (RBCs), or saline was infused in mice transplanted with murine colon carcinoma with near-infrared spectroscopy (NIRS) detectors set at the tumor (right leg) and intact muscle (left leg). NIRS recorded changes in the amount of oxyhemoglobin (oxyHb), deoxyhemoglobin (deoxyHb), and their sum (tHb) with the animals spontaneously breathing room air (10 min), pure O 2 (5 min), and then back to room air. The tumor was finally excised for histological examination. In mice treated with h-LEH, tHb significantly increased compared to mice receiving other solutions. The magnitude was significantly attenuated in the tumor compared to the intact muscle under room air. Reciprocal changes in oxyHb and deoxyHb between intact muscle and tumor in response to infused solutions allowed assumption of average tissue PO 2 between 30 and 40 mm Hg in muscle and at around 10 mm Hg in tumor. While O 2 respiration increased oxyHb and decreased deoxyHb both in muscle and tumor, their sum or tHb consistently decreased in muscle and increased in tumor regardless of preceding infusion. Such responses were totally reversed when mice were placed under hypoxia (10% O 2), suggesting that a lack of physiological circulatory regulation in tumor may account for heavier immunohistochemical staining for human hemoglobin in tumors of mice treated with h-LEH than with l-LEH. The results suggest that h-LEH may cause significant tumor oxygenation compared to RBC, l-LEH, or saline probably due to its nanometer size (vs. RBC) and high O 2 affinity (vs. l-LEH) without increasing O 2 content in the intact tissue (vs. O 2 respiration) probably due to a lack of physiological circulatory regulation.
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.
Free Radical Biology and Medicine, 2014
Blood flow and pO 2 changes after vascular-targeted photodynamic therapy (V-PDT) or cellular-targeted PDT (C-PDT) using 5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl) bacteriochlorin (F 2 BMet) as photosensitizer were investigated in DBA/2 mice with S91 Cloudman mouse melanoma, and correlated with long-term tumor responses. F 2 BMet generates both singlet oxygen and hydroxyl radicals under near-infrared radiation, which consume oxygen. Partial oxygen pressure was lowered in PDT-treated tumors and this was ascribed both to oxygen consumption during PDT and to fluctuations in oxygen transport after PDT. Similarly, microcirculatory blood flow changed as a result of the disruption of blood vessels by the treatment. A novel noninvasive approach combining electron paramagnetic resonance oximetry and laser Doppler blood perfusion measurements allowed longitudinal monitoring of hypoxia and vascular function changes in the same animals, after PDT. C-PDT induced parallel changes in tumor pO 2 and blood flow, i.e., an initial decrease immediately after treatment, followed by a slow increase. In contrast, V-PDT led to a strong and persistent depletion of pO 2 , although the microcirculatory blood flow increased. Strong hypoxia after V-PDT led to a slight increase in VEGF level 24 h after treatment. C-PDT caused a ca. 5-day delay in tumor growth, whereas V-PDT was much more efficient and led to tumor growth inhibition in 90% of animals. The tumors of 44% of mice treated with V-PDT regressed completely and did not reappear for over 1 year. In conclusion, mild and transient hypoxia after C-PDT led to intense pO 2 compensatory effects and modest tumor inhibition, but strong and persistent local hypoxia after V-PDT caused tumor growth inhibition.