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John R Griffiths - One of the best experts on this subject based on the ideXlab platform.

  • evaluation and immunohistochemical qualification of Carbogen induced δr2 as a noninvasive imaging biomarker of improved tumor oxygenation
    International Journal of Radiation Oncology Biology Physics, 2013
    Co-Authors: Lauren C J Baker, Franklyn A Howe, John R Griffiths, Jessica K R Boult, Yann Jamin, Lesley D Gilmour, Simon Walkersamuel, Jake S Burrell, Margaret Ashcroft, James A Raleigh
    Abstract:

    Purpose To evaluate and histologically qualify Carbogen-induced ΔR 2 * as a noninvasive magnetic resonance imaging biomarker of improved tumor oxygenation using a double 2-nitroimidazole hypoxia marker approach. Methods and Materials Multigradient echo images were acquired from mice bearing GH3 prolactinomas, preadministered with the hypoxia marker CCI-103F, to quantify tumor R 2 * during air breathing. With the mouse remaining positioned within the magnet bore, the gas supply was switched to Carbogen (95% O 2 , 5% CO 2 ), during which a second hypoxia marker, pimonidazole, was administered via an intraperitoneal line, and an additional set of identical multigradient echo images acquired to quantify any changes in tumor R 2 *. Hypoxic fraction was quantified histologically using immunofluorescence detection of CCI-103F and pimonidazole adduct formation from the same whole tumor section. Carbogen-induced changes in tumor pO 2 were further validated using the Oxylite fiberoptic probe. Results Carbogen challenge significantly reduced mean tumor R 2 * from 116 ± 13 s −1 to 97 ± 9 s −1 ( P P 2 * and Δhypoxic fraction (r=0.55, P 2 during Carbogen breathing significantly increased from 6.3 ± 2.2 mm Hg to 36.0 ± 7.5 mm Hg ( P Conclusions The combined use of intrinsic susceptibility magnetic resonance imaging with a double hypoxia marker approach corroborates Carbogen-induced ΔR 2 * as a noninvasive imaging biomarker of increased tumor oxygenation.

  • investigations in vivo of the effects of Carbogen breathing on 5 fluorouracil pharmacokinetics and physiology of solid rodent tumours
    Cancer Chemotherapy and Pharmacology, 2005
    Co-Authors: Paul M J Mcsheehy, Simon P Robinson, Marion Stubbs, Martin O Leach, I Judson, Loreta M. Rodrigues, R E Port, K Van Der Borns, Godefridus J Peters, John R Griffiths
    Abstract:

    Purpose We have shown previously that Carbogen (95% 02, 5% CO2) breathing by rodents can increase uptake of anticancer drugs into tumours. The aim of this study was to extend these observations to other rodent models using the anticancer drug 5-fluorouracil (5FU). 5FU pharmacokinetics in tumour and plasma and physiological effects on the tumour by Carbogen were investigated to determine the locus of Carbogen action on augmenting tumour uptake of 5FU.

  • effects of nicotinamide and Carbogen on tumour oxygenation blood flow energetics and blood glucose levels
    British Journal of Cancer, 2000
    Co-Authors: Simon P Robinson, Franklyn A Howe, Marion Stubbs, John R Griffiths
    Abstract:

    Both host Carbogen (95% oxygen/5% carbon dioxide) breathing and nicotinamide administration enhance tumour radiotherapeutic response and are being re-evaluated in the clinic. Non-invasive magnetic resonance imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) methods have been used to give information on the effects of nicotinamide alone and in combination with host Carbogen breathing on transplanted rat GH3 prolactinomas. Gradient recalled echo (GRE) MRI, sensitive to blood oxygenation changes, and spin echo (SE) MRI, sensitive to perfusion/flow, showed large signal intensity increases with Carbogen breathing. Nicotinamide, thought to act by suppressing the transient closure of small blood vessels that cause intermittent tumour hypoxia, induced a small increase in blood oxygenation but no detectable change in perfusion/flow. Carbogen combined with nicotinamide was no more effective than Carbogen alone. Both Carbogen and nicotinamide caused significant increases in the nucleoside triphosphate/inorganic phosphate (βNTP/P i) ratio, implying that the tumour cells normally receive sub-optimal substrate supply, and is consistent with either increased glycolysis and/or a switch to more oxidative metabolism. The most striking observation was the marked increase in blood glucose (twofold) induced by both nicotinamide and Carbogen. Whether this may play a role in tumour radiosensitivity has yet to be determined. Copyright 2000 Cancer Research Campaign© 2000 Cancer Research Campaign

  • Response of Hepatoma 9618a and Normal Liver to Host Carbogen and Carbon Monoxide Breathing
    Neoplasia, 1999
    Co-Authors: Simon P Robinson, John R Griffiths, Loreta M. Rodrigues, Marion Stubbs
    Abstract:

    The effects of hyperoxia (induced by host Carbogen [95% oxygen/5% carbon dioxide breathing] and hypoxia (induced by host carbon monoxide [CO at 660 ppm] breathing) were compared by using noninvasive magnetic resonance (MR) methods to gain simultaneous information on blood flow/oxygenation and the bioenergetic status of rat Morris H9618a hepatomas. Both Carbogen and CO breathing induced a 1.5- to 2-fold increase in signal intensity in blood oxygenation level dependent (BOLD) MR images. This was due to a decrease in deoxyhemoglobin (deoxyHb), which acts as an endogenous contrast agent, caused either by formation of oxyhemoglobin in the case of Carbogen breathing, or carboxyhemoglobin with CO breathing. The results were confirmed by observation of similar changes in deoxyHb in arterial blood samples examined ex vivo after Carbogen or CO breathing. There was no change in nucleoside triphosphates (NTP)/Pi in either tumor or liver after CO breathing, whereas NTP/Pi increased twofold in the hepatoma (but not in the liver) after Carbogen breathing. No changes in tumor intracellular pH were seen after either treatment, whereas extracellular pH became more alkaline after CO breathing and more acid after Carbogen breathing, respectively. This tumor type and the liver are unaffected by CO breathing at 660 ppm, which implies an adequate oxygen supply.

  • Carbogen breathing increases 5 fluorouracil uptake and cytotoxicity in hypoxic murine rif 1 tumors a magnetic resonance study in vivo
    Cancer Research, 1998
    Co-Authors: Paul M J Mcsheehy, Simon P Robinson, A S E Ojugo, Eric O Aboagye, Mark B Cannell, Martin O Leach, I Judson, John R Griffiths
    Abstract:

    The purpose of this study was to examine the effect of Carbogen gas (95% O2-5% CO2) on uptake and metabolism of 5-fluorouracil (5FU) in murine RIF-1 tumors and their growth in vivo . In addition, we have explored the mechanisms by which Carbogen can transiently affect the physiology of RIF-1 tumors. After i.p. injection of 1 mmol/kg 5FU into C3H mice, the uptake and metabolism of the drug by s.c. RIF-1 tumors was followed for 2 h noninvasively using 19F-magnetic resonance spectroscopy (MRS). In all animals, irrespective of tumor size, Carbogen caused a significant increase in the half-life ( t ½) of the elimination of 5FU by the tumor and a significant increase in growth inhibition. In 2–3-g tumors (group II), Carbogen also caused increased 5FU uptake and metabolism to the cytotoxic 5-fluoronucleotides, whereas in 0.8–1.5-g tumors (group I), only the t ½ was slightly increased. These results suggested that tumor size was an important factor in the effect of Carbogen on tumor physiology. Measurements of RIF-1 tumor vascular and necrotic volume showed no significant differences between group I and group II tumors. However, 1H-MR images of RIF-1 tumors showed that Carbogen caused a transient decrease in signal intensity, which correlated positively ( P = 0.02) with tumor size, suggesting that larger tumors responded to Carbogen by transiently increasing O2 uptake from the blood. 19F-MRS was used to measure RIF-1 tumor retention of the fluorinated nitroimidazole SR-4554. These studies also showed a positive correlation ( P = 0.001) with tumor size, implying greater hypoxia in larger tumors. We propose that Carbogen may transiently open nonfunctional blood vessels in the tumor, allowing increased leakage of 5FU from the plasma into the extracellular space. 5FU transport is known to be pH dependent. Intra- and extracellular tumor pH was measured using 31P- and 19F-MRS, which showed that Carbogen caused a significant decrease in the extracellular pH of 0.1 unit in group II tumors and a consequent increase in the negative pH gradient across the tumor plasma membrane, which can cause increased 5FU uptake. The pH gradient was unaffected in group I tumors. We conclude that Carbogen breathing can increase tumor uptake of 5FU by two independent mechanisms involving changes in tumor blood flow and pH, which consequently cause increased formation of 5-fluoronucleotides and cytotoxicity. The effect seems more pronounced in hypoxic tumors, implying that Carbogen would be a valuable aid in clinical chemotherapy.

Simon P Robinson - One of the best experts on this subject based on the ideXlab platform.

  • investigating temporal fluctuations in tumor vasculature with combined Carbogen and ultrasmall superparamagnetic iron oxide particle cuspio imaging
    Magnetic Resonance in Medicine, 2011
    Co-Authors: Jake S Burrell, Lauren C J Baker, Jessica K R Boult, Simon Walkersamuel, Anderson J Ryan, John C Waterton, Jane Halliday, Simon P Robinson
    Abstract:

    A combined Carbogen ultrasmall superparamagnetic iron oxide (USPIO) imaging protocol was developed and applied in vivo in two murine colorectal tumor xenograft models, HCT116 and SW1222, with established disparate vascular morphology, to investigate whether additional information could be extracted from the combination of two susceptibility MRI biomarkers. Tumors were imaged before and during Carbogen breathing and subsequently following intravenous administration of USPIO particles. A novel segmentation method was applied to the image data, from which six categories of R(2)* response were identified, and compared with histological analysis of the vasculature. In particular, a strong association between a negative ?R(2)*(Carbogen) followed by positive ?R(2)*(USPIO) with the uptake of the perfusion marker Hoechst 33342 was determined. Regions of tumor tissue where there was a significant ?R(2)*(Carbogen) but no significant ?R(2)*(USPIO) were also identified, suggesting these regions became temporally isolated from the vascular supply during the experimental timecourse. These areas correlated with regions of tumor tissue where there was CD31 staining but no Hoechst 33342 uptake. Significantly, different combined Carbogen USPIO responses were determined between the two tumor models. Combining ?R(2)*(Carbogen) and ?R(2)*(USPIO) with a novel segmentation scheme can facilitate the interpretation of susceptibility contrast MRI data and enable a deeper interrogation of tumor vascular function and architecture.

  • investigations in vivo of the effects of Carbogen breathing on 5 fluorouracil pharmacokinetics and physiology of solid rodent tumours
    Cancer Chemotherapy and Pharmacology, 2005
    Co-Authors: Paul M J Mcsheehy, Simon P Robinson, Marion Stubbs, Martin O Leach, I Judson, Loreta M. Rodrigues, R E Port, K Van Der Borns, Godefridus J Peters, John R Griffiths
    Abstract:

    Purpose We have shown previously that Carbogen (95% 02, 5% CO2) breathing by rodents can increase uptake of anticancer drugs into tumours. The aim of this study was to extend these observations to other rodent models using the anticancer drug 5-fluorouracil (5FU). 5FU pharmacokinetics in tumour and plasma and physiological effects on the tumour by Carbogen were investigated to determine the locus of Carbogen action on augmenting tumour uptake of 5FU.

  • effects of nicotinamide and Carbogen on tumour oxygenation blood flow energetics and blood glucose levels
    British Journal of Cancer, 2000
    Co-Authors: Simon P Robinson, Franklyn A Howe, Marion Stubbs, John R Griffiths
    Abstract:

    Both host Carbogen (95% oxygen/5% carbon dioxide) breathing and nicotinamide administration enhance tumour radiotherapeutic response and are being re-evaluated in the clinic. Non-invasive magnetic resonance imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) methods have been used to give information on the effects of nicotinamide alone and in combination with host Carbogen breathing on transplanted rat GH3 prolactinomas. Gradient recalled echo (GRE) MRI, sensitive to blood oxygenation changes, and spin echo (SE) MRI, sensitive to perfusion/flow, showed large signal intensity increases with Carbogen breathing. Nicotinamide, thought to act by suppressing the transient closure of small blood vessels that cause intermittent tumour hypoxia, induced a small increase in blood oxygenation but no detectable change in perfusion/flow. Carbogen combined with nicotinamide was no more effective than Carbogen alone. Both Carbogen and nicotinamide caused significant increases in the nucleoside triphosphate/inorganic phosphate (βNTP/P i) ratio, implying that the tumour cells normally receive sub-optimal substrate supply, and is consistent with either increased glycolysis and/or a switch to more oxidative metabolism. The most striking observation was the marked increase in blood glucose (twofold) induced by both nicotinamide and Carbogen. Whether this may play a role in tumour radiosensitivity has yet to be determined. Copyright 2000 Cancer Research Campaign© 2000 Cancer Research Campaign

  • Response of Hepatoma 9618a and Normal Liver to Host Carbogen and Carbon Monoxide Breathing
    Neoplasia, 1999
    Co-Authors: Simon P Robinson, John R Griffiths, Loreta M. Rodrigues, Marion Stubbs
    Abstract:

    The effects of hyperoxia (induced by host Carbogen [95% oxygen/5% carbon dioxide breathing] and hypoxia (induced by host carbon monoxide [CO at 660 ppm] breathing) were compared by using noninvasive magnetic resonance (MR) methods to gain simultaneous information on blood flow/oxygenation and the bioenergetic status of rat Morris H9618a hepatomas. Both Carbogen and CO breathing induced a 1.5- to 2-fold increase in signal intensity in blood oxygenation level dependent (BOLD) MR images. This was due to a decrease in deoxyhemoglobin (deoxyHb), which acts as an endogenous contrast agent, caused either by formation of oxyhemoglobin in the case of Carbogen breathing, or carboxyhemoglobin with CO breathing. The results were confirmed by observation of similar changes in deoxyHb in arterial blood samples examined ex vivo after Carbogen or CO breathing. There was no change in nucleoside triphosphates (NTP)/Pi in either tumor or liver after CO breathing, whereas NTP/Pi increased twofold in the hepatoma (but not in the liver) after Carbogen breathing. No changes in tumor intracellular pH were seen after either treatment, whereas extracellular pH became more alkaline after CO breathing and more acid after Carbogen breathing, respectively. This tumor type and the liver are unaffected by CO breathing at 660 ppm, which implies an adequate oxygen supply.

  • Carbogen breathing increases 5 fluorouracil uptake and cytotoxicity in hypoxic murine rif 1 tumors a magnetic resonance study in vivo
    Cancer Research, 1998
    Co-Authors: Paul M J Mcsheehy, Simon P Robinson, A S E Ojugo, Eric O Aboagye, Mark B Cannell, Martin O Leach, I Judson, John R Griffiths
    Abstract:

    The purpose of this study was to examine the effect of Carbogen gas (95% O2-5% CO2) on uptake and metabolism of 5-fluorouracil (5FU) in murine RIF-1 tumors and their growth in vivo . In addition, we have explored the mechanisms by which Carbogen can transiently affect the physiology of RIF-1 tumors. After i.p. injection of 1 mmol/kg 5FU into C3H mice, the uptake and metabolism of the drug by s.c. RIF-1 tumors was followed for 2 h noninvasively using 19F-magnetic resonance spectroscopy (MRS). In all animals, irrespective of tumor size, Carbogen caused a significant increase in the half-life ( t ½) of the elimination of 5FU by the tumor and a significant increase in growth inhibition. In 2–3-g tumors (group II), Carbogen also caused increased 5FU uptake and metabolism to the cytotoxic 5-fluoronucleotides, whereas in 0.8–1.5-g tumors (group I), only the t ½ was slightly increased. These results suggested that tumor size was an important factor in the effect of Carbogen on tumor physiology. Measurements of RIF-1 tumor vascular and necrotic volume showed no significant differences between group I and group II tumors. However, 1H-MR images of RIF-1 tumors showed that Carbogen caused a transient decrease in signal intensity, which correlated positively ( P = 0.02) with tumor size, suggesting that larger tumors responded to Carbogen by transiently increasing O2 uptake from the blood. 19F-MRS was used to measure RIF-1 tumor retention of the fluorinated nitroimidazole SR-4554. These studies also showed a positive correlation ( P = 0.001) with tumor size, implying greater hypoxia in larger tumors. We propose that Carbogen may transiently open nonfunctional blood vessels in the tumor, allowing increased leakage of 5FU from the plasma into the extracellular space. 5FU transport is known to be pH dependent. Intra- and extracellular tumor pH was measured using 31P- and 19F-MRS, which showed that Carbogen caused a significant decrease in the extracellular pH of 0.1 unit in group II tumors and a consequent increase in the negative pH gradient across the tumor plasma membrane, which can cause increased 5FU uptake. The pH gradient was unaffected in group I tumors. We conclude that Carbogen breathing can increase tumor uptake of 5FU by two independent mechanisms involving changes in tumor blood flow and pH, which consequently cause increased formation of 5-fluoronucleotides and cytotoxicity. The effect seems more pronounced in hypoxic tumors, implying that Carbogen would be a valuable aid in clinical chemotherapy.

Peter Hoskin - One of the best experts on this subject based on the ideXlab platform.

  • The modification of human tumour blood flow using pentoxifylline, nicotinamide and Carbogen.
    Radiotherapy and Oncology, 2020
    Co-Authors: A Sibtain, Sally A. Hill, K. Goodchild, N Shah, Michele I. Saunders, Peter Hoskin
    Abstract:

    Abstract Aim : To assess the effect of combining oral nicotinamide, oral pentoxifylline and Carbogen gas (2% CO 2 , 98% O 2 ) breathing on human tumour red cell flux. Methods and materials : Microregional red blood cell flux was measured in accessible tumour nodules using laser Doppler microprobes in 11 patients with histologically proven malignancy. Patients received single oral doses of nicotinamide 40mgkg −1 and pentoxifylline 1200mg 2h before a 10-min period of Carbogen gas breathing, corresponding to peak plasma concentrations of these drugs. Red cell flux in up to six microregions in each tumour was measured for 30min, recording pre-, during and post-Carbogen breathing for 10min each. Results : Data from ten of the 11 patients could be assessed. The red cell flux in 48 microregions was analysed and the mean red cell flux was calculated. A mean relative increase in red cell flux of 1.18 (±0.09, 95% confidence interval (CI)) was observed after 6min of Carbogen breathing, 2h after the administration of nicotinamide and pentoxifylline. This compares to relative increases of 1.4 (±0.39, 95%CI) after nicotinamide with Carbogen and 1.15 (±0.10, 95%CI) after pentoxifylline with Carbogen. These differences are not statistically significant ( P >0.05). The increased red cell flux persisted after the cessation of Carbogen gas breathing. Conclusions : A combination of pentoxifylline, nicotinamide and Carbogen produces an increase in human tumour red cell flux, similar to that observed when each of the drugs are used alone with Carbogen breathing.

  • Modification of human tumour blood flow using pentoxifylline, nicotinamide and Carbogen
    British Journal of Cancer, 2020
    Co-Authors: A Sibtain, Sally A. Hill, K. Goodchild, N Shah, Michele I. Saunders, Peter Hoskin
    Abstract:

    Aim: To assess the effect of combining oral nicotinamide, oral pentoxifylline and Carbogen gas (2% CO2, 98% O2) breathing on human tumour red cell flux. Methods and materials: Microregional red blood cell flux was measured in accessible tumour nodules using laser Doppler microprobes in 11 patients with histologically proven malignancy. Patients received single oral doses of nicotinamide 40 mg kg 21 and pentoxifylline 1200 mg 2 h before a 10-min period of Carbogen gas breathing, corresponding to peak plasma concentrations of these drugs. Red cell flux in up to six microregions in each tumour was measured for 30 min, recording pre-, during and post-Carbogen breathing for 10 min each. Results: Data from ten of the 11 patients could be assessed. The red cell flux in 48 microregions was analysed and the mean red cell flux was calculated. A mean relative increase in red cell flux of 1.18 (^0.09, 95% confidence interval (CI)) was observed after 6 min of Carbogen breathing, 2 h after the administration of nicotinamide and pentoxifylline. This compares to relative increases of 1.4 (^0.39, 95%CI) after nicotinamide with Carbogen and 1.15 (^0.10, 95%CI) after pentoxifylline with Carbogen. These differences are not statistically significant ðP . 0:05Þ. The increased red cell flux persisted after the cessation of Carbogen gas breathing. Conclusions: A combination of pentoxifylline, nicotinamide and Carbogen produces an increase in human tumour red cell flux, similar to that observed when each of the drugs are used alone with Carbogen breathing. q 2002 Elsevier Science Ireland Ltd. All rights reserved.

  • Carbogen breathing increases prostate cancer oxygenation a translational mri study in murine xenografts and humans
    British Journal of Cancer, 2009
    Co-Authors: R Alonzi, Anwar R Padhani, Ross J Maxwell, N J Taylor, J J Stirling, J Wilson, J A D Arcy, D J Collins, M I Saunders, Peter Hoskin
    Abstract:

    Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing Carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of Carbogen gas breathing. Quantitative R2* pixel maps were produced for each tumour and at each time point and changes in R2* induced by Carbogen were determined. There was a mean reduction in R2* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R2* during Carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R2* in both animal models and human patients as a result of Carbogen inhalation suggests the presence of significant hypoxia. The finding that Carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining Carbogen gas breathing with radiotherapy in prostate cancer patients.

  • bold mri of human tumor oxygenation during Carbogen breathing
    Journal of Magnetic Resonance Imaging, 2001
    Co-Authors: Jane N Taylor, K. Goodchild, Michele I. Saunders, Peter Hoskin, J J Stirling, Melanie E B Powell, Hiram Baddeley, Michelle Thoumine, Linda Culver, H Phillips
    Abstract:

    An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during Carbogen inhalation (95% O2, 5% CO2). T-weighted gradient-echo imaging was performed before, during, and after Carbogen breathing in 47 tumor patients and 13 male volunteers. Analysis of artifacts and signal intensity was performed. Thirty-six successful tumor examinations were obtained. Twenty showed significant whole-tumor signal increases (mean 21.0%, range 6.5–82.4%), and one decreased (−26.5 ± 8.0%). Patterns of signal change were heterogeneous in responding tumors. Five of 13 normal prostate glands (four volunteers and nine patients with nonprostatic tumors) showed significant enhancement (mean 11.4%, range 8.4–14.0%). An increase in brain signal was seen in 11 of 13 assessable patients (mean 8.0 ± 3.7%, range 5.0–11.7%). T-weighted tumor MRI during Carbogen breathing is possible in humans. High failure rates occurred due to respiratory distress. Significant enhancement was seen in 56%, suggesting improved tissue oxygenation and blood flow, which could identify these patients as more likely to benefit from Carbogen radiosensitization. J. Magn. Reson. Imaging 2001;14:156–163. © 2001 Wiley-Liss, Inc.

  • gas exchange parameters in radiotherapy patients during breathing of 2 3 5 and 5 Carbogen gas mixtures
    British Journal of Radiology, 2000
    Co-Authors: Hiram Baddeley, N J Taylor, M I Saunders, H Phillips, P M Brodrick, M O Abdelatti, L C Jordan, A S Vasudevan, Peter Hoskin
    Abstract:

    The gas mixture Carbogen may be breathed by patients to enhance the oxygenation level and therefore the radiosensitivity of tumours. However, owing to the high CO2 content, its inhalation is associated with patient intolerance. Our aim was to determine a suitable carbon dioxide and oxygen gas mixture with similar enhancement of arterial oxygenation to 5% Carbogen and with improved patient tolerance. 14 patients entered the study; of those 14, 8 were able to tolerate 2%, 3.5% and 5% Carbogen mixtures as well as a control gas for sufficient time to allow successful arterial blood gas sampling. Gas exchange parameters were measured using a carbon dioxide monitor and a blood gas analyser. Arterial carbon dioxide tension ranged from 2.9 kPa to 6.82 kPa whilst breathing the Carbogen mixtures, and arterial oxygen tension increased at least three-fold from basal values. There were no significant changes in the respiratory rate, heart rate and blood pH. The results suggest that 2% CO2 in O2 enhances arterial oxygen levels to a similar extent as 3.5% and 5% CO2 and that it is well tolerated.

Mark W Dewhirst - One of the best experts on this subject based on the ideXlab platform.

  • variability in blood flow and po2 in tumors in response to Carbogen breathing
    International Journal of Radiation Oncology Biology Physics, 1998
    Co-Authors: Jennifer L Lanzen, Rod D Braun, Mark W Dewhirst
    Abstract:

    PURPOSE: There is speculation that the CO2 in Carbogen (95% O2, 5% CO2) can block the vasoconstrictive effects of oxygen. However, it has recently been shown that blood flow in human tumors is variable while patients breathe Carbogen. Furthermore, we have shown a consistent decrease in tumor blood flow (TBF) with Carbogen breathing in the rat window chamber model. Also, we have previously shown that there is no significant difference in tumor growth time after radiation with air vs. Carbogen breathing. This study was designed to investigate the effects of Carbogen breathing on blood flow and oxygen levels in a solid tumor. METHODS: Measurements were made in Fischer-344 rats with 8-10 mm diameter R3230Ac tumors transplanted either within the quadriceps muscle (n = 16) or subcutis (n = 14). Nontumor-bearing quadriceps muscle was studied in six other rats. After a 20-minute air-breathing baseline, rats breathed Carbogen for an additional 40 minutes. Partial pressure of oxygen (pO2) was continuously monitored at one position for 60 minutes using 9-12 microm diameter oxygen microelectrodes. Blood flow was simultaneously monitored in all animals using laser Doppler flowmetry (1-2 probes/tumor). RESULTS: Blood flow changes during Carbogen breathing were variable in all tissues and intratumoral heterogeneity was observed. Despite variability in blood flow, pO2 consistently increased in normal muscle but varied in both tumor sites. During Carbogen breathing, the percent pO2 measurements greater than the baseline average were 99.5% +/- 0.4% (mean +/- SEM), 42.7% +/- 13.8%, and 79.8% +/- 11.0% in normal muscle, subcutaneous tumor, and muscle tumor, respectively. To show the magnitude of change, average pO2 values during air and Carbogen breathing were calculated for each site. Normal muscle increased from 14.9 +/- 2.3 to 39.0 +/- 6.4 mm Hg (paired t-test; p = 0.009). Muscle tumors showed a rise from 14.6 +/- 3.2 to 34.5 +/- 8.2 mm Hg (p = 0.019). However, pO2 in subcutaneous tumors remained unchanged, with a pO2 of 7.3 +/- 2.0 mm Hg on air and 7.3 +/- 4.1 mm Hg (p = 0.995) during Carbogen breathing. CONCLUSIONS: Carbogen had no consistent effect on blood flow and was ineffective at increasing tumor pO2. These results may partially explain why Carbogen breathing failed to improve the efficacy of radiation in this tumor model when transplanted subcutaneously.

  • hyperbaric oxygen improves tumor radiation response significantly more than Carbogen nicotinamide
    Radiation Research, 1997
    Co-Authors: David M Brizel, William D Hage, Richard K Dodge, Michael T Munley, Claude A Piantadosi, Mark W Dewhirst
    Abstract:

    This laboratory previously demonstrated that hyperbaric oxygen and hyperbaric Carbogen improved oxygenation in the R3230Ac tumor, but normobaric 100% O2 and Carbogen did not. The current study assessed tumor growth after exposure to radiation plus either hyperbaric oxygen, Carbogen or Carbogen/nicotinamide and the relationship between pretreatment tumor oxygenation and growth time. R3230Ac carcinomas were grown in the flanks of F344 rats. Animals were randomized to one of seven radiation treatment groups: sham irradiation or irradiation plus room air, hyperbaric oxygen (100% ${\rm O}_{2}/3$ atmospheres), nicotinamide (0.3 mg/g intraperitoneally 20 min before irradiation), Carbogen, Carbogen/nicotinamide or hyperbaric oxygen/nicotinamide. Tumors received 20 Gy in a single dose. Median growth times were 6, 18, 18, 20, 22, 28 and 27 days for controls and irradiation plus room air, Carbogen, nicotinamide, Carbogen/nicotinamide, hyperbaric oxygen and hyperbaric oxygen/nicotinamide, respectively. Irradiation wi...

  • Hyperbaric Oxygen Improves Tumor Radiation Response Significantly More Than Carbogen/Nicotinamide
    Radiation Research, 1997
    Co-Authors: David M Brizel, William D Hage, Richard K Dodge, Michael T Munley, Claude A Piantadosi, Mark W Dewhirst
    Abstract:

    This laboratory previously demonstrated that hyperbaric oxygen and hyperbaric Carbogen improved oxygenation in the R3230Ac tumor, but normobaric 100% O2 and Carbogen did not. The current study assessed tumor growth after exposure to radiation plus either hyperbaric oxygen, Carbogen or Carbogen/nicotinamide and the relationship between pretreatment tumor oxygenation and growth time. R3230Ac carcinomas were grown in the flanks of F344 rats. Animals were randomized to one of seven radiation treatment groups: sham irradiation or irradiation plus room air, hyperbaric oxygen (100% O2/3 atmospheres), nicotinamide (0.3 mg/g intraperitoneally 20 min before irradiation), Carbogen, Carbogen/nicotinamide or hyperbaric oxygen/nicotinamide. Tumors received 20 Gy in a single dose. Median growth times were 6, 18, 18, 20, 22, 28 and 27 days for controls and irradiation plus room air, Carbogen, nicotinamide, Carbogen/nicotinamide, hyperbaric oxygen and hyperbaric oxygen/nicotinamide, respectively. Irradiation with hyperbaric oxygen, hyperbaric oxygen/ nicotinamide and Carbogen/nicotinamide increased growth time (P < 0.001, P < 0.001 and P = 0.003, respectively) relative to room air. Hyperbaric oxygen was significantly more effective than Carbogen/nicotinamide (P = 0.001). Growth times for all tumors exposed to hyperbaric oxygen were longer than those of the most fully oxygenated tumors (no baseline pO2 values < 10 mm Hg) not exposed to hyperbaric oxygen (P < 0.001). These results suggest that hyperbaric oxygen may improve radiation response by additional mechanisms separate from overcoming the oxygen effect.

  • the mechanisms by which hyperbaric oxygen and Carbogen improve tumour oxygenation
    British Journal of Cancer, 1995
    Co-Authors: David M Brizel, Mark W Dewhirst, Jeffrey L Johnson, J Brooks, Claude A Piantadosi
    Abstract:

    Hyperbaric oxygen (HBO) has been proposed to reduce tumour hypoxia by increasing the amount of dissolved oxygen in the plasma. That this actually occurs has not been verified experimentally. This study was performed to explore changes in tumour oxygenation induced by treatment with normobaric and hyperbaric oxygen and Carbogen. R3230Ac mammary adenocarcinomas were implanted into Fisher 344 rats. Arterial blood gases, blood pressure and heart rate were monitored. Tumour oxygenation was measured polarographically in five sets of animals. They received either normobaric 100% oxygen, hyperbaric (3 atmospheres; atm) 100% oxygen, normobaric Carbogen or hyperbaric (3 atm) Carbogen (HBC) +/- bretylium. HBO reduced the mean level of low pO2 values (< 5 mmHg) from 0.49 to 0.07 (P = 0.0003) and increased the average median pO2 from 8 mmHg to 55 mmHg (P = 0.001). HBC reduced the level of low pO2 values from 0.82 to 0.51 (P = 0.002) an increased median pO2 from 2 mmHg to 6 mmHg (P = 0.05). Normobaric oxygen and Carbogen did not change tumour oxygenation significantly. Sympathetic blockade with bretylium before HBC exposure improved oxygenation significantly more than HBC alone (low pO2 0.55-0.17, median pO2 4-17 mmHg). HBO and hyperbaric Carbogen improved tumour oxygenation in this model, while normobaric oxygen or Carbogen had no effect. Sympathetic-mediated vasoconstriction during hyperbaric Carbogen caused it to be less effective than HBO. This mechanism also appeared to operate during normobaric Carbogen breathing.

  • Therapeutic effect of infused fluosol-da/Carbogen with ephedrine, flunarizine, or nitroprusside
    International Journal of Radiation Oncology Biology Physics, 1993
    Co-Authors: Beverly A Teicher, Sylvia A Holden, Mark W Dewhirst, I David Northey, Terence S. Herman
    Abstract:

    Abstract The perfluorochemical emulsion Fluosol-DA plus Carbogen breathing has been shown to increase the effectiveness or radiation therapy in preclinical solid tumors when the emulsion was administered by i.v. bolus injection. Much of the enhancement in tumor radiation response was lost when the emulsion was administered slowly. Purpose: We hypothesized that an increase in tumor perfusion resulted when Fluosol-DA was administered rapidly. Methods and Materials: In the present study, the α/,β agonist ephedrine, the Ca 2+ channel blocker flunarizine and the nitric oxide producing vasodilating drug nitroprusside have been tested. Results: Ephedrine administration resulted in a decrease in the radiation plus Fluosol-DA ± Carbogen antitumor effects in both the Lewis lung carcinoma and FSaIIC tumor systems. In contrast, flunarizine administration resulted in an increase in the efficacy of the radiation plus Carbogen and the radiation plus Fluosol-DA/Carbogen in both tumor systems. Even with flunarizine administration Fluosol-DA delivered slowly was less effective than when the emulsion was given rapidly. Flunarizine with Fluosol-DA infused i.v. over 30 min followed by Carbogen breathing prior to and during radiation therapy resulted in a 1.7-1.6-fold increase in response compared with 2.4-2.2-fold with Fluosol-DA administered by injection i.v. and Carbogen breathing prior to and during radiation therapy using growth delay of the Lewis lung carcinoma. The effects of nitroprusside were complex. This drug had considerably more effect at 10 Gy than at higher radiation doses. Conclusion: These studies suggest that Fluosol-DA given by i.v. injection may increase tumor perfusion and that a drug like flunarizine may be beneficial if the Fluosol-DA is administered slowly followed by Carbogen breathing and radiation therapy.

David J Chaplin - One of the best experts on this subject based on the ideXlab platform.

  • effect of Carbogen breathing on tumour microregional blood flow in humans
    Radiotherapy and Oncology, 1996
    Co-Authors: Melanie E B Powell, Michele I. Saunders, Peter Hoskin, Sally Hill, David J Chaplin
    Abstract:

    Abstract Background and purpose : Carbogen is currently being re-evaluated as a radiosensitiser. It acts primarily by increasing tissue pO 2 , although there is evidence to suggest that enhanced tumour blood flow may also be a component of its action. Materials and methods : Ten tumours in eight patients with advanced malignant disease were studied. Up to six microprobes, each with an estimated sampling volume of 10 −2 mm 3 , were inserted into the tumours. Ten min of baseline readings were taken prior to a 10 min Carbogen (95% O25% CO2) breathing period, measurements were continued for a further 10 min. Results : The results show that in 34 microregions analysed no overall change in tumour perfusion was seen with Carbogen breathing. Individual tumour analysis demonstrated variation in response between patients to Carbogen — after 6 min of Carbogen four tumours showed an increase in blood flow by more than 10% of the pre-breathing value, two a decrease and four no change. The magnitude of change was small, with only two tumours fluctuating by more than 25%. Conclusions : These findings confirm the presence of transient fluctuations in microregional blood flow in human tumours but suggest that the radiosensitising action of Carbogen lies primarily in its effect on increasing the oxygen capacity of blood. This supports the addition of agents such as nicotinamide with Carbogen in order to overcome both diffusion and perfusion limited hypoxia.

  • Transient perfusion and radiosensitizing effect after nicotinamide, Carbogen, and perflubron emulsion administration
    Radiotherapy and Oncology, 1996
    Co-Authors: Carole D Thomas, David J Chaplin, Sabine Stern, Marcelle Guichard
    Abstract:

    Abstract In order to improve the effect of radiation on tumour response, nicotinamide, perflubron emulsion and Carbogen were administered which act on both diffusion limited hypoxia and intermittent perfusion limited hypoxia. These treatments were used in different combinations. The maximal radiosensitizing effect was found with the combination of the three treatments. The aim of this study was to use a double staining method (Hoechst 33342 and DiOC 7 (3)) to evaluate the influence of nicotinamide, perflubron emulsion and Carbogen on transient perfusion in three tumour cell lines transplanted onto nude mice: one rodent (EMT6), two human (HRT18, a rectal adenocarcinoma; and Na11+, a melanoma). For untreated groups, the percentage of closed and mismatched vessels depended on the tumour cell line. Carbogen alone or Carbogen plus perflubron emulsion decreased the number of mismatched and closed vessels only for the two human cell lines. Nicotinamide was effective in decreasing the percentage of mismatched and closed vessels only for the melanoma cell line. The combination of nicotinamide, Carbogen and perflubron emulsion was the most effective at decreasing both percentage of mismatched and closed vessels in all three tumours studies. This combination was also the most effective at enhancing the radiation response in all three tumours.

  • the radiation response of kht sarcomas following nicotinamide treatment and Carbogen breathing
    Radiotherapy and Oncology, 1994
    Co-Authors: Dietmar W Siemann, M R Horsman, David J Chaplin
    Abstract:

    Abstract Preclinical investigations have demonstrated that both diffusion- and perfusion-limited hypoxic cells may exist in tumors. One approach to target such hypoxic cell subpopulations is through the combined application of nicotinamide (NIC) administration and Carbogen (5% CO 2 :95% O 2 ) breathing. Because Carbogen pre-irradiation breathing time (PIBT) can markedly influence the radiosensitizing effectiveness of this gas mixture, in the present experiments the effect of localized radiation on the transplantable KHT sarcoma was investigated in mice receiving NIC while breathing Carbogen for various periods of time. When mice were given Carbogen prior to radiation therapy, there was a minimum in tumor cell survival for PIBTs of 2–30 min. Longer PIBTs led to a loss of the radiosensitizing effect. NIC, administered as a 1000-mg/kg dose, effectively enhanced radiation cell killing in this tumor if given 45 min to 2 h prior to radiotherapy. In experiments in which either agent was combined on its own under optimum conditions (Carbogen, 10 min PIBT; or NIC, 1000 mg/kg 2 h prior to irradiation), with a range of single doses of radiation, the results showed an enhancement ratio of ∼1.9 as determined from the ratio of the slopes of the cell survival curves obtained in the absence or presence of the radiation sensitizer. This sensitizing effect could not be increased further when NIC and Carbogen breathing were combined under optimum conditions.

  • reducing acute and chronic hypoxia in tumours by combining nicotinamide with Carbogen breathing
    Acta Oncologica, 1994
    Co-Authors: M R Horsman, Sally A. Hill, Dietmar W Siemann, David J Chaplin, Marianne Nordsmark, A A Khalil, Jens Overgaard
    Abstract:

    The ability of nicotinamide and Carbogen breathing to improve the radiation response of a C3H mammary carcinoma by reducing both acute and chronic hypoxia was investigated. Using a tumour growth delay assay the response of 200 mm3 foot tumours to local irradiation was found to be increased by either injecting nicotinamide (100–1 000mg/kg) 20 min prior to irradiation, or by allowing mice to breathe Carbogen for 10 min before and during the radiation treatment. The greatest radiosensitization occurred when nicotinamide and Carbogen were combined. With a histological fluorescent staining technique nicotinamide was shown to prevent transient stoppages in microregional blood flow, and also appeared to improve tumour oxygenation as measured with an Eppendorf oxygen electrode, both effects being consistent with its ability to decrease perfusion limited acute hypoxia. Carbogen had no effect on vessel closure, but it significantly improved tumour oxygenation, which was indicative of it reducing diffusion limited c...

  • further evaluation of nicotinamide and Carbogen as a strategy to reoxygenate hypoxic cells in vivo importance of nicotinamide dose and pre irradiation breathing time
    British Journal of Cancer, 1993
    Co-Authors: David J Chaplin, M R Horsman, Dietmar W Siemann
    Abstract:

    The combination of nicotinamide and Carbogen breathing is awaiting clinical evaluation as a strategy to overcome tumour hypoxia and thus enhance radiation response. We have continued our evaluation of this approach in the murine SCCVII tumour with the aim of determining the importance of nicotinamide dose and the pre-irradiation breathing time (PIBT) for Carbogen. For Carbogen breathing alone maximal enhancement of radiation response was observed with PIBT's of between 5 and 30 min. When nicotinamide (1,000 mg kg-1 IP) was administered 60 min prior to irradiation little or no variation in radiation response was observed for all the PIBT's examined (5-90 min). Indeed at all PIBT's the cell survival obtained for the Carbogen nicotinamide and radiation combination was indistinguishable from that expected for a fully aerobic response. For PIBT's of 15 and 60 min we examined the influence of nicotinamide doses between 50 and 1,000 mg kg-1. Significant radiosensitizing effects were observed for all nicotinamide doses tested above 50 mg kg-1. Moreover for doses of 250 mg kg-1 and above the cell survival data was consistent with that expected for a fully aerobic response. No additional benefit accrued from raising the nicotinamide dose above 250 mg kg-1. These results indicate that significant radiosensitization may be expected even with clinically achievable nicotinamide doses when it is combined with Carbogen breathing. Furthermore, the use of nicotinamide may reduce the critical importance of PIBT on the radiosensitization observed with Carbogen.