Changes in tumor oxygenation/perfusion induced by the no donor, isosorbide dinitrate, in comparison with carbogen: monitoring by EPR and MRI (original) (raw)
Related papers
Magnetic resonance imaging techniques for monitoring changes in tumor oxygenation and blood flow
Seminars in Radiation Oncology, 1998
The application of functional magnetic resonance (MR) imaging techniques to the measurement of oxygenation and blood flow in tumors is described. Gradient recalled echo MR imaging (GRE-MRI) offers a real-time noninvasive method for monitoring tumor response to vasomodulators such as carbogen (95% 02/5% CO2) breathing in attempts to overcome tumor hypoxia and improve treatment efficacy. Although the response is tumor-type dependent, increases in signal intensity of up to 100% have been observed in several animal tumor types. Responses are also seen in human tumors. The observed increases in GRE-MRI signal intensity are due to a combination of a reduction of deoxyhemoglobin in the blood causing changes in the MR imaging relaxation time T2* and changes in blood flow and may also reflect the capillary density. Thus, the magnitude of the GRE image intensity change gives an indication of the potential response of an individual tumor to treatments that aim to improve tissue oxygenation and therefore how the tumor may respond to therapy. In addition, carbogen breathing by the host has been shown to increase the uptake and efficacy of chemotherapeutic agents in animal tumors.
Targeting Tumor Perfusion and Oxygenation to Improve the Outcome of Anticancer Therapy1
Frontiers in Pharmacology, 2012
Radiotherapy and chemotherapy are widespread clinical modalities for cancer treatment. Among other biological influences, hypoxia is a main factor limiting the efficacy of radiotherapy, primarily because oxygen is involved in the stabilization of the DNA damage caused by ionizing radiations. Radiobiological hypoxia is found in regions of rodent and human tumors with a tissue oxygenation level below 10 mmHg at which tumor cells become increasingly resistant to radiation damage. Since hypoxic tumor cells remain clonogenic, their resistance to the treatment strongly influences the therapeutic outcome of radiotherapy. There is therefore an urgent need to identify adjuvant treatment modalities aimed to increase tumor pO 2 at the time of radiotherapy. Since tumor hypoxia fundamentally results from an imbalance between oxygen delivery by poorly efficient blood vessels and oxygen consumption by tumor cells with high metabolic activities, two promising approaches are those targeting vascular reactivity and tumor cell respiration. This review summarizes the current knowledge about the development and use of tumor-selective vasodilators, inhibitors of tumor cell respiration, and drugs and treatments combining both activities in the context of tumor sensitization to X-ray radiotherapy. Tumor-selective vasodilation may also be used to improve the delivery of circulating anticancer agents to tumors. Imaging tumor perfusion and oxygenation is of importance not only for the development and validation of such combination treatments, but also to determine which patients could benefit from the therapy. Numerous techniques have been developed in the preclinical setting. Hence, this review also briefly describes both magnetic resonance and non-magnetic resonance in vivo methods and compares them in terms of sensitivity, quantitative or semi-quantitative properties, temporal, and spatial resolutions, as well as translational aspects.
International Journal of Radiation Oncology*Biology*Physics, 1995
Purpose: The response of tumors to radiotherapy can be enhanced if carbogen (95% 0,, 5% COz) is breathed. The timing of carbogen administration is critical, and a noninvasive method of monitoring the response of individual tumors would have obvious utility. Functional gradient recalled echo (GRR) magnetic resonance imaging (MRI) techniques are sensitive to changes in the concentrations of deoxyhemoglobin, which, thus, acts as an endogenons contrast agent for oxygenation status and blood flow. Methods and Materials: Subcutaneous GH3 prolactinomas in three rats were imaged at 4.7 Tesla with a GRE 'II sequence [echo time (TR) = 20 ms, repetition time (TR) = 80 ms, flip angle = 45", 1 mm slice, 256 phase encode steps, 4 cm field of view, in-plane resolution 0.08 x 0.08 mm, acquisition time = 4 mitt]. The rats breathed air or carbogen for four periods of 20 mitt; three control rats breathed only air. Results: Carbogen breathing caused increases of up to 100% in the GRE image intensity of the tumors. Reversion to air breathing caused the image intensity to fail; essentially the same response was observed with the second cycle of carbogen and air breathing. Control rat tumors showed no sign&ant change. Conclusions: The response of tumors to carbogen can be monitored noninvasively by GRR MRI. In principle, tbis could be due to an increase in oxygen content of the blood, a decrease in tumor cell oxygen consumption, or an increase in tumor blood flow. Tbe very large changes in signal intensity suggest that a blood flow increase is the most probable explanation. If tbis technique can be successfully applied in man, it should be possible to optimize carbogen treatment for individual radiotherapy patients, and perhaps also to enhance tumor uptake of chemotherapeutic agents.
Blood flow and oxygenation status of human tumors
Coloproctology, 1999
There is a large body of evidence suggesting that blood ¡ and oxygenation of human tumors ate important research topics which may explain, in particular, resistance to radiation and to many antineoplastic drugs, which can limit the curability of solid tumors by radiotherapy and chemotherapy. This manuscirpt reviews the clinical investigations which have been perforrned regarding blood flow and oxygenation status of human tumors in radiation oncology. The possible uses and limitations of the prognostic significance and the changes under therapy measuring blood flow and oxygenation in human tumors were discussed. In addition, several aproaches were summarized, which can improve the microvascular 02 availability and perfusion-limited O2 delivery. The clinical data concerning the prognostic significance of blood flow, vascular function and oxygenation of human tumors are relevant for patient selection in clinical oncology. Strategies to improve traditional cancer therapy by modulation of the oxygenation status remain quite promising but more critical research and sophisticated clinical studies are necessary before its true potential is known.
NMR in Biomedicine
Hypoxia is a crucial factor in cancer therapy, determining prognosis and the effectiveness of treatment. Although efforts are being made to develop methods for assessing tumor hypoxia, no markers of hypoxia are currently used in routine clinical practice. Recently, we showed that the combined endogenous MR biomarkers, R 1 and R 2 *, which are sensitive to [dissolved O 2 ] and [dHb], respectively, were able to detect changes in tumor oxygenation induced by a hyperoxic breathing challenge. In this study, we further validated the ability of the combined MR biomarkers to assess the change in tumor oxygenation induced by an allosteric effector of hemoglobin, myo-inositol trispyrophosphate (ITPP), on rat tumor models. ITPP induced an increase in tumor pO 2 , as observed using L-band electron paramagnetic resonance oximetry, as well as an increase in both R 1 and R 2 * MR parameters. The increase in R 1 indicated an increase in [O 2 ], whereas the increase in R 2 * resulted from an increase in O 2 release from blood, inducing an increase in [dHb]. The impact of ITPP was then evaluated on factors that can influence tumor oxygenation, including tumor perfusion, saturation rate of hemoglobin, blood pH and oxygen consumption rate (OCR). ITPP decreased blood [HbO 2 ] and significantly increased blood acidity, which is also a factor that right-shifts the oxygen dissociation curve. No change in tumor perfusion was observed after ITPP treatment. Interestingly, ITPP decreased OCR in both tumor cell lines. In conclusion, ITPP increased tumor pO 2 via a combined mechanism involving a decrease in OCR and an allosteric effect on hemoglobin that was further enhanced by a decrease in blood pH. MR biomarkers could assess the change in tumor oxygenation induced by ITPP. At the intra-tumoral level, a majority of tumor voxels were responsive to ITPP treatment in both of the models studied.
International Journal of Radiation OncologyBiologyPhysics, 1998
Purpose: The aim of this work was to test the hypothesis that decreases in the linewidth of magnetic resonance (MR) water signals in tumors caused by oxygenating treatments are due to increases in capillary and venous oxygen saturation of hemoglobin, which are tightly coupled to increases in extravascular oxygen tension (pO 2 ). To establish this link, changes measured by MR were compared to changes in tissue pO 2 measured directly by oxygen microelectrodes during carbogen (95% O 2 /5% CO 2 ) inhalation. Methods and Materials: Mammary adenocarcinomas (R3230AC) in nine rats were imaged at 4.7 Tesla. T 1 -weighted (TR ؍ 200 ms, flip angle ؍ 45°) spectroscopic images of the water resonance in a single slice through each tumor were acquired with spectral resolution of 3.9 Hz and bandwidth of ؎1000 Hz. In the same slices in these tumors, microelectrode measurements were made using a non-Clark style oxygen electrode with a 350-micron tip. MR and microelectrode measurements were made during alternating periods of air and carbogen inhalation.
International Journal of Radiation Oncology*Biology*Physics, 2010
Lack of methods for repeated assessment of tumor pO(2) limits the ability to test and optimize hypoxia-modifying procedures being developed for clinical applications. We report repeated measurements of orthotopic F98 tumor pO(2) and relate this to the effect of carbogen inhalation on tumor growth when combined with hypofractionated radiotherapy. Electron paramagnetic resonance (EPR) oximetry was used for repeated measurements of tumor and contralateral brain pO(2) in rats during 30% O(2) and carbogen inhalation for 5 consecutive days. The T(1)-enhanced volumes and diffusion coefficients of the tumors were assessed by magnetic resonance imaging (MRI). The tumors were irradiated with 9.3 Gy x 4 fractions in rats breathing 30% O(2) or carbogen to determine the effect on tumor growth. The pretreatment F98 tumor pO(2) varied between 8 and 16 mmHg, while the contralateral brain had 41 to 45 mmHg pO(2) during repeated measurements. Carbogen breathing led to a significant increase in tumor and contralateral brain pO(2); however, this effect declined over days. Irradiation of the tumors in rats breathing carbogen resulted in a significant decrease in tumor growth and an increase in the diffusion coefficient measured by MRI. The results provide quantitative measurements of the effect of carbogen inhalation on intracerebral tumor pO(2) and its effect on therapeutic outcome. Such direct repeated pO(2) measurements by EPR oximetry can provide temporal information that could be used to improve therapeutic outcome by scheduling doses at times of improved tumor oxygenation. EPR oximetry is currently being tested for clinical applications.