Increased oxygenation of intracranial tumors by efaproxyn (efaproxiral), an allosteric hemoglobin modifier: In vivo EPR oximetry study
ABSTRACT To determine quantitatively the changes in oxygenation of intracranial tumors induced by efaproxiral, an allosteric hemoglobin modifier. Efaproxiral reduces hemoglobin-oxygen binding affinity, which facilitates oxygen release from hemoglobin into surrounding tissues and potentially increases the pO(2) of the tumors.
The study was performed on 10 male Fisher 344 rats with 9L intracranial tumors. Electron paramagnetic resonance (EPR) oximetry was used to measure quantitatively the changes in the pO(2) in the tumors. Lithium phthalocyanine (LiPc) crystals were implanted in the tumors and in the normal brain tissue in the opposite hemispheres. We monitored the cerebral pO(2) starting 7 to 10 days after the tumor cells were implanted. NMR imaging determined the position and size of tumor in the brain. After an initial baseline EPR measurement, efaproxiral (150 mg/kg) was injected intravenously over 15 minutes, and measurements of tumor and normal brain oxygen tension were made alternately at 10-minute intervals for the next 60 minutes; the procedure was repeated for 6 consecutive days.
Efaproxiral significantly increased the pO(2) of both the intracranial tumors and the normal brain tissue on all days. The maximum increase was reached at 52.9 to 59.7 minutes and 54.1 to 63.2 minutes after injection, respectively. The pO(2) returned to baseline values at 106 to 126.5 minutes after treatment. The maximum tumor and normal tissue pO(2) values achieved after efaproxiral treatment from Day 1 through Day 6 ranged from 139.7 to 197.7 mm Hg and 103.0 to 135.9 mm Hg, respectively. The maximum increase in tumor tissue pO(2) values from Day 2 to Day 5 was greater than the maximum increase in normal tissue pO(2).
We obtained quantitative data on the timing and extent of efaproxiral-induced changes in the pO(2) of intracerebral 9L tumors. These results illustrate a unique and useful capability of in vivo EPR oximetry to obtain repeated noninvasive measurements of tumor oxygenation over a number of days. The information on the dynamics of tumor pO(2) after efaproxiral administration illustrates the ability of efaproxiral to increase intracranial tumor oxygenation.
- SourceAvailable from: Bénédicte F Jordan
[Show abstract] [Hide abstract]
- "It has been demonstrated that a transient increase in tumor oxygenation and/or perfusion may be beneficial when combined with radiotherapy or chemotherapy  . The tumor oxygenation may be modified by changing the oxygen supply (perfusion or haemoglobin saturation)         or by changing the local oxygen consumption  . "
ABSTRACT: We have previously reported that insulin significantly enhances tumor oxygenation (pO(2)) and increases radiation-induced tumor regrowth delay in experimental models. Considering the large radiosensitizing effect, clinical trials might be envisioned. The aim of the present pre-clinical study was to obtain a more complete set of safety and efficacy data which would further justify the commencement of such clinical trials. Toxicity on normal (early and late-responding) tissues was measured by the intestinal crypt regeneration assay and the late leg contracture assay. Efficacy in terms of enhancement of pO(2) (measured by in vivo EPR oximetry) and increase in radiation-induced tumor regrowth delay was evaluated with a dose-response study on mice bearing FSaII fibrosarcoma. The effect on regrowth delay was directly correlated with the effect on the tumor pO(2), with a maximal effect using 400 mU kg(-1) insulin. Importantly, there was no increase in the radiation toxicity for normal tissues. Finally, we found that the hypoglycaemia induced by insulin can be corrected by simultaneous glucose infusion without modification of efficacy. Insulin here demonstrated a therapeutic gain and a lack of toxicity to normal tissues. The results of this study fully justify further larger preclinical assays such as the use of fractionated irradiation and a tumor control dose assay, before determining the utility of insulin as a radiosensitizer for human patients in the clinic.Radiotherapy and Oncology 11/2006; 81(1):112-7. DOI:10.1016/j.radonc.2006.08.023 · 4.86 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Competition is a natural part of human nature. Techniques and substances employed to enhance athletic performance and to achieve unfair success in sport have a long history, and there has been little knowledge or acceptance of potential harmful effects. Among doping practices, blood doping has become an integral part of endurance sport disciplines over the past decade. The definition of blood doping includes methods or substances administered for non-medical reasons to healthy athletes for improving aerobic performance. It includes all means aimed at producing an increased or more efficient mechanism of oxygen transport and delivery to peripheral tissues and muscles. The aim of this review is to discuss the biochemistry, physiology, and complications of blood doping and to provide an update on current antidoping policies.Critical Reviews in Clinical Laboratory Sciences 02/2006; 43(4):349-91. DOI:10.1080/10408360600755313 · 7.00 Impact Factor
- Journal of Clinical Oncology 02/2006; 24(1):13-5. DOI:10.1200/JCO.2005.03.8281 · 18.43 Impact Factor