Changes in tumor oxygenation/perfusion induced by the no donor, isosorbide dinitrate, in comparison with carbogen: monitoring by EPR and MRI.
OBJECTIVE
In an effort to improve radiotherapy treatments, methods aimed at increasing the quantity of oxygen delivered to tumors were investigated. The aim of this study was to evaluate the effect of one nitric oxide (NO) donor (isosorbide dinitrate) on pO(2) and blood flow in a murine tumor model. The effect was compared to carbogen, used as a reference treatment.


METHODS
Thirty-six liver tumors implanted in mouse thighs were imaged using magnetic resonance imaging (MRI) at 4.7 Tesla with dynamic Gd-DTPA and blood oxygen level-dependent (BOLD) contrast-enhanced imaging after administration of isosorbide dinitrate or carbogen. The effect on the pO(2) was also tested by EPR oximetry (1.1 GHz) on 52 mice.


RESULTS
A significant increase in MRI intensity was observed for both treatments in comparison with the control group. EPR oximetry showed a dose-dependant increase in tumor pO(2) for isosorbide dinitrate (by 5.9 mmHg at 0.2 mg/kg) and a substantially greater change for carbogen breathing (by 23 mmHg).


CONCLUSIONS
Both tumor blood flow and pO(2) were increased by isosorbide dinitrate and carbogen. Carbogen is more efficient than isosorbide dinitrate in increasing the BOLD image intensity, as well as the tumor pO(2), but as efficient as isosorbide dinitrate in the Gd-DTPA contrast-enhanced imaging. We conclude that the effects of carbogen on improving tumor pO(2) involve both improved blood flow and improved hemoglobin oxygenation, whereas the effects of isosorbide dinitrate are predominantly mediated by improved blood flow alone.
Jordan
B F
BF
Laboratories of Medicinal Chemistry and Radiopharmacy, Université Catholique de Louvain, Brussels, Belgium.
Misson
P
P
Demeure
R
R
Baudelet
C
C
Beghein
N
N
Gallez
B
B
D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000503:physiopathology / Q000532:radiotherapy; D008279:Magnetic Resonance Imaging; D051379:Mice; D009369:Neoplasms / Q000097:blood* / Q000503:physiopathology / Q000532:radiotherapy; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology*; D010313:Partial Pressure; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011853:Radiobiology; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D020030:Nitric Oxide Donors; D011838:Radiation-Sensitizing Agents; D014665:Vasodilator Agents; D002245:Carbon Dioxide; C011700:carbogen; D007548:Isosorbide Dinitrate; D010100:Oxygen