Nitric oxide-mediated increase in tumor blood flow and oxygenation of tumors implanted in muscles stimulated by electric pulses.
OBJECTIVE
Oxygen deficiency in tumors reduces the efficacy of nonsurgical treatment modalities. We tested the hypothesis that electrical stimulation of the sciatic nerve could modify the oxygenation status and the blood flow of tumors implanted in the thigh of mice.


METHODS
The sciatic nerve was electrically stimulated at 5 Hz. Local transplantable liver tumor (TLT) and fibrosarcoma (FSaII) tumor oxygen pressure (pO(2)) and perfusion measurements were carried out using electron paramagnetic resonance (EPR) oximetry and the OxyLite/OxyFlo technique. The radiosensitizing effect of the protocol was assessed by irradiating FSaII tumors with X-rays.


RESULTS
Tumor pO(2) increased from approximately 3 mm Hg to approximately 8 mm Hg, and relative tumor blood flow was increased by 241% and 162% for TLT and FSaII tumor models, respectively. The effect on the tumor oxygenation was inhibited by a nitric oxide synthase (NOS) inhibitor, and an increase in the tumor nitric oxide (NO) content was observed using EPR spin-trapping. The tumor oxygen consumption rate was decreased after the stimulation protocol. In addition, the electrical stimulation of the host tissue increased regrowth delays by a factor of 1.65.


CONCLUSIONS
This increase in tumor oxygenation is due to the temporary increase in tumor blood flow, but particularly to a decrease in the tumor oxygen consumption rate (inhibition of respiration) that is mediated by a local production of NO during the protocol. Those tumor hemodynamic changes resulted in a radiosensitizing effect.
Jordan
Bénédicte F
BF
Laboratory of Medicinal Chemistry and Radiopharmacy, Université Catholique de Louvain, Brussels, Belgium.
Sonveaux
Pierre
P
Feron
Olivier
O
Grégoire
Vincent
V
Beghein
Nelson
N
Gallez
Bernard
B
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D004558:Electric Stimulation; D005434:Flow Cytometry / Q000379:methods; D017078:Laser-Doppler Flowmetry; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000532:radiotherapy; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D010092:Oximetry; D010101:Oxygen Consumption / Q000502:physiology*; D010313:Partial Pressure; D005082:Physical Exertion / Q000502:physiology; D011836:Radiation Tolerance / Q000502:physiology; D012039:Regional Blood Flow / Q000502:physiology; D012584:Sciatic Nerve / Q000502:physiology; D019097:Spin Trapping / Q000379:methods
D009569:Nitric Oxide; D006152:Cyclic GMP