Increased oxygenation of intracranial tumors by efaproxyn (efaproxiral), an allosteric hemoglobin modifier: In vivo EPR oximetry study.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Hou
Huagang
H
Department of Diagnostic Radiology, EPR Center for the Study of Viable Systems, Dartmouth Medical School, Hanover, NH, USA.
Khan
Nadeem
N
O'Hara
Julia A
JA
Grinberg
Oleg Y
OY
Dunn
Jeff F
JF
Abajian
Michelle A
MA
Wilmot
Carmen M
CM
Demidenko
Eugene
E
Lu
Shiyi
S
Steffen
Robert P
RP
Swartz
Harold M
HM
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D019069:Cell Respiration / Q000187:drug effects* / Q000502:physiology; D006454:Hemoglobins / Q000378:metabolism*; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011422:Propionates / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D000814:Aniline Compounds; D006454:Hemoglobins; D011422:Propionates; D011838:Radiation-Sensitizing Agents; C067396:efaproxiral; D010100:Oxygen