Systemic administration of hemoglobin vesicle elevates tumor tissue oxygen tension and modifies tumor response to irradiation.
BACKGROUND
We have developed a phospholipid liposome vesicle encapsulating concentrated human hemoglobin (hemoglobin vesicle, HbV) as an artificial oxygen carrier, as an alternative to red cell transfusion. We have verified its oxygen transporting capability in a variety of preclinical models. Recent evidence suggests that artificial oxygen carriers may also be applicable for better oxygenation of ischemic or hypoxic tissues including tumors. To our knowledge, tumor oxygenation using a liposome-type artificial oxygen carrier has not been closely tested. In the present study, we tested whether systemic HbV administration changes tumor tissue oxygen tension, and if it modifies tumor response to irradiation.


METHODS
Lewis lung carcinoma was grown subcutaneously in the left hindleg of C57BL/6 mice. Experiments were initiated when the tumors reached approximately 8 mm. All experiments were done under room air. Tumor tissue oxygen tension was measured by phosphorescence quenching up to 45 min after systemic sample administration (saline: n = 5; HbV: n = 5; HbV containing methemoglobin (metHbV): n = 4; HbV with high oxygen affinity (lowP50HbV): n = 8) and compared between samples. To test the effects on irradiation response, samples (saline: n = 7; HbV: n = 7; metHbV: n = 7; lowP50HbV: n = 7) were administered prior to single 20-Gy irradiation, and tumor growth was compared.


RESULTS
Tumor tissue oxygen tension transiently increased approximately 2-fold after HbV administration in comparison to other samples. Tumor growth was marginally delayed after irradiation by prior administration of HbV in comparison to other samples. HbV administration without irradiation did not affect significant tumor growth delay.


CONCLUSIONS
These results correlatively suggest that HbV augmented tumor growth delay following irradiation, at least in part, by affecting tumor tissue oxygen tension.
Yamamoto
Manabu
M
Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
Izumi
Yotaro
Y
Horinouchi
Hirohisa
H
Teramura
Yuji
Y
Sakai
Hiromi
H
Kohno
Mitsutomo
M
Watanabe
Masazumi
M
Kawamura
Masafumi
M
Adachi
Takeshi
T
Ikeda
Eiji
E
Takeoka
Shinji
S
Tsuchida
Eishun
E
Kobayashi
Koichi
K
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000008:administration & dosage* / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism*; D011878:Radiotherapy; D016896:Treatment Outcome; D053835:Unilamellar Liposomes; D023041:Xenograft Model Antitumor Assays
D006454:Hemoglobins; D053835:Unilamellar Liposomes; D010100:Oxygen