title: Systemic administration of hemoglobin vesicle elevates tumor tissue oxygen tension and modifies tumor response to irradiation.
abstract: 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.
authors.affiliation: Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Izumi
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Horinouchi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Teramura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakai
authors.forename: Mitsutomo
authors.initials: M
authors.lastname: Kohno
authors.forename: Masazumi
authors.initials: M
authors.lastname: Watanabe
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kawamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
authors.forename: Eiji
authors.initials: E
authors.lastname: Ikeda
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeoka
authors.forename: Eishun
authors.initials: E
authors.lastname: Tsuchida
authors.forename: Koichi
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: 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
chemical_list: D006454:Hemoglobins; D053835:Unilamellar Liposomes; D010100:Oxygen