Systemic Administration of Hemoglobin Vesicle Elevates Tumor Tissue Oxygen Tension and Modifies Tumor Response to Irradiation

Yamamoto, Manabu; Izumi, Yotaro; Horinouchi, Hirohisa; Teramura, Yuji; Sakai, Hiromi; Kohno, Mitsutomo; Watanabe, Masazumi; Kawamura, Masafumi; Adachi, Takeshi; Ikeda, Eiji; Takeoka, Shinji; Tsuchida, Eishun; Kobayashi, Koichi

doi:10.1016/j.jss.2007.12.770

« Previous Next »Journal of Surgical Research
Volume 151, Issue 1 , Pages 48-54, January 2009

Systemic Administration of Hemoglobin Vesicle Elevates Tumor Tissue Oxygen Tension and Modifies Tumor Response to Irradiation

Manabu Yamamoto, M.D.
- Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
Yotaro Izumi, M.D., Ph.D.
- Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
- To whom correspondence and reprint requests should be addressed at Division of General Thoracic Surgery, Department of Surgery, School of Medicine Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Hirohisa Horinouchi, M.D., Ph.D.
- Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
Yuji Teramura, Ph.D.
- Research Institute for Science and Engineering, Waseda University, Tokyo, Japan
Hiromi Sakai, Ph.D.
- Research Institute for Science and Engineering, Waseda University, Tokyo, Japan
Mitsutomo Kohno, M.D., Ph.D.
- Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
Masazumi Watanabe, M.D., Ph.D.
- Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
Masafumi Kawamura, M.D., Ph.D.
- Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
Takeshi Adachi, M.D., Ph.D.
- Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, Tokyo, Japan
Eiji Ikeda, M.D., Ph.D.
- Department of Pathology, School of Medicine, Keio University, Tokyo, Japan
Shinji Takeoka, Ph.D.
- Research Institute for Science and Engineering, Waseda University, Tokyo, Japan
- Current affiliation: Consolidated Research Institute for Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Eishun Tsuchida, Ph.D.
- Research Institute for Science and Engineering, Waseda University, Tokyo, Japan
Koichi Kobayashi, M.D., Ph.D.
- Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan

Received 22 September 2007 published online 13 February 2008.

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.

Materials and 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.

Key Words: hemoglobin vesicle, artificial oxygen carrier, tumor oxygenation, radiosensitizer, liposome, HIF1alpha