Oxygenation in tumors by modified hemoglobins.
The effect of systemic injection of modified hemoglobin (Hb) prepared from bovine, human, or mouse Hb on tumor oxygenation was investigated. Hb was modified by (1) diisothiocyanatobenzenesulfonate (DIBS) to yield cross-linking within a tetramer; (2) glycolaldehyde (Glyal) to yield cross-linking between and within tetramers; (3) carboxymethylation (Cm) to change oxygen affinity; or (4) poly(ethylene glycol) (PEG) to yield attachment between tetramers. HGL9 (human glioma) in nude mice and FSaII (mice fibrosarcoma) in C3H mice were used as tumor models. Dose and time dependency were detected in the oxygenation effect by bovine-PEG-Hb. Internal cross-linkage prolonged the half-life in the circulation, and thus showed a significant effect. Compared to bovine-CmHb, bovine-DIBS-Hb and bovine-DIBS-CmHb were more effective. Decreasing the oxygen affinity by Cm significantly enhanced tumor oxygenation. Human-DIBS-CmHb was more effective than human-DIBS-Hb. These effects were caused by oxygen carrying capacity of modified Hbs as well as hemodynamic factors, and the injection seemed to reduce both perfusion-limited (acute) and diffusion-limited (chronic) hypoxia.
Nozue
M
M
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Lee
I
I
Manning
J M
JM
Manning
L R
LR
Jain
R K
RK
D000818:Animals; D001794:Blood Pressure; D002245:Carbon Dioxide / Q000494:pharmacology*; D002417:Cattle; D015687:Cell Hypoxia; D004305:Dose-Response Relationship, Drug; D005354:Fibrosarcoma / Q000378:metabolism; D005910:Glioma / Q000378:metabolism; D006207:Half-Life; D006454:Hemoglobins / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D006454:Hemoglobins; D002245:Carbon Dioxide; C011700:carbogen; D010100:Oxygen