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. © 1996 Wiley‐Liss, Inc.

[1]  J. Manning.  Design of Chemically Modified and Recombinant Hemoglobins as Potential Red Cell Substitutes , 1995 .

[2]  M. Intaglietta,et al.  Microcirculatory Consequences of Blood Substitution with αα-Hemoglobin , 1995 .

[3]  R. Jain,et al.  Effect of hemodilution and resuscitation on tumor interstitial fluid pressure, blood flow, and oxygenation. , 1994, Microvascular research.

[4]  R. Jain,et al.  Microvascular permeability of albumin, vascular surface area, and vascular volume measured in human adenocarcinoma LS174T using dorsal chamber in SCID mice. , 1993, Microvascular research.

[5]  P Vaupel,et al.  Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. , 1993, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[6]  D. Siemann.  Keynote address: Tissue oxygen manipulation and tumor blood flow , 1992 .

[7]  S. Zalipsky,et al.  PEG-Modified Hemoglobin as an Oxygen Carrier , 1992 .

[8]  S. Levitt,et al.  Improvement in RBC flux, acidosis and oxygenation in tumour microregions by Fluosol-DA 20%. , 1991, International journal of radiation biology.

[9]  B. Teicher,et al.  Effect of oxygen level on the enhancement of tumor response to radiation by perfluorochemical emulsions or a bovine hemoglobin preparation. , 1991, International journal of radiation oncology, biology, physics.

[10]  L. R. Manning,et al.  Preparation, properties, and plasma retention of human hemoglobin derivatives: comparison of uncrosslinked carboxymethylated hemoglobin with crosslinked tetrameric hemoglobin. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[11]  P. Vaupel,et al.  Tumor tissue oxygenation as evaluated by computerized-pO2-histography. , 1990, International journal of radiation oncology, biology, physics.

[12]  C. Song,et al.  Radiosensitization of murine tumors by Fluosol-DA 20%. , 1990, Radiation research.

[13]  H. Dvorak,et al.  Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. , 1988, The American journal of pathology.

[14]  L. R. Manning,et al.  Influence of ligation state and concentration of hemoglobin A on its cross-linking by glycolaldehyde: functional properties of cross-linked, carboxymethylated hemoglobin. , 1988, Biochemistry.

[15]  R K Jain,et al.  Determinants of tumor blood flow: a review. , 1988, Cancer research.

[16]  R. Gatenby,et al.  Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. , 1988, International journal of radiation oncology, biology, physics.

[17]  D. Hirst,et al.  The influence of haemoglobin affinity for oxygen on tumour radiosensitivity. , 1987, British Journal of Cancer.

[18]  D. Siemann,et al.  Tumor radiosensitization through reductions in hemoglobin affinity. , 1986, International journal of radiation oncology, biology, physics.

[19]  B. Teicher,et al.  Effects of dose and scheduling on growth delay of the Lewis lung carcinoma produced by the perfluorochemical emulsion, Fluosol-DA. , 1986, International journal of radiation oncology, biology, physics.

[20]  P. Vaupel,et al.  Tumor blood flow and O2 availability during hemodilution. , 1984, Advances in experimental medicine and biology.

[21]  E. Braunwald,et al.  Fluorocarbons reduce myocardial ischemic damage after coronary occlusion. , 1981, Science.

[22]  B. Teicher,et al.  The hypoxic tumor cell: a target for selective cancer chemotherapy. , 1980, Biochemical pharmacology.