Skip to main content
NCBI home page
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1993 Jan;120(1-2):85–90. doi: 10.1007/BF01200729

Oxygenation of tumors by a hemoglobin solution

Beverly A Teicher 1,✉, Gary N Schwartz 1, Enrique Alvarez Sotomayor 1, Michael F Robinson 1, Norman P Dupuis 1, Krishna Menon 1
PMCID: PMC12201829  PMID: 8270614

Abstract

Tumor oxygen tensions were measured using a computer-controlledPO2 microelectrode in two preclinical solid tumor models, the rat 9L gliosarcoma and the rat 13672 mammary carcinoma. Tumor oxygenation profiles were determined under four conditions: (a) during normal air breathing, (b) during carbogen breathing, (c) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with normal air breathing and (d) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with carbogen breathing. Both tumors had severely hypoxic regions under normal air-breathing conditions. Although carbogen breathing increased the oxygenation of the better-oxygenated portions of the tumor, it made no impact on the severely hypoxic tumor regions. Administration of the hemoglobin solution was effective in increasing the oxygenation throughout both tumors under normal air-breathing conditions. The addition of carbogen breathing to administration of the hemoglobin solution eliminated severe hypoxia in the 9L gliosarcoma and markedly reduced the severely hypoxic regions of the 13672 mammary carcinoma. At 24 h after administration of the hemoglobin solution the 13672 mammary carcinoma showed greater hypoxia than before treatment, which was partially corrected with carbogen breathing.

Key words: Tumor oxygenation, Hemoglobin, Oxygen pressure, Carbogen breathing

Footnotes

This work is supported by NIH grant P01-CA19589 and a gift from Biopure Corporation, Boston, Mass.

References

  1. Adams GE (1990) The clinical relevance of tumour hypoxia. Eur J Cancer 26:420–421 [DOI] [PubMed] [Google Scholar]
  2. Breepel PM, Kreuzer F, Hazevoet M (1981) Interactions of organic phosphates with bovine hemoglobin. I. Oxylabile and phosphatelabile proton binding. Pflügers Arch 389:219 [DOI] [PubMed] [Google Scholar]
  3. Bunn HF (1971) Differences in the interaction of 2,3-diphosphoglycerate with certain mammalian hemoglobins. Science 172:1049–1050 [DOI] [PubMed] [Google Scholar]
  4. Chang TMS (1988a) Attempts to find a method to prepare artificial hemoglobin corpuscles. Biomater Artif Cells Artif Organs 16:1–11 [PubMed] [Google Scholar]
  5. Chang TMS (1988b) Red blood cell substitutes: microencapsulated hemoglobin and cross-linked hemoglobin including pyridoxylated polyhemoglobin and conjugated hemoglobin. Biomater Artif Cells Artif Organs 16:11–29 [DOI] [PubMed] [Google Scholar]
  6. Chang TMS (1992) Blood substitutes based on modified hemoglobin prepared by encapsulation or crosslinking: an overview. Biomater Artif Cells Immob Biotechnol 20:159–179 [DOI] [PubMed] [Google Scholar]
  7. Cochin A, Das Gupta TK, DeWoskin R, Moss GS (1974) Immunologic properties of stroma vs. stroma-free hemoglobin solution. J Surg Oncol 4:19 [PubMed] [Google Scholar]
  8. Coleman CN (1988) Hypoxia in tumors: a paradigm for the approach to biochemical and physiologic heterogeneity. JNCI 80:310–317 [DOI] [PubMed] [Google Scholar]
  9. Cunnington PG, Jenkins SN, Tam SC, Wong JT (1981) Oxygen-binding and immunological properties of complexes between dextran and animal hemoglobins. Biochem J 193:261–266 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. De Venuto F (1988a) Evaluation of human and bovine modified-hemoglobin solution as oxygen carrying fluid for blood volume replacement. Biomater Artif Cells Artif Organs 16:77–84 [DOI] [PubMed] [Google Scholar]
  11. De Venuto F (1988b) Evaluation of human and bovine modified-hemoglobin solution as oxygen-carrying fluid for blood volume replacement. Biomater Artif Cells Artif Organs 16:77–83 [DOI] [PubMed] [Google Scholar]
  12. Duncan W (1973) Exploitation of the oxygen enhancement ratio in clinical practice. Br Med Bull 29:33 [DOI] [PubMed] [Google Scholar]
  13. Evans RG, Kimler BF, Morantz RA, Tribhawan SV, Gemer LS, O'Kell V, Low N (1989) A phase I–II study of the use of Fluosol-DA 20% as an adjuvant to radiation therapy in the treatment of primary high-grade brain tumors. Int J Radiat Oncol Biol Phys 19:415–420 [DOI] [PubMed] [Google Scholar]
  14. Fowler JR, Thomlinson RH, Howes AE (1970) Time-dose relationships in radiotherapy. Eur J Cancer 6:207 [DOI] [PubMed] [Google Scholar]
  15. Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, Broder GJ (1988) Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 14:831–838 [DOI] [PubMed] [Google Scholar]
  16. Herman TS, Teicher BA, Coleman CN (1990) The interaction of SR-4233 with hyperthermia and radiation in the FSaIIC murine fibrosarcoma tumor system in vitro and in vivo. Cancer Res 50:5055–5059 [PubMed] [Google Scholar]
  17. Hodakowski GT, Page RD, Harringer W, Jacobs EE Jr, La Raja PJ, Svizzero T, Guerrero JL, Austen WG, Vlahakes GJ (1992) Ultrapure polymerized bovine hemoglobin blood substitute: effects on the coronary circulation. Biomater Artif Cells Immob Biotechnol 20:669–672 [DOI] [PubMed] [Google Scholar]
  18. Holden SA, Herman TS, Teicher BA (1990) Addition of a hypoxic cell selective cytotoxic agent (mitomycin C or porfiromycin) to treatment with Fluosol-DA/carbogen/radiation. Radiother Oncol 18:59–70 [DOI] [PubMed] [Google Scholar]
  19. Kallinowski F, Zander R, Hoeckel M, Vaupel P (1990) Tumor tissue oxygenation as evaluation by computerized-pO2-histography. Int J Radiat Oncol Biol Phys 19:953–961 [DOI] [PubMed] [Google Scholar]
  20. Keipert PE, Gomez CL, Gonzales A, Macdonald VW, Winslow RM (1992) The role of the kidneys in the excretion of chemically modified hemoglobins. Biomater Artif Cells Immob Biotechnol 20:737–745 [DOI] [PubMed] [Google Scholar]
  21. Kim HW, Clancy T, Chen F, Greenburg AG (1992) Hepatic reticuloendothelial function following resuscitation with hemoglobin solutions. Biomater Artif Cells Immob Biotechnol 20:789–791 [DOI] [PubMed] [Google Scholar]
  22. Laver MD, Jackson E, Scherperel M, Tung C, Radford EP (1977) Hemoglobin-O2 affinity regulation; DPF, monovalent ions, and hemoglobin concentration. J Appl Physiol 43:632 [DOI] [PubMed] [Google Scholar]
  23. Lustig R, McIntosh-Lowe NL, Rose C, Haas J, Krasnow S, Spaulding M, Prosnitz L (1989) Phase I–II study of Fluosol-DA and 100% oxygen breathing as an adjuvant to radiation in the treatment of advanced squamous cell tumors of the head and neck. Int J Radiat Oncol Biol Phys 16:1587–1594 [DOI] [PubMed] [Google Scholar]
  24. Lustig R, Lowe N, Prosnitz L, Spaulding M, Cohen M, Stitt S, Brannon R (1990) Phase I/II study of fluosol and 100% oxygen breathing as an adjuvant to radiation in the treatment of unresectable non small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 19:97–102 [DOI] [PubMed] [Google Scholar]
  25. Martin DF, Porter EA, Fischer JJ, Rockwell S (1987a) Effect of a perfluorochemical emulsion on the radiation response of BA 1112 rhabdomysarcomas. Radiat Res 112:45–53 [PubMed] [Google Scholar]
  26. Martin DF, Porter EA, Rockwell S, Fischer JJ (1987b) Enhancement of tumor radiation response by the combination of a perfluorochemical emulsion and hyperbaric oxygen. Int J Radiat Oncol Biol Phys 13:747–751 [DOI] [PubMed] [Google Scholar]
  27. Okunieff P, Dunphy EP, Hoeckel M, Terris DJ, Vaupel P (1992) The role of oxygen tension distribution on the radiation response of human breast carcinoma. Adv Exp Med Biol (in press) [DOI] [PubMed]
  28. Rapoport S, Guest GM (1941) Distribution of acid-soluble phosphorous in the blook cells of various vertebrates. J Biol Chem 138:269–280 [Google Scholar]
  29. Rooney MW, Hirsch LJ, Aasen MK, Goldberg SA, Mathru M (1992) Lack of increased cardiac output during hemoglobin hemodilution can be reversed with sodium nitroprusside. Biomater Artif Cells Immob Biotechnol 20:689–692 [DOI] [PubMed] [Google Scholar]
  30. Rose CM, Lustig R, McIntosh N, Teicher BA (1986) A clinical trial of Fluosol-DA 20% in advanced squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 12:1325–1327 [DOI] [PubMed] [Google Scholar]
  31. Sartorelli AC (1988) Therapeutic attack of hypoxic cells of solid tumors: preclinical addess. Cancer Res 48:775–778 [PubMed] [Google Scholar]
  32. Siemann DW (1992) Keynote address: tissue oxygen manipulation and tumor blood flow. Int J Radiat Oncol Biol Phys 22:393–395 [DOI] [PubMed] [Google Scholar]
  33. Teicher BA, Lazo JS, Sartorelli AC (1981) Classification of antineoplastic agents by their selective toxicities toward oxygenate and hypoxic tumor cells. Cancer Res 41:73–81 [PubMed] [Google Scholar]
  34. Teicher BA, Holden SA, Rose CM (1985a) Differential enhancement of melphalan cytotoxicity in tumor and normal tissue by Fluosol-DA and oxygen breathing. Int J Cancer 36:585–589 [DOI] [PubMed] [Google Scholar]
  35. Teicher BA, Bernal SD, Holden SA, Cathcart KNS (1988a) Effect of Fluosol-DA/carbogen on etoposide/alkylating agent antitumor activity. Cancer Chemother Pharmacol 21:281–285 [DOI] [PubMed] [Google Scholar]
  36. Teicher BA, Herman TS, Holden SA, Cathcart KNS (1988b) The effect of Fluosol-DA and oxygenation status on the activity of cyclophosphamide in vivo. Cancer Chemother Pharmacol 21:286–291 [DOI] [PubMed] [Google Scholar]
  37. Teicher BA, Holden SA, Cathcart KNS, Herman TS (1988c) Effect of various oxygenation conditions and Fluosol-DA on the cytotoxicity and antitumor activity of bleomycin. JNCI 80:599–603 [DOI] [PubMed] [Google Scholar]
  38. Teicher BA, Herman TS, Rose CM (1988d) Effect of fluosol-DA on the response of intracranial 9L tumors to x rays and BCNU. Int J Radiat Oncol Biol Phys 15:1187–1192 [DOI] [PubMed] [Google Scholar]
  39. Teicher BA, Holden SA, Crawford JM (1988e) Effects of Fluosol-DA and oxygen breathing on adriamycin antitumor activity and cardiac toxicity in mice. Cancer 61:2196–2201 [DOI] [PubMed] [Google Scholar]
  40. Teicher BA, McIntosh-Lowe NL, Rose CM (1988f) Effect of various oxygenation conditions and Fluosol-DA on cancer chemotherapeutic agents. Biomater Artif Cells Artif Organs 16:533–546 [DOI] [PubMed] [Google Scholar]
  41. Teicher BA, Herman TS, Jones SM (1989) Optimization of perfluorochemical levels with radiation therapy in mice. Cancer Res 49:2693–2697 [PubMed] [Google Scholar]
  42. Teicher BA, Holden SA, Al-Achi A, Herman TS (1990) Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma. Cancer Res 50:3339–3344 [PubMed] [Google Scholar]
  43. Teicher BA, Herman TS, Hopkins RE, Menon K (1992a) Effect of a bovine hemoglobin preparation on the response of the FSaIIC fibrosarcoma to chemotherapeutic alkylating agents. J Cancer Res Clin Oncol 118:123–128 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Teicher BA, Holden SA, Ara G, Herman TS, Hopkins RE, Menon K (1992b) Effect of a bovine hemoglobin preparation (SBHS) on the response of two murine solid tumors to radiation therapy or chemotherapeutic alkylating agents. Biomater Artif Cells Immob Biotechnol 20:657–660 [DOI] [PubMed] [Google Scholar]
  45. Teicher BA, Holden SA, Ara G, Sotomayor EA, Menon K, Tarbell NJ, Sallan SE (1992c) Etanidazole as a modulator of combined modality therapy in the rat 9L gliosarcoma. Int J Oncol 1:625–630 [DOI] [PubMed] [Google Scholar]
  46. Teicher BA, Herman TS, Frei E III (1992d) Perfluorochemical emulsions: oxygen breathing in radiation sensitization and chemotherapy modulation. In: Devita VT Jr, Hellman S, Rosenberg SA (eds) Important advances in oncology 1992. Lippincott, Philadelphia, pp 39–59 [PubMed] [Google Scholar]
  47. Teicher BA, Holden SA, Northey D, Dewhirst MW, Herman TS (1993) Therapeutic effect of infused Fluosol-DA/carbogen with ephendrine, flunarizine or nitroprusside. Int J Radiat Oncol Biol Phys (in press) [DOI] [PubMed]
  48. Vaupel P (1990) Oxygenation of human tumors. Strahlenther Onkol 166:377–386 [PubMed] [Google Scholar]
  49. Vaupel PW (1993) Oxygenation of solid tumors. In: Teicher BA (ed) Drug resistance in oncology. Dekker, New York, pp 53–85 [Google Scholar]
  50. Vaupel P, Schlenger K, Knoop C, Hockel M (1991) Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancer by computerized O2 tension measurements. Cancer Res 51:3316–3322 [PubMed] [Google Scholar]
  51. Weissberg JB, Son YH, Papac RJ, Sasaki C, Fischer DB, Lawerence R, Rockwell S, Sartorelli AC, Fischer JJ (1989) Randomized clinical trial of mitomycin C as an adjunct to radiotherapy in head and neck cancer. Int J Radiat Oncol Biol Phys 17:3–9 [DOI] [PubMed] [Google Scholar]
  52. Winslow RM (1988) Optimal hematologic variables for oxygen transport including P50, hemoglobin cooperativity, hematocrit, acid-base status, and cardiac function. Biomater Artif Cells Artif Organs 16:149–172 [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES