Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma.

Hypoxia occurs in two forms in tumors. Chronic or diffusion-limited hypoxia is relatively well characterized. In contrast, intermittent or perfusion-limited hypoxia is not well characterized, and it is not known how common it is in tumors. The purpose of this study was to determine whether spontaneous fluctuations in tumor microvessel flow rate can modify vessel oxygen tension (pO2) sufficiently to cause intermittent hypoxia (IH; tissue pO2 < 3 mmHg) in the tumor parenchyma supplied by such vessels. Microvessel red cell flux (RCF) and perivascular pO2 were measured simultaneously and continuously in dorsal flap window chambers of Fischer-344 rats with implanted R3230Ac tumors. In all vessels, RCF was unstable, with apex/nadir ratios ranging from 1.5 to 10. RCF and pO2 were temporally coordinated, and there were linear relationships between the two parameters. Vascular pO2 was less sensitive to changes in RCF in well-vascularized tumor regions compared with poorly vascularized regions. Simulations of oxygen transport in a well-vascularized region of a tumor demonstrated that two-fold variations in RCF can produce IH in 30% of the tissue in that region. In poorly vascularized regions, such fluctuations would lead to an even greater percentage of tissue involved in transient hypoxia. These results suggest that IH is a relatively common phenomenon. It could affect binding of hypoxic cytotoxins to tumor cells, in addition to being an important source of treatment resistance. Intermittent hypoxia also could contribute to tumor progression by providing repeated exposure of tumor cells to hypoxia-reoxygenation injury.

[1]  P. Okunieff,et al.  Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. , 1989, Cancer research.

[2]  P. Hutchins,et al.  Long-term micro- and macrocirculatory measurements in conscious rats. , 1985, Microvascular research.

[3]  R. Linsenmeier,et al.  Improved fabrication of double-barreled recessed cathode O2 microelectrodes. , 1987, Journal of applied physiology.

[4]  F. Szoka,et al.  Comparative properties and methods of preparation of lipid vesicles (liposomes). , 1980, Annual review of biophysics and bioengineering.

[5]  T. Matsuzawa,et al.  Tumor regrowth after irradiation; an experimental approach. , 1979, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[6]  T. Secomb,et al.  A Green's function method for analysis of oxygen delivery to tissue by microvascular networks. , 1989, Mathematical biosciences.

[7]  C. Valeri,et al.  Pathophysiology of ischaemia reperfusion injury: Central role of the neutrophil , 1991, The British journal of surgery.

[8]  G L Rosner,et al.  Arteriolar oxygenation in tumour and subcutaneous arterioles: effects of inspired air oxygen content. , 1996, The British journal of cancer. Supplement.

[9]  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.

[10]  G. Rosner,et al.  A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model. , 1993, International journal of radiation oncology, biology, physics.

[11]  M. Dewhirst,et al.  Microvascular studies on the origins of perfusion-limited hypoxia. , 1996, The British journal of cancer. Supplement.

[12]  M. Trotter,et al.  Possible mechanisms for intermittent blood flow in the murine SCCVII carcinoma. , 1991, International journal of radiation biology.

[13]  R. Hill,et al.  Factors influencing the thermosensitivity of two rodent tumors. , 1992, Radiation research.

[14]  J F Gross,et al.  Analysis of oxygen transport to tumor tissue by microvascular networks. , 1993, International journal of radiation oncology, biology, physics.

[15]  D. Chaplin,et al.  Intermittent blood flow in a murine tumor: radiobiological effects. , 1987, Cancer research.

[16]  G. Casarett,et al.  Development of the vascular system in the hamster malignant neurilemmoma. , 1973, Microvascular research.

[17]  R. Jain,et al.  Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis. , 1996, Microvascular research.

[18]  M. Dewhirst,et al.  Perivascular oxygen tensions in a transplantable mammary tumor growing in a dorsal flap window chamber. , 1992, Radiation research.

[19]  S. Dische.  Hyperbaric oxygen: the Medical Research Council trials and their clinical significance. , 1978, The British journal of radiology.

[20]  E. Keshet,et al.  Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis , 1992, Nature.

[21]  J. Gross,et al.  A transparent access chamber for the rat dorsal skin fold. , 1979, Microvascular research.

[22]  S. Hill,et al.  Temporal heterogeneity in microregional erythrocyte flux in experimental solid tumours. , 1995, British Journal of Cancer.

[23]  B. Fenton,et al.  Should direct measurements of tumor oxygenation relate to the radiobiological hypoxic fraction of a tumor? , 1995, International journal of radiation oncology, biology, physics.

[24]  J M Brown,et al.  Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. , 1979, The British journal of radiology.

[25]  H. Bohlen,et al.  Evaluation of carbocyanine-labeled erythrocytes for microvascular measurements. , 1993, Microvascular research.

[26]  D. Thrall,et al.  Immunohistochemical detection of a hypoxia marker in spontaneous canine tumours. , 1990, British Journal of Cancer.

[27]  Erwin G. Van Meir.  Hypoxia-mediated selection of cells with diminished apoptotic potential to solid tumours. , 1996, Neurosurgery.

[28]  A. Koong,et al.  Therapeutic advantage of hypoxic cells in tumors: a theoretical study. , 1991, Journal of the National Cancer Institute.

[29]  J F Gross,et al.  Determination of local oxygen consumption rates in tumors. , 1994, Cancer research.

[30]  E. Rofstad,et al.  Correlation of high lactate levels in human cervical cancer with incidence of metastasis. , 1995, Cancer research.

[31]  M. Dewhirst,et al.  Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. , 1996, Cancer research.

[32]  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.

[33]  P. Hoskin,et al.  Microregional blood flow in murine and human tumours assessed using laser Doppler microprobes. , 1996, The British journal of cancer. Supplement.

[34]  Sutherland,et al.  Tumor Hypoxia and Heterogeneity: Challenges and Opportunities for the Future. , 1996, Seminars in radiation oncology.

[35]  C. Grau,et al.  Relationship between radiobiological hypoxia in tumors and electrode measurements of tumor oxygenation. , 1994, International journal of radiation oncology, biology, physics.

[36]  S. Dische.  Chemical sensitizers for hypoxic cells: a decade of experience in clinical radiotherapy. , 1985, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.