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Department of Radiation Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114
The objective of this review article is to summarize current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies. A compilation of available data from the literature on blood flow, oxygen and nutrient supply, and tissue oxygen and pH distribution in human tumors is presented. Whenever possible, data obtained for human tumors are compared with the respective parameters in normal tissues, isotransplanted or spontaneous rodent tumors, and xenografted human tumors. Although data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements, experimental evidence is provided for the existence of a compromised and anisotropic blood supply to many tumors. As a result, O2-depleted areas develop in human malignancies which coincide with nutrient and energy deprivation and with a hostile metabolic microenvironment (e.g., existence of severe tissue acidosis). Significant variations in these relevant parameters must be expected between different locations within the same tumor, at the same location at different times, and between individual tumors of the same grading and staging. Furthermore, this synopsis will attempt to identify relevant pathophysiological parameters and other related areas future research of which might be most beneficial for designing individually tailored treatment protocols with the goal of predicting the acute and/or long-term response of tumors to therapy.
1 Dedicated to Dr. Pietro M. Gullino, an outstanding pioneer in tumor pathophysiology, on the occasion of his 70th birthday.
2 A. Werk Cook Professor of Radiation Biology/Physiology at Harvard Medical School. To whom requests for reprints should be addressed, at Department of Physiology and Pathophysiology, Pathophysiology Division, University of Mainz, D-6500 Mainz, Federal Republic of Germany.
Received 4/25/89. Revised 7/17/89. Accepted 8/14/89.
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|
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|
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|
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|
|
|
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|
|
|
|
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|
|
|
|
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|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
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|
|
|
|
|
|
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|
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|
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|
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|
|
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