Keynote Address
Modulation of tumor oxygenation

Presented at the 10th International Conference on Chemical Modifiers of Cancer Treatment, Clearwater, FL, Jan 28–31, 1998.
https://doi.org/10.1016/S0360-3016(98)00324-1Get rights and content

Abstract

There is a large body of evidence suggesting that deficiencies in the O2 supply of tumors exist due to restrictions (i) in the O2 delivery by perfusion and/or diffusion, and (ii) in the O2 transport capacity. Whereas the former are mostly based on inadequate and heterogeneous microcirculatory functions, the latter are predominantly due to tumor-associated anemia. Possible uses and limitations of measures are discussed which can increase the microvascular O2 content and thus may preferentially serve to enhance diffusion-limited O2 availability. In addition, means are described for improving and increasing the uniformity of microcirculation thus possibly enhancing perfusion-limited O2 delivery. Reducing cellular respiration rate should be of benefit in both pathophysiological conditions. Because both types of O2 limitation coexist in solid tumors, appropriate combinations should be aimed at eradicating tumor hypoxia which is present in at least one third of cancers in the clinical setting.

Introduction

Tumor oxygenation, a parameter which reflects the distribution of O2 partial pressures (tensions) or O2 concentrations within a tumor, results from O2 supply (or availability) to the tissue and the respiration rate of the cells of which the tissue is composed 1, 2, 3, 4. The oxygenation status of a tumor has been shown to be a pivotal factor (i) in the efficacy of standard radiotherapy, O2-dependent chemotherapy, humoral and cell-mediated immunotherapy, photodynamic therapy, and localized hyperthermia (5), (ii) in the cellular proliferation activity within tumors, (iii) in the energy metabolism and cellular homeostasis, (iv) in the regulation of gene expression responsible for the malignant progression of tumors (6), (v) in the long-term prediction of local control of treated tumors and in the overall survival of cancer patients 7, 8, 9, 10, and (vi) in the selection of patients as candidates for modified treatment approaches.

O2 supply to the respiring cells is mainly determined by convective transport via the blood and by diffusional flux from the microvessels (“exchange vessels”) to the O2-consuming sites. Peculiarities of tumor tissue oxygenation can therefore mainly be attributed to characteristic structural and functional abnormalities of the tumor microcirculation (perfusion-limited O2 delivery) and to a deterioration of the diffusion geometry (diffusion-limited O2 delivery). As a result of a compromised and heterogeneous microcirculation, the O2 availability to cancer cells shows great variability, and many human malignancies reveal hypoxic or even anoxic tissue areas which are heterogeneously distributed within the tumor mass and which may be located next to well-perfused tumor areas (intratumor heterogeneity). In many tumor entities investigated so far, tumor-to-tumor variability is greater than intratumor heterogeneity. The situation in some tumors—which might already be hypoxic because of perfusion and diffusion-related limitations—may be further exasperated by the development of anemia leading to a reduced O2 transport capacity of the arterial blood.

As a rule, in most solid malignancies the tissue O2 status is poorer than in normal tissues at the site of tumor growth. This has been shown for a series of solid tumors 4, 11, 12. Tumor oxygenation is not regulated according to the metabolic demand as is the case in normal tissues. In addition, the tumor O2 status is unpredictable considering clinical stage and histopathological grade (12).

If inadequate tumor oxygenation is a considerable obstacle in the successful therapy of some human tumors as mentioned above, one major approach should be the improvement of the O2 status of hypoxic tumors or hypoxic tumor areas. A number of strategies to improve tumor oxygenation and increase its uniformity have been considered. These include enhancing O2 availability and/or reducing cellular respiration rate, parameters which crucially determine the O2 status of a given tissue (Fig. 1). Several authors have critically reviewed this area of experimental and clinical research in the past 13, 14, 15, 16, 17.

Section snippets

Increase in O2 availability

Since the oxygenation status depends on the balance between O2 availability (O2 supply) and O2 demand (O2 uptake, O2 consumption) one possible course for improving the tumor tissue O2 status is increasing the amount of O2 available to the tissue. O2 availability is the product of perfusion and the arterial O2 content. For this reason, increasing the O2 availability should be achievable either by raising the arterial O2 content or by improving nutritive flow, or by changing both parameters in a

Decrease in cellular respiration rate

As already mentioned above, tumor oxygenation is a matter of O2 supply and demand of the respiring cancer cells. In theoretical simulations based on actual in vivo data, modulation of O2 consumption seems to be a much more efficient way of affecting the oxygenation status than modification of the O2 availability (O2 supply, O2 delivery) through elevating blood flow or O2 content in the blood 14, 52. According to these studies, a reduction in consumption rate of ≥ 30% (relative to control), or

Future perspectives

Hypoxic or anoxic cell populations in solid tumors may arise from both limitations in O2 delivery by perfusion and/or diffusion, and in the O2 transport capacity. Whereas the former insufficiencies are mostly based on inadequate and heterogeneous microcirculatory functions, the latter is predominantly due to tumor-associated anemia. While increasing the microvascular O2 content would preferentially serve to enhance diffusion-limited O2 delivery, improvement and an increase in uniformity of

Acknowledgements

This study was supported by a grant from the Deutsche Krebshilfe (70-1920 Va 2).

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