Importance of hypoxia in the biology and treatment of brain tumors☆
Section snippets
Evidence for hypoxia in gliomas
In the St. Anne-Mayo grading system for astrocytic gliomas, the histopathological features of nuclear atypia, mitoses, endothelial proliferation, and necrosis that are recognized readily on routine staining are used to assign tumor grade. This grading system has been shown to be reproducible and can separate out prognostic groups [8]. The histopathological hallmark of glioblastoma multiforme is necrosis, with pseudopalisading tumor cells evident at the edge of the necrotic zone. These areas of
Therapeutic implications of hypoxia in gliomas
It is unclear whether the presence of hypoxia in gliomas is the factor that leads to the remarkable refractoriness of gliomas to therapeutic interventions, although the radioresistance [18], [19], [20], [21], [22] and drug resistance [23], [24] associated with hypoxia supports this hypothesis.
Tissue hypoxia at the time of irradiation has been recognized for almost a century as conferring protection to irradiated tissues [25]. It was theorized 50 years ago that the presence of hypoxia in tumors
Hyperbaric oxygen
Because of these studies, hypoxia rapidly became a target for therapeutic intervention in radiation oncology in a variety of tumors. These began with trials of hyperbaric oxygen in the 1950s [32]. Small single-institution series evaluating therapeutic outcomes for a variety of tumor types were promising enough that randomized trials were mounted in the 1960s to evaluate adjunctive hyperbaric oxygen therapy during irradiation for locally advanced malignancies in a variety of sites. These trials
Hypoxic cell radiosensitizers
The idea of using hypoxic cell radiosensitizers was introduced initially in the early 1960s [40]. These electron-affinic molecules replace molecular oxygen in the radiation chemistry that leads to the production of DNA damage, and therefore sensitize hypoxic cells to irradiation. Because aerobic cells are already fully radiosensitive (see Fig. 3), these compounds do not increase the radiation response of aerobic cells in culture or aerobic tissues in vivo. In 1973, Urtasun initiated a
Other approaches to modulating tumor hypoxia
Improved understanding of normal and abnormal vascular physiology recently has been brought to bear in addressing tumor physiology. The spatial and temporal heterogeneity of oxygen delivery that exist within tumors is in part a function of the dysregulation of the factors affecting vascular tone and blood flow [12], [13]. A greater appreciation of the nature of the homeostatic mechanisms that regulate vascular characteristics and perfusion in normal tissue and how these mechanisms do (or do
Hypoxia-selective drugs
Drugs that are preferentially toxic to hypoxic cells have been combined with radiation therapy as adjunctive therapy for gliomas. This approach is based on the fact that the conditions of hypoxia and low pH within tumors provide unique reducing environments, in which the activities of many cellular reductases are altered [9], [10], [28]. Under these conditions, the metabolic activation of many drugs is altered. For many common anticancer drugs, this alteration in metabolism results in decreased
Altered approaches to the delivery of radiotherapy
These attempts to address hypoxia through increasing oxygen delivery, using oxygen-mimetic radiosensitizers, or using drugs selectively toxic in hypoxia were not the only approaches tested for use in circumventing the effects of hypoxia during radiotherapy. Approaches using novel methods of delivering radiation also have been tested. One such avenue was the use of densely ionizing, high linear energy transfer radiation to circumvent the radioprotective effects of hypoxia in tumor cells. It had
Summary
The resistance of gliomas to treatment with radiation and antineoplastic drugs may result in part from the effects of the extensive, severe hypoxia that is present in these tumors. It is clear that brain tumors contain extensive regions in which the tumor cells are subjected to unphysiological levels of hypoxia. Hypoxic cells are resistant to radiation. Hypoxia and the perfusion deficits and metabolic changes that accompany hypoxia in vivo also produce resistance to many commonly used
References (70)
- et al.
Hypoxia and necrosis in rat 9L glioma and Morris 7777 hepatoma tumors: comparative measurements using EF5 binding and the Eppendorf needle electrode
Int J Radiat Oncol Biol Phys
(2000) - et al.
Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors
Int J Radiat Oncol Biol Phys
(1994) - et al.
Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue
Radiother Oncol
(1999) - et al.
Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers
Semin Radiat Oncol
(1996) - et al.
Thirty years of Medical Research Council randomized trials in solid tumours
Clin Oncol
(1997) - et al.
Hydrated electrons and radiobiological sensitization
Biochem Biophys Res Commun
(1963) - et al.
Glioblastoma multiforme: treatment by large dose fraction irradiation and metronidazole
Int J Radiat Oncol Biol Phys
(1982) - et al.
Improvement in human tumour oxygenation with carbogen of varying carbon dioxide concentrations
Radiother Oncol
(1999) - et al.
Conventional radiotherapy combined with carbogen breathing and nicotinamide for malignant gliomas
Radiother Oncol
(1995) - et al.
Nicotinamide as a radiosensitizer of a C3H mouse mammary adenocarcinoma
Radiother Oncol
(1984)
A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer Consortium
Int J Radiat Oncol Biol Phys
Neon heavy charged particle radiotherapy of glioblastoma of the brain
Int J Radiat Oncol Biol Phys
Randomized neutron dose searching study for malignant gliomas of the brain: Results of an RTOG study. Radiation Therapy Oncology Group
Int J Radiat Oncol Biol Phys
Pion radiation for high grade astrocytoma: Results of a randomized study
Int J Radiat Oncol Biol Phys
The use of hypofractionated accelerated intensity modulated irradiation in the treatment of glioblastoma multiforme: Preliminary results of a phase I trial
Int J Radiat Oncol Biol Phys
Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma
Int J Radiat Oncol Biol Phys
Phase III trial comparing stereotactic radiosurgery (SRS) followed by conventional radiotherapy (RT) with BCNU to RT with BCNU for selected patients (Pts) with supratentorial glioblastoma multiforme (GBM): Results of RTOG 9305 Protocol
Int J Radiat Oncol Phys
Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy±boost hyperthermia for glioblastoma multiforme
Int J Radiat Oncol Biol Phys
Cancer statistics 2002
CA
Epidemiology of brain tumors: the national survey of intracranial neoplasms
Neurology
Primary and secondary glioblastomas: from concept to clinical diagnosis
J Neurooncol
Hypoxia induces and selects for IGF-1 receptor expression: A possible pathway of tumor progression
Radiat Res
Genomic instability in cancer
Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH
Cancer Res
Hypoxia induces accumulation of p53 protein, but activation of a G1 checkpoint by low oxygen conditions is independent of p53 status
Mol Cell Biol
Grading of astrocytomas. A simple and reproducible method
Cancer
Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis
Nature
PET: blood flow and oxygen consumption in brain tumors
J Neurooncol
Blood flow and metabolic microenvironment of brain tumors
J Neurooncol
Expression of hypoxia-inducible factor 1α in brain tumors
Cancer
Hypoxia-induced tumour cell migration in an in vivo chicken model
Pathobiology
Intratumoral oxygen pressure in malignant brain tumor
J Neurosurg
Concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy
Br J Radiol
The phenomenon of reoxygenation and its implications for fractionated radiotherapy
Radiology
Radiobiology's contribution to radiotherapy: Promise or mirage? Failla memorial lecture
Radiat Res
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Research performed by the authors is supported in part by grants and contracts from the National Cancer Institute, the US Army Prostate Cancer Research Program, the Donaghue Woman's Health Program, the American Institute for Cancer Research, the American Cancer Society, the National Institute for Heart, Lung and Blood, and Proxima Therapeutics, Inc.