Oxygenation status of malignant tumors: Pathogenesis of hypoxia and significance for tumor therapy

Vaupel, Peter; Kelleher, Debra K.; Höckel, Michael

doi:10.1016/s0093-7754(01)90210-6

Cited by 394 publications

(179 citation statements)

References 14 publications

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“…High expression of HIF-1a was also associated with resistance to radiotherapy treatment of oropharyngeal and cervical carcinomas. [4][5][6][7]21 In the current study, we found expression of HIF-1a protein was correlated with aggressive tumor characteristics (higher grade of tumor, depth of tumor invasion and adnexal invasion) in type I endometrial adenocarcinoma, but failed to show similar correlation in type II endometrial adenocarcinoma. This may be due to the different biologic nature of these two types and the inherent high-grade property of type II endometrial adenocarcinoma.…”

Section: Myometrial Invasionmentioning

confidence: 59%

“…It makes solid tumors resistant to radiation and chemotherapy. 4,5,8 This has been well studied in the head and neck, and uterine cervix. [5][6][7] Significant correlation of HIF-1a was also noted with radiotherapy treatment of oropharyngeal and cervical carcinomas.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7][8][9][10][11]20 The negative impact of HIF-1a protein overexpression on prognosis has been shown in cancers of head and neck, cervix and soft tissue sarcomas. [5][6][7][8][9][10] It has been suggested that tumor hypoxia makes solid tumors resistant to radiation and chemotherapy.…”

Section: Myometrial Invasionmentioning

confidence: 99%

“…3 Experimental and clinical evidence suggest that the hypoxic fraction in solid tumors reduces sensitivity to conventional treatment modalities, influences growth and may increase malignant progression. 3,4 Importantly, hypoxia has been clinically demonstrated to predict an adverse treatment outcome in the radiotherapeutic management of cancer of the head and neck, uterine cervix and soft tissue sarcomas. [5][6][7][8][9][10] Upregulation of HIF-1a has also been identified in low-stage endometrioid adenocarcinomas.…”

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confidence: 99%

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Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

et al. 2007

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Hypoxia-inducible factor 1a (HIF-1a) is a nuclear protein that is upregulated in many tumors and triggers biologic events intimately associated with aggressive tumor behavior. The aim of this study was to analyze the expression of HIF-1a, vascular endothelial growth factor (VEGF), Ki-67 and p53 in type I and type II endometrial adenocarcinoma. In total, 149 patients diagnosed with endometrial adenocarcinoma in our institute from 1995 to 2001 were included in this study, of which 108 were type I and 41 were type II endometrial adenocarcinoma. Patient demographics, clinical and pathological data were reviewed. Tissue microarrays were prepared from the paraffin blocks and immunohistochemistry was performed for antibodies against HIF-1a, VEGF, Ki-67 and p53. High expression of HIF-1a, VEGF, Ki-67 and p53 were significantly more frequent in type II than type I endometrial adenocarcinoma (Po0.001). HIF-1a expression was highly correlated with VEGF expression in the tumor cells (P ¼ 0.001). In type I endometrial adenocarcinoma, high expression of HIF-1a showed a significant correlation with higher grade of the tumor, depth of myometrial invasion, adnexal invasion and clinical stage. A similar correlation was not observed in type II endometrial adenocarcinoma. Surgical stage was the only independent prognostic marker for survival. In conclusion, high expression of HIF-1a is more frequent in type II than in type I endometrial adenocarcinoma. In type I endometrial adenocarcinoma, HIF-1a expression correlates with morphologic features of aggressiveness. In type II endometrial adenocarcinoma, there is no correlation between HIF-1a expression and these features. Thus, HIF-1a may play an important role in endometrial adenocarcinoma progression, particularly in type I endometrial adenocarcinoma. Additional investigations of HIF-1a as a biomarker of aggressive potential and as a novel target for therapeutics in endometrial adenocarcinoma are warranted. Hypoxia-inducible factor 1 (HIF-1) is a nuclear protein that activates gene transcription specifically in response to reduced cellular oxygen concentration and therefore acts as a marker for hypoxia. It is a dimeric protein with two subunits, a and b. HIF-1a is the specific hypoxia-regulated subunit. 2 Hypoxia results in stabilization of HIF-1a, facilitating nuclear HIF-1a binding and restoration of oxygen homeostasis by inducing glycolysis and angiogenesis through upregulation of vascular endothelial growth

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Section: Myometrial Invasionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Myometrial Invasionmentioning

confidence: 99%

mentioning

confidence: 99%

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Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

et al. 2007

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“…3 An advantage of the HRP/IAA combination over several other enzyme/ prodrug combinations is that it is effective under hypoxia; a tumor-specific condition and an adverse prognostic factor in a variety of human tumors. 4 When put into a GDEPT setting, the combination is effective even under catalyst-induced anoxia, 5 and also when the expression of the enzyme is placed under the control of hypoxia response elements. 6 In this study, we used a multicellular spheroid model composed of human squamous cell carcinoma cells (FaDu), to mimic the microenvironmental conditions seen in human tumors.…”

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confidence: 99%

Analysis of the horseradish peroxidase/indole-3-acetic acid combination in a three-dimensional tumor model

et al. 2004

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Horseradish peroxidase has previously been shown to catalyze the conversion of indole-3-acetic acid (IAA) to a potent cytotoxin in a gene therapy setting. A three-dimensional spheroid model composed of a human head and neck carcinoma cell line, has been used to mimic the tumor microenvironment, such as regions of hypoxia. Exposure of intact spheroids to 0.05-5 mM concentrations of IAA and the halogenated indole, 5-bromoindole-3-acetic acid (5Br-IAA), resulted in decreased cell survival, and demonstrates that this combination is effective under tumor-simulated conditions. In addition, 5Br-IAA, displayed selectivity for spheroids with a large hypoxic fraction following short exposure times. Keywords: horseradish peroxidase; hypoxia; indoles; spheroids G ene-directed enzyme prodrug therapy (GDEPT) is a multistep strategy designed to specifically target tumor tissue and reduce normal tissue side effects. The gene coding for an enzyme is delivered to the tumor, followed by the administration of a nontoxic prodrug which can be converted to a cytotoxin by the enzyme, 1 thereby killing surrounding tumor cells.A variety of GDEPT combinations have been proposed, including the horseradish peroxidase/indole-3-acetic acid (HRP/IAA) combination. 2 HRP is a plant enzyme capable of converting the auxin IAA, and other indoles, to cytotoxins via a one-electron oxidation followed by subsequent nonenzymatic reactions. 3 An advantage of the HRP/IAA combination over several other enzyme/ prodrug combinations is that it is effective under hypoxia; a tumor-specific condition and an adverse prognostic factor in a variety of human tumors. 4 When put into a GDEPT setting, the combination is effective even under catalyst-induced anoxia, 5 and also when the expression of the enzyme is placed under the control of hypoxia response elements. 6 In this study, we used a multicellular spheroid model composed of human squamous cell carcinoma cells (FaDu), to mimic the microenvironmental conditions seen in human tumors. This allows evaluation of the HRP/IAA combination under tumor-simulated conditions prior to in vivo investigations. The more complex three-dimensional nature of spheroids compared with monolayers allows for a more heterogeneous cell population. Regions within the spheroid experience different environments, ranging from well oxygenated via hypoxic regions to the necrotic core, 7 accompanied by alterations in the nutrient composition. Oxygen has been shown to have a diffusion range through metabolizing cells of about 150 mm, which results in a diffusion limited, chronically hypoxic cell population in the spheroids.In this study, the efficacy of the HRP gene therapy system was analyzed in a multicellular spheroid system using a cell line with dysfunctional p53 activity. 8 Small and large spheroids with different hypoxic fractions were compared with monolayers. The parent compound IAA was also evaluated against a halogenated indole derivative, 5Br-IAA, which previously showed enhanced anoxic toxicity. 5 Materials and methods Cell cultur...

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Red Blood Cell Transfusion Practices for Patients With Cervical Cancer Undergoing Radiotherapy

et al. 2021

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Key Points Question What is the hemoglobin transfusion threshold and target recommended for patients with cervical cancer undergoing curative-intent radiotherapy (RT)? Findings In this international Delphi consensus study, 39 experts in gynecologic radiation oncology did not agree on a hemoglobin transfusion threshold, highlighting significant variability in clinical practice. For both external beam RT and brachytherapy, a hemoglobin transfusion target of 9 or more g/dL and less than 12 g/dL, respectively, was agreed on by an 89% consensus. Meaning A liberal packed red blood cell transfusion strategy was recommended by consensus to overcome hypoxia-induced radioresistance in patients with cervical cancer receiving curative RT.

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Oxygenation status of malignant tumors: Pathogenesis of hypoxia and significance for tumor therapy

Cited by 394 publications

References 14 publications

Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

Analysis of the horseradish peroxidase/indole-3-acetic acid combination in a three-dimensional tumor model

Red Blood Cell Transfusion Practices for Patients With Cervical Cancer Undergoing Radiotherapy

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