Vascular Meets of Localized Hyperthermia

When hyperthermia is applied in vitro, no fundamental differences can be seen between the response to normal and tumor cells. In vivo however, selective damage of tumor cells can be achieved and this phenomenon can be largely attributed to a number of characteristic properties of the blood vessels within solid tumors. Changes in blood flow induced by hyperthermia can influence the response of a tumor to heat either by affecting the delivery of heat through changes in heat dissipation or by a modulation of the tumor microenvironment which may in turn affect the thermosensitivity of tumor cells. Studies in experimental and human tumors suggest however that an accurate prediction of changes in…

Impact of therapeutically induced reactive oxygen species and radical scavenging by α-tocopherol on tumor cell adhesion

Many tumor treatment modalities such as ionizing radiation or some chemotherapy induce reactive oxygen species (ROS) resulting in therapeutic cell damage. The aim of this study was to analyze whether such ROS induction may affect the mechanical stability of solid tumor tissue by degradation of the extracellular matrix proteins or by a loss of cell adhesion molecules. Additionally, the protective impact of alpha-tocopherol treatment on these processes was studied. Experimental DS-sarcomas in rats were treated with a combination of localized 44 degrees C hyperthermia, inspiratory hyperoxia and xanthine oxidase in order to induce pronounced oxidative stress. A second group of animals were pret…

Tumor hypoxia and therapeutic resistance

For many years, the identification of tumor hypoxia, its systematic characterization and the assessment of its clinical relevance were not possible due to the lack of methods suitable for the routine measurement of intratumoral oxygen tensions in patients. In the late 1980s, a novel and clinically applicable standardized procedure was established enabling the determination of tumor oxygenation in accessible primary tumors, local recurrences, and metastatic lesions in patients using a computerized polarographic needle electrode system (Vaupel et al. 1991; Hockel et al. 1991). Within a relatively short period of time, the significance of tumor oxygenation for therapy outcome became evident in…

Direct Measurement of Reoxygenation in Malignant Mammary Tumors after a Single Large Dose of Irradiation

Due to functional and morphological abnormalities of the terminal vascular bed in malignant tumors, a severe restriction of convective transport occurs even in very early growth stages. This leads to nutritional deprivation of the cancer cells and to unfavourable cellular microenvironments as well. During advanced tumor growth stages, the nutritional deprivation and the milieu conditions get worse because pronounced deterioration of diffusive transport is superimposed on the insufficient blood supply. This transport limitation is mainly caused by increases of intercapillary distances and by decreases of vascular surface areas per unit tissue volume. Moreover, these peculiarities of the tumo…

Dreidimensionale Registrierung stationärer Po2-Werte im Tumorgewebe unter in vivo-Bedingungen bei Verwendung von Multi-Goldmikroelektroden

Zur Ermittlung der O2-Partialdruckverteilung im Gewebe stehen zwei Verfahren zur Verfugung. Eine erste Moglichkeit ist durch die mathematische Analyse der O2-Versorgungsbedingungen auf der Grundlage der bekannten Diffusionsgesetze gegeben. Eine zweite Moglichkeit besteht in der Anwendung der polarographischen Mikroelektrodentechnik. Eine Messung der regionalen O2-Partialdrucke im Mikrobereich ermoglichen Einstichelektroden aus Platin oder Gold mit sehr feinen Spitzen (Durchmesser: 1 bis 5 µm). Mit Einzelelektroden kann jedoch nur ein lineares Po2-Profil erfast werden, ohne das es moglich ist, Po2-Gradienten zu dem umgebenden Gewebe zu messen. Mit einer neuen Mehrfachelektrode (vgl. Erdmann …

Energiehaushalt und Arbeitsphysiologie

Zur Aufrechterhaltung der Korperfunktionen und der Korperstruktur ist eine standige Energiezufuhr in Form von Nahrstoffen erforderlich. Die beim Abbau der Nahrstoffe anfallende Energie kann nur teilweise in Arbeit umgesetzt werden, ein anderer Teil wird zwangslaufig — dem 2. Hauptsatz der Thermodynamik entsprechend — als Warme frei. Daruber hinaus dient die Stoffwechselenergie zur Biosynthese von Enzymen, Hormonen und zellularen Strukturelementen sowie zur Anlage von Nahrstoffdepots.

Biological consequences of tumor hypoxia

Growing evidence from experimental and clinical studies points to the fundamental, pathophysiologic role of hypoxia in solid tumors. Intratumoral hypoxia is a consequence of a structurally and functionally disturbed microcirculation, with deterioration of the diffusion geometry and of tumor-associated anemia. Hypoxia-induced changes of the proteome in the neoplastic and stroma cells may lead to neoplastic growth impairment through molecular mechanisms, resulting in cellular quiescence, differentiation, and apoptosis. Alternatively, hypoxia-induced proteome changes activating nonspecific stress response, anaerobic metabolism, angiogenesis, tissue remodeling, and change of cell contacts may p…

Prognostic Potential Of The Pretherapeutic Tumor Oxygenation Status

Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a key factor of the tumor pathophysiome, since it can promote tumor progression and resistance to therapy. Independent of established prognostic parameters, such as clinical tumor stage, histology, histological grade and nodal status, hypoxia has been identified as an adverse prognostic factor for patient outcome. Studies of pretreatment tumor hypoxia involving direct assessment (polarographic oxygen tension measurements) have suggested a poor prognosis for patients with hypoxic tumors. These investigations indicate a worse disease-free survival for patients with hypoxic cancers of the uterine cervix or soft …

Oxygen Diffusion Constants D and K of Tumor Tissue (DS-Carcinosarcoma) and Their Temperature Dependence

To understand more thoroughly the tumor O2 supply conditions, knowledge of O2 diffusivity in tumor tissue is required. Since exact measurements of the O2 diffusion constants of tumor tissue have not been carried out to date, previous investigations of tumor O2 supply had to employ estimated values (6 – 8, 10). The results of these studies are in part contradictory.

TNFα Primes Polymorphonuclear Leukocytes for an Enhanced Respiratory Burst to a Similar Extent As Bacterial Lipopolysaccharide

We examined whether preincubating polymorphonuclear leukocytes (PMN) with TNF alpha would result in an enhanced respiratory burst upon subsequent stimulation by various agents. Bacterial lipopolysaccharide (LPS), a known primer of PMN, was used as control. We found that both LPS (0.01 to 10.0 microgram/ml) and recombinant TNF alpha (0.001 to 1.0 microgram/ml) act as direct stimulants of PMN as measured by chemiluminescence. Sixty minutes of preincubation of PMN with 1 microgram/ml TNF alpha or 10 micrograms/ml LPS resulted in similar priming for the respiratory burst elicited by opsonized zymosan, phorbol myristate acetate, zymosan, zymosan-activated serum, aggregated immunoglobulin, and f-…

No improvement in perfusion and oxygenation of experimental tumors upon application of vasodilator drugs

The oxygen deficiency seen in solid tumors is predominantly caused by an insufficient O2 supply as a result of inadequate tumor perfusion. The aim of this study was to analyze whether a number of vasodilator drugs might be suitable to increase tumor perfusion and consequently improve the oxygenation status of experimental tumors. Rats with s.c. DS-sarcomas were treated with either Na+-nitroprusside (7-25 microg x min(-1) x kg(-1) BW) or nifedipine (10 microg x min(-1) x kg(-1) BW). Red blood cell (RBC) flux was assessed continuously using laser-Doppler flowmetry and mean tumor pO2 was measured polarographically using O2-sensitive catheter electrodes. Systemic application of the vasodilator …

Microcirculatory and pH Alterations in Isotransplanted Rat and Xenotransplanted Human Tumors Associated with Hyperthermia

The rationale for considering the use of hyperthermia as an antitumor agent is based on three different mechanisms of action depending on the hyperthermia levels chosen: At moderate hyperthermia levels (40°–42.5° C) heat can increase the radiosensitivity and/or the chemosensitivity. At higher tissue temperatures ( > 42.5° C) hyperthermia acts as a cytotoxic agent since mammalian cells die after heating in a temperature-, time-, and cell cycle-dependent manner. Besides direct effects on the cell membranes, on the cytoskeleton, on metabolic processes, on DNA replication, and on RNA and protein synthesis, indirect effects distinctly modulating the anticancer action of heat have to be considere…

Transport- und Regelprozesse

Die Funktionen der Zellen und Gewebe — Stoffwechsel, Reproduktion, Wachstum, Regeneration, Kontraktion, Sekretion und Erregbarkeit — erfordern einen standigen Transport von Stoffen und Flussigkeiten innerhalb des Organismus. Sauerstoff und Nahrstoffe mussen laufend den Zellen zugefuhrt, Kohlendioxid und andere Stoffwechselendprodukte an die Umgebung abgegeben werden. Voraussetzung fur den kontrollierten Ablauf der Stoffwechsel- und Erregungsprozesse sind ferner bestimmte Ionenkonzentrationen innerhalb der Zellen, die durch spezifische Transportsysteme der Zellmembran aufrechterhalten werden. In Abhangigkeit von der Flussigkeitsaufnahme und -ausscheidung vollzieht sich schlieslich der Flussi…

Changes in microregional perfusion, oxygenation, ATP and lactate distribution in subcutaneous rat tumours upon water-filtered IR-A hyperthermia

The effect of hyperthermia on microcirculatory and metabolic parameters in s.c. DS-sarcomas of different sizes on the hind foot dorsum of SD-rats was investigated. Hyperthermia was carried out using a novel water-filtered, infrared-A radiation technique. Heating was performed at a rate of 0.5 degrees C/min until 44 degrees C was achieved in the tumour centre, which was maintained for 60 min. Using a multichannel laser Doppler flowmeter, red blood cell flux could be assessed continuously and at several sites within the tumour tissue simultaneously. Substantial inter-site variations in laser Doppler flux (LDF) were observed during hyperthermia which were independent of tumour size, site of me…

Microregional distributions of glucose, lactate, ATP and tissue pH in experimental tumours upon local hyperthermia and/or hyperglycaemia

Microregional distributions of glucose, lactate and ATP concentrations as well as tissue pH values were determined in subcutaneous rat tumours during normothermia and normoglycaemia, and upon local hyperthermia (HT) and/or hyperglycaemia (HG). Experiments were performed in order to investigate whether, and to what extent, these adjuvant therapeutic measures applied alone or in combination can modify the bioenergetic and metabolic status, parameters that are known to markedly influence the therapeutic response of tumours to heat. Local HT was performed in a saline bath (44 degrees C/2 h) and HG was induced by i.v. infusion of glucose for 2.5 h (blood glucose levels during heating: 35-40 mM).…

Therapeutic Angiogenesis in Surgery and Oncology

The aim of this presentation is to demonstrate the pathological importance of microenvironmental tissue hypoxia and to elucidate a general treatment concept for this situation which we have termed therapeutic angiogenesis 1. Hypoxia not only represents an insufficient oxygen supply for the cells of a given tissue area but is also regarded as an indicator for their metabolic deprivation and the concomitant accumulation of waste products. Therapeutic angiogenesis applied either with clinically established methods or using novel ways, which are the objectives of laboratory research and clinical trials at present, or in so far hypothetical forms, should lead to an expansion of the functional mi…

The impact of treatment for genital cancer on quality of life and body image—results of a prospective longitudinal 10-year study

Abstract Objective . To evaluate the impact of treatment for genital cancer on quality of life and body image to determine patients' therapy-related needs for quality improvement of medical care before and after surgery. Methods . We started to evaluate women with cervical cancer planned for pelvic exenteration in 1993 and integrated women planned for a Wertheim–Meigs surgery in 1995 before surgery, 4 and 12 months after surgery. Thanks to funding since 1999, more than 400 patients with a diagnosis of genital ( n = 185) or breast ( n = 217) cancer participated in this prospective study until July 2003. In this paper, we will focus on n = 129 women with cervical cancer. The assessment protoc…

Wachstumsgeschwindigkeit, Angiogenese, Durchblutung und lokale Gewebsoxygenierung ras-Onkogen-induzierter Tumoren

Bosartiges Wachstum beruht auf der Aktivierung sog. Onkogene oder auf dem Verlust von Tumorsuppressor-Genen. Solche genetischen Veranderungen konnen direkt die Sensibilitat der Tumorzellen fur verschiedene Therapieformen modulieren. Weiterhin kann sich sekundar in Tumoren ein besonderes Mikromilieu auspragen, das das biologische Verhalten der Tumorzellen beeinflust. Da bislang nur sparliche Daten vorliegen, wurden mogliche Zusammenhange zwischen einer Onkogen-Aktivierung, dem Wachstumsverhalten, der Durchblutung und der Oxygenierung maligner Tumoren an Onkogen-transformierten Rattenfibroblasten untersucht.

Microregional expression of glucose transporter-1 and oxygenation status: lack of correlation in locally advanced cervical cancers.

Abstract Purpose: Glucose transporter-1 (GLUT-1), a target gene of hypoxia-inducible factor-1, has been considered a candidate endogenous marker of tumor hypoxia. Expression of GLUT-1 may also serve as an indicator for the induction of the transcriptional response to hypoxia, which has been linked to enhanced proliferation, resistance to therapy, and metastatic propagation of cancer cells. Overexpression of GLUT-1 has been shown to correlate with poor prognosis in several tumor entities, among them cancers of the uterine cervix. The validity of these hypotheses is investigated. Experimental Design: The expression of GLUT-1 was assessed in 80 biopsies of Eppendorf oxygenation measurement tra…

Detection and characterization of tumor hypoxia using pO2 histography.

Data from 125 studies describing the pretreatment oxygenation status as measured in the clinical setting using the computerized Eppendorf pO2 histography system have been compiled in this article. Tumor oxygenation is heterogeneous and severely compromised as compared to normal tissue. Hypoxia results from inadequate perfusion and diffusion within tumors and from a reduced O2 transport capacity in anemic patients. The development of tumor hypoxia is independent of a series of relevant tumor characteristics (e.g., clinical size, stage, histology, and grade) and various patient demographics. Overall median pO2 in cancers of the uterine cervix, head and neck, and breast is 10 mm Hg with the ov…

Tumor Oxygenation Under Normobaric and Hyperbaric Hyperoxia

Tumor hypoxia is an important factor limiting the efficiency of sparsely ionizing ra-diation and O2-dependent chemotherapy. Since the tumor pO2 is the result of a dynamic steady state between oxygen supply and O2 consumption of the tumor tissue, hypoxia could be reduced either by increasing the O2-supply or by reducing the O2 demand of the tumor cells. The O2 supply can be improved for instance by (i) increasing the arterial oxy-gen partial pressure, (ii) improving (and homogenizing) the tumor perfusion, or (iii) en-hancing the O2 release from blood into the tissue by right-shifting the HbO2 dissociation curve. Theoretically, it should also be possible to improve tumor oxygenation by a rela…

Combined hyperthermia and chlorophyll-based photodynamic therapy: tumour growth and metabolic microenvironment

The effects of combined and simultaneously applied localised 43 degrees C hyperthermia (HT) and an antivascular bacteriochlorophyll-serine-based photodynamic therapy (Bchl-ser-PDT) on tumour growth and several microenvironmental parameters were examined. Rats bearing DS-sarcomas were allocated to treatment groups: (i) sham-treatment (control), (ii) Bchl-ser-PDT (20 mg kg(-1) i.v.), (iii) localised HT, (iv) Bchl-ser-PDT+HT. The light source used was an infrared-A irradiator, which, by use of appropriate filters, delivered the different ranges of wavelengths required. Following treatment, tumour volume was monitored. The greatest tumour growth inhibition was seen with Bchl-ser-PDT+HT, and sub…

Pancreatic tumors show high levels of hypoxia: regarding Koong et al. IJROBP 2000;48:919–922

Red Cell Interactions with the Microcirculation

We have measured RBC velocity profiles for mammalian arterioles and venules from high-speed cinematographic motion pictures. Measurements were made at 320× and 400× optical magnification over an averaging time period of 10 ms. In vivo profiles are uniformly nonsymmetrical, the RBCs exhibit rotation, and they frequently deviate sidewise from the overall axial direction of motion. In general, this is more pronounced on the venous side. Since all of the profiles are time variant and the average values are synchronous with the midstream velocity, individual RBC velocities will vary about the average. Profiles become more blunted in vessels with smaller diameters. In vessels below 16 μm diameter…

Wasser-, Elektrolyt- und Säure-Basen-Haushalt

Von allen Bestandteilen des Korpers hat das Wasser den grosten Anteil. Beim Neugeborenen entfallen darauf etwa 75%, beim erwachsenen Mann (je nach Korpergewicht und Alter) 50–70% des Korpergewichts.

Lack of correlation between expression of HIF-1alpha protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix.

Abstract Hypoxia inducible factor-1α (HIF-1α) has been proposed as a candidate endogenous marker of tumor hypoxia and as a molecular mediator of hypoxia-driven malignant progression and acquired treatment resistance. In this study, HIF-1α expression in 68 biopsies of oxygenation measurement tracks from squamous cell carcinomas of the uterine cervix of 38 patients was assessed. Expression of HIF-1α was commonly found to increase as a function of distance from microvessels, at the center of tumor cell aggregations, and in the vicinity of necrotic areas. However, there was no correlation of HIF-1α expression with median oxygen tension (oxygen partial pressure; pO2) and hypoxic fractions (hypox…

Measurements of Tumor Blood Flow Using Intraperitoneal Deuterium and 2H-NMR Spectroscopy

Tumors usually have a sparse, disorganized, and inefficient vascular network that leaves a large fraction of the tumor cells in an oxygen deprived and hostile metabolic microenvironment. Hence tumor blood flow, or more correctly nutritive perfusion, has important interactions with treatment efficacy. For example, hypoxic tumor cells, which occur in tumors with low blood flow, are less susceptible to radiation and are probably responsible for most radiation treatment failures (Adams, 1981). Similarly, cytotoxic drug delivery could be predicted by blood flow measurements, with clear implications regarding the expected success of chemotherapy. Thus, the ability to conveniently measure tumor bl…

Blood flow, oxygen consumption and substrate utilization of human tumors xenotransplanted into nude rats

Impact of Localized Microwave Hyperthermia on the Oxygenation Status of Malignant Tumors

Considerable insight into the mechanisms of heat induced cell death in vitro has been gained during recent years (for reviews see 1–3). Besides the direct cell killing effect of heat, many microenvironmental or milieu factors seem to play an important role during heat treatment of solid tumors in vivo, such that a preferential effect of hyperthermia on tumors has been postulated for the in situ conditions. Environmental factors affecting the tumor milieu, such as tissue oxygen partial pressures, pH values, glucose (?) and lactate levels, nutrient supply and drainage of wastes, have thus become a subject of topical interest.

No Sustained Improvement in Tumor Oxygenation After Localized Mild Hyperthermia

This study has attempted to address the controversy concerning sustained increases in tumor oxygenation upon localized mild hyperthermia. While some previous studies have reported transient increases, others have reported persistent increases in tumor oxygenation, lasting for upto 2 days after application of mild hyperthermia. In order to determine changes in oxygenation at clinically relevant tumor temperatures, experimental tumors in rats underwent localized hyperthermia at either 40, 41.8°C or 43°C for 1 h using water-filtered infrared-A irradiation. Oxygenation was continuously measured before, during and upto 60 min after hyperthermia in the tumors of anesthetized rats using oxygen-sen…

Lack of Hypoxic Response in Uterine Leiomyomas despite Severe Tissue Hypoxia

Abstract Hypoxia is now established as a key factor influencing the pathophysiology of malignant growth. Among other effects, hypoxia modulates the expression of a multitude of genes through the induction of hypoxia-inducible transcription factors. This differential gene expression favors angiogenesis, cell survival, an invasive/metastatic phenotype, and resistance to anticancer therapies. Because benign tumors do not exhibit these traits, one might expect these entities to be neither hypoxic nor to induce the genetic hypoxia response program. To test this hypothesis, an investigation of the oxygenation status of 17 leiomyomas and 1 leiomyosarcoma of the uterus using polarographic needle el…

Blood supply, oxygenation status and metabolic micromilieu of breast cancers: characterization and therapeutic relevance.

The metabolic microenvironment of a tumor is predominantly determined by the efficacy of blood flow, flux parameters (such as diffusion and convective currents in the interstitial space) and metabolic rates. The most important factors in this context include oxygen and nutrient supply, tissue pH and the bioenergetic status. It is now widely accepted that the metabolic microenvironment of a tumor can dramatically influence a range of factors such as proliferation rate, cell cycle position, growth rate and the development of apoptosis and necrosis. At the same time, these parameters can have an impact on tumor detection, therapeutic response to conventional irradiation, some chemotherapy agen…

Evaluation of Oxygen Diffusion Distances in Human Breast Cancer Using Cell Line Specific in Vivo Data: Role of Various Pathogenetic Mechanisms in the Development of Tumor Hypoxia

Radiobiological hypoxia in malignant tumors has been shown to originate (i) from spatial and temporal functional disturbances of tumor microcirculation resulting in a limited convective O2 flux in microregions even in tissue areas exhibiting high vascular densities, and (ii) from morphological abnormalities of the microcirculatory bed leading to a limitation of the diffusive O2 flux. In addition to these pathogenetic mechanisms, systemic factors (anemia, arterial hypoxia) can also play a role in the development of tumor hypoxia.

The Role of Tumor Volume in ‘Reoxygenation’ upon Cyclophosphamide Treatment

The effect of cyclophosphamide (CP) injection (60 mg/kg i.p., single dose) on volume growth and tissue oxygenation (pO2 distribution) was investigated in rat DS-sarcomas. CP was administered 4 days after subcutaneous (s.c.) tumor implantation (volume approximately 0.35 ml). Polarographic pO2 measurements were performed in the subcutis at the hind foot dorsum and in tumors 72 h after CP administration. The oxygenation status of these tissues was compared with that of saline-treated controls. CP-injection caused a mean growth delay of 11 days in DS-sarcomas and had no impact on the oxygenation status of the subcutis. In contrast, in s.c. growing DS-sarcomas the pO2 distribution improved signi…

Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis

Abstract Tumor hypoxia, mostly resulting from poor perfusion and anemia, is one of the key factors in inducing the development of cell clones with an aggressive and treatment-resistant phenotype that leads to rapid progression and poor prognosis. Studies in patients with solid tumors suggest that there is a range of hemoglobin (Hb) concentrations that is optimum for tumor oxygenation. When used to achieve an Hb level within this range, erythropoiesis-stimulating agents (ESAs) can be expected to increase tumor oxygenation, and this may favorably influence sensitivity to treatment as well as quality of life. There is no robust evidence that ESAs, when used as indicated, have a negative effect…

Physiological properties of malignant tumours

It is generally accepted that tumour microcirculation, blood flow, oxygen and nutrient supply, tissue pH distribution, and the bioenergetic status--factors which are usually closely linked and which define the so-called metabolic microenvironment--can markedly influence the therapeutic response of malignant tumours to conventional irradiation, chemotherapy, other non-surgical treatment modalities, and the cell proliferation activity within the tumours. Currently available information on the parameters defining the metabolic micromilieu in human tumours is presented in this paper. According to these data, significant variations in these relevant factors are likely to occur between different …

Role of Hypoxia and the Adenosine System in Immune Evasion and Prognosis of Patients with Brain Metastases of Melanoma: A Multiplex Whole Slide Immunofluorescence Study

Simple Summary The introduction of immune-checkpoint inhibitors improved the therapeutic landscape for patients with advanced malignant melanoma. However, many patients, including patients with melanoma brain metastases, do not derive benefit from immune-checkpoint blockade. Hence, biomarkers are needed to identify potential mechanisms of resistance and optimize patient selection. This study aimed to explore the role of hypoxia-mediated immunosuppression within the tumor microenvironment of patients with metastatic melanoma using multiplex immunofluorescence. We analyzed the prognostic relevance of the hypoxia surrogate marker GLUT-1, the adenosine-synthesizing ectoenzymes CD73/CD39, and th…

Current Status of Knowledge and Critical Issues in Tumor Oxygenation

In 1972 we started the systematic investigation of oxygenation status in (a) experimental tumor systems in rats and mice [e.g., 1–6], (b) in human tumors xenotransplanted into immune-deficient rnu/rnu-rats [e.g., 7–9], (c) in tumors derived from spontaneously tumorigenic or ras-transformed cell lines [10], and (d) in human tumors in situ [e.g., 11–15] under various pathophysiological conditions using polarographic O2 needle electrodes. In the earlier studies a cryospectrophotometric ex vivomicrotechnique was also used that allowed the measurement of HbO2 saturation in individual red blood cells in tumor microvessels [e.g., 16, 17]. Besides polarographic and cryospectrophotometric microtechn…

Atemgaswechsel und Glucosestoffwechsel von Tumoren (DS-Carcinosarkom) in vivo

An 35 Implantationstumoren (DS-Carcinosarkom) in Rattennieren wurden die Tumordurchblutung, die O2- und Glucoseaufnahme sowie die Lactatabgabe unter standardisierten Bedingungen in vivo ermittelt. In Paralleluntersuchungen wurden an Injektionspraparaten die Intercapillardistanzen, die Capillarlangen und die Capillardurchmesser bestimmt. Mit zunehmendem Tumoralter resp. Tumorgewicht zeigte sich: Die geringe O2- und Glucoseaufnahme der Tumoren wird zuruckgefuhrt auf die Veranderungen der Versorgungsbedingungen durch die Abnahme des O2- und Glucosetransportes mit dem Blut und die Vergroserung der Versorgungsbezirke der einzelnen Capillaren. Nur bei kleinen, jungen Tumoren sind Gewebsareale mit…

Blood Flow, Vascular Resistance and Oxygen Availability in Malignant Tumours upon Intravenous Flunarizine

Tumour blood flow, an important determinant of the efficacy of presently available nonsurgical cancer treatments, significantly increased following a single I.V. injection of the calcium antagonist flunarizine. At a dose of 1 mg/kg, tumour blood flow increased approximately by 28% without a significant change in mean arterial blood pressure. The flow increase was paralleled by a similar improvement of the O2 availability to the cancer cells. The data suggest that flunarizine may provide a means of improving delivery of antineoplastic agents to tumours. Furthermore, flunarizine may also enhance the effectiveness of irradiation by increasing tumour oxygenation.

Strikingly High Respiratory Quotients: A Further Characteristic of the Tumor Pathophysiome

Conspicuously high respiratory quotients (RQs) are found in solid tumors in vivo. RQs in the range between 1.29 and 1.95 neither reflect the degree of substrate oxidation by tumor cells nor indicate the types of fuels involved in metabolic processes. Instead, such tumor RQs most probably are caused by (a) channeling of glycolytic end-products into lipogenesis, and by (b) CO2 release from the tumor following extracellular buffering of H+ -inos by bicarbonate. H+ -inos exported from the intracellular space into the interstitial compartment titrate extracellular bicarbonate to CO2 and H2O with the aid of the ectoenzyme carbonic anhydrase IX, which is activated at low pH. Strikingly high (RQs) …

Impact of oxygenation status and patient age on DNA content in cancers of the uterine cervix.

Abstract Purpose In carcinomas of the uterine cervix, the tumor oxygenation status has been shown to be a prognostic indicator that is independent of treatment modality. In vitro studies suggest gene amplification and polyploidization to be among the major consequences of hypoxia (with or without consecutive reoxygenation) and to be associated with treatment resistance and tumor progression. This study analyzed whether hypoxia alters net DNA content in uterine cervix cancer cells to the extent that it is identifiable by DNA image cytometry. Methods and materials In 64 patients with primary cervical cancer, tumor oxygenation was assessed polarographically and correlated with cell DNA content…

Hypoxia and anemia: effects on tumor biology and treatment resistance

In locally advanced solid tumors, oxygen (O2) delivery is frequently reduced or even abolished. This is due to abnormalities of the tumor microvasculature, adverse diffusion geometries, and tumor-associated and/or therapy-induced anemia. Up to 50-60% of locally advanced solid tumors may exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumor mass. In approximately 30% of pretreatment patients, a decreased O2 transport capacity of the blood as a result of tumor-associated anemia can greatly contribute to the development of tumor hypoxia. While normal tissues can compensate for this O2 deficiency status by a rise in blood flow rate, locally advanced tu…

Concurrent Measurements of O2 Partial Pressures and pH Values in Human Mammary Carcinoma Xenotransplants

Due to severe restrictions of convective and diffusive transport, hypoxic or even anoxic areas exist in malignant tumors. In addition, a high glycolytic rate in tumors both in the presence and absence of oxygen and the insufficient removal of the hereby produced lactic acid lead to an acidification of the tumor tissue. Both hypoxia and acidosis can influence the efficacy of irradiation, chemotherapy and hyperthermia. However, no comprehensive data on the development of both hypoxia and acidosis within the same tumor are available to date. In particular, there is no information regarding human tumors. Therefore, a new model has been developed which allows the systematic evaluation of both pa…

Physiological Mechanisms of Treatment Resistance

It is generally accepted that tumor perfusion, microcirculation, characteristics of the interstitial space of tumors, oxygen (and nutrient) supply, tissue pH distribution and the bioenergetic status—factors that are usually closely linked and that define the so-called pathophysiological microenvironment—can markedly influence the therapeutic response of malignant tumors to sparsely ionizing radiation, chemotherapy, photodynamic therapy, hormonal therapy and immunotherapy. Besides more direct mechanisms involved in the development of acquired therapeutic resistance, there are in addition, obstacles in intratumor pharmacokinetics of antitumor agents due to delivery problems caused by an inade…

Effects of Recombinant Human Erythropoietin (rHuEPO) on Tumor Control in Patients with Cancer-Induced Anemia

It is well recognized that anemia-induced tumor hypoxia is associated with a reduced sensitivity of tumors to radiation and some forms of chemotherapy. Thus, the correction of lower hemoglobin (Hb) concentrations with recombinant human erythropoietin (rHuEPO) can play an essential role by improving tumor oxygenation. Based on evidence from a number of trials, treatment with rHuEPO will effectively ameliorate anemia and improve quality of life. However, one of the most essential prerequisites for achieving this benefit is the use of rHuEPO in agreement with the evidence-based ASCO/ASH-guidelines recommending a target Hb concentration of 12 g/dl (7.44 mmol/l).

Intracapillary HbO2 Saturation in Tumor Tissue of DS-Carcinosarcoma During Normoxia

Investigations on solid tumor tissue have shown that O2 uptake by cancer cells depends largely on the supply conditions. The absence of sufficient neovascularization and a general rarefaction of the terminal vascular bed during tumor growth as well as reduced and inhcmogeneous blood flew due to vascular stasis in neoplastic tissue prevent normal functions of the terminal vascular bed. In some areas of the tumor circulating blood is not visible despite the intactness of vessels. Stasis occurs since lacuna-like, sinusoidal and cystiform blood vessels cannot be drained completely because ‘tissue-pressure’ due to continuous cell proliferation can prevent efficient circulation. Thrombosis follow…

Microenvironmental adaptation of experimental tumours to chronic vs acute hypoxia

This study investigated long-term microenvironmental responses (oxygenation, perfusion, metabolic status, proliferation, vascular endothelial growth factor (VEGF) expression and vascularisation) to chronic hypoxia in experimental tumours. Experiments were performed using s.c.-implanted DS-sarcomas in rats. In order to induce more pronounced tumour hypoxia, one group of animals was housed in a hypoxic atmosphere (8% O(2)) for the whole period of tumour growth (chronic hypoxia). A second group was acutely exposed to inspiratory hypoxia for only 20 min prior to the measurements (acute hypoxia), whereas animals housed under normal atmospheric conditions served as controls. Acute hypoxia reduced…

Nierenfunktion und Miktion

Gliederung des Nierenparenchyms. Die Niere gliedert sich in die Nierenrinde und das Nierenmark, in dem sich wiederum eine Ausenzone und eine Innenzone unterscheiden lassen (Abb. 10-1). Das Mark ist durch Saulen der Rindensubstanz in 8–16 Markpyramiden unterteilt, deren Spitzen zum Zentrum hin konvergieren. Diese Spitzen, die Nierenpapillen, sind von den schlauchformigen Nierenkelchen uberzogen. Sie fangen den fertigen Harn auf und leiten ihn uber den Sammelraum des Nierenbeckens in den Ureter.

Respiratory gas exchange in the rat spleen in situ and intrasplenic oxyhemoglobin saturation.

Measurements of splenic respiratory gas exchange and of HbO2 saturations in the red pulp of the rat spleen have shown that there are no indications of a reduced intrasplenic O2 availability during normoxia. The present studies provide evidence that, in the normal spleen, the intrasplenic sequestration of red blood cells cannot be explained by an O2 deficiency in the red pulp since the commonly accepted notion of an intrasplenic hypoxia is not true.

Tumour Blood Flow Following Local Ultrasound Heating Computed from Thermal Clearance Curves

Thermal clearance curves following termination of ultrasound-induced hyperthermia in human mammary carcinomas implanted into the flanks of nude rats were studied. They were found to be monoexponential in form, both with and without blood flow. From the difference between the inverse time constants with and without flow, the tumour blood flow rate could be calculated. Blood flow was found to increase with very short exposure times at the therapeutic hyperthermia temperature and subsequently decrease as the exposure time increased. A higher therapeutic hyperthermia temperature augmented this effect.

Stable bioenergetic status despite substantial changes in blood flow and tissue oxygenation in a rat tumour.

Experiments on s.c. rat tumours (DS sarcoma) were performed to determine whether chronic or acute changes in tumour perfusion necessarily lead to changes in tissue oxygenation and bioenergetic status since, as a rule, blood flow is thought to be the ultimate determinant of the tumour bioenergetic status. Based on this study, there is clear experimental evidence that growth-related or acute (following i.v. administration of tumour necrosis factor alpha) decreases in tumour blood flow are accompanied by parallel alterations in tissue oxygenation. In contrast, tumour energy status remains stable as long as flow values do not fall below 0.4-0.5 ml g-1 min-1, and provided that glucose as the mai…

Treatment Resistance of Solid Tumors

Hypoxia is a characteristic property of locally advanced solid tumors, resulting from an imbalance between the supply and consumption of oxygen. Major pathogenetic mechanisms for the development of hypoxia are (1) structural and functional abnormalities of the tumor microvasculature, (2) increased diffusion distances, and (3) tumor-associated and therapy-induced anemia. The oxygenation status is independent of clinical tumor size, stage, grade, and histopathological type, but is affected by the hemoglobin level. Hypoxia is intensified in anemic patients, especially in tumors with low perfusion rates. Hypoxia and anemia (most probably via worsening of tumor hypoxia) can lead to therapeutic p…

Tumour-growth inhibition by induced hyperglycaemia/hyperlactacidaemia and localized hyperthermia.

The present study was undertaken to exploit pathophysiological properties of solid tumours for a tumour-specific therapy. Experiments were carried out on DS-sarcomas implanted s.c. in the hind foot dorsum of Sprague Dawley rats. Treatment strategies included tumour acidification, lactate accumulation and disturbance of the microcirculation by induced systemic hyperglycaemia/hyperlact-acidaemia (15-25/10 mmol/L; for 60 min) as well as localized hyperthermia (water-bath; 43 degrees C, 30 min.). A special infusion solution was developed for the systemic treatment containing glucose, lactic acid and organic buffer without inorganic ions. Growth kinetics of tumour volume and animal survival were…

Erythropoietin to treat anaemia in patients with head and neck cancer

based on the improvement of tumour oxygenation through direct effects (oxygen enhancement effect of radiotherapy) and indirect effects (counteraction of the adverse influence of tumour hypoxia on malignant progression), only increases in haemoglobin concentration that result in improvements in tumour oxygenation can be expected to have a favourable effect on prognosis. The haemoglobin concentration range leading to the highest tumour oxygen levels is most probably between 130 and 140 g/L, since this concentration represents an optimum in terms of the counteracting effects of increasing the blood’s oxygen-carrying capacity and rising viscous resistance to flow. At higher haemoglobin concentr…

Computer-assisted interpretation of flow cytometry data in hematology.

A computer program has been developed for computer-assisted diagnosis (including subclassification) of flow cytometry data of acute leukaemias and non-Hodgkin lymphomas by means of artificial intelligence. The knowledge base for the system has been formulatedas semantic networks that describe physiological hematopoiesisas well as the pathological situation (eg., aberrant antigen expression) of hematological disorders. The semantic networks reflect the hierarchy of cells and their occurrence in diseases, the normal and pathological antigen expression patterns of cells, cell maturation, and the frequency of cell populations in normal blood and bone marrow. Using these semantic networks, the d…

Erythropoietin restores the anemia-induced reduction in radiosensitivity of experimental human tumors in nude mice

Abstract Purpose The effect of recombinant human erythropoietin (rhEPO) on the radiosensitivity of human tumor xenografts growing in anemic and nonanemic nude mice was studied. Methods and materials Anemia was induced by total body irradiation ([TBI], 2 × 4 Gy) of mice before tumor implantation into the subcutis of the hind leg. The development of anemia was prevented by rhEPO (750 U/kg s.c.) given 3 times weekly starting 2 weeks before TBI. Fourteen days after fractionated TBI (tumor volume of approx. 40 mm 3 ), single-dose irradiation of the tumor with varying doses was performed so that in full dose–response relationship for the probability of tumor cure was obtained. Results Radiation-i…

Do Changes in Tumor Blood Flow Necessarily Lead to Changes in Tissue Oxygenation and in Bioenergetic Status?

An increasing number of investigations carried out in recent years provide evidence suggesting that “chronic” decreases in tumor blood flow and/or tissue oxygenation (e.g., during tumor growth) or acute declines in the tissue perfusion (e.g., following therapeutic measures) might be accompanied by significant reductions in the energy status. In several instances, positive correlations between energy status and tumor blood flow or oxygenation have been reported (Lilly et al., 1985; Evelhoch et al., 1986; Tozer et al., 1989; Vaupel et al., 1989a, 1989b; Steen and Graham, 1991), and these investigations have led to the conclusion that blood flow may be the limiting factor in determining the bi…

Cell Line and Growth Site as Relevant Parameters Governing Tumor Tissue Oxygenation

Experimental rodent tumors commonly used in radiobiology exhibit a large inter-individual variability in the oxygenation status [1,2] and in the hypoxic cell fraction [3,4]. Paramount factors contributing to this variability may be tumor growth stage or tumor size [5], the cell line used, the growth site, the use of anaesthesia and certain tumor-host interactions (e.g. tumor-induced anemia). Concerning the basic pathogenetic mechanisms through which the above mentioned parameters can modulate tumor tissue oxygenation, variations of nutritive blood flow, inherent characteristics of the cell line (e.g. respiration rate or tumor growth rate), and finally changes in the O2 transport capacity of…

Lack of Association Between Tumor Hypoxia, Glut-1 Expression and Glucose Uptake in Experimental Sarcomas

Hypoxia is a common phenomenon in experimental and human tumors which not only limits the efficacy of non-surgical treatment modalities such as irradiation and 02-dependent chemotherapy but also affects the long-term prognosis of cancer patients. Numerous studies have clearly demonstrated that patients with more hypoxic tumors have a reduced probability for survival and disease-free survival’. For this reason it might be helpful to non-invasively identify patients with hypoxic malignancies.

Acute Effects of Tumor Necrosis Factor-α or Lymphotoxin on Oxygenation and Bioenergetic Status in Experimental Tumors

Recombinant human tumor necrosis factor-α (rhTNF-α) exerts direct cytolytic and cytostatic effects on tumor cells in vitro (Fiers,1991).In vivo,indirect actions on the tumor microvasculature have been described, such as the formation of fibrin thrombi (Nawroth et al.,1988),which cause stasis and damage of tumor microvessels with subsequent hemorrhagic necrosis.

Oxygenation Status of Gynecologic Tumors: What is the Optimal Hemoglobin Level?

Tumor hypoxia has been linked to the development of treatment resistance, tumor progression, and poor prognosis. Since anemia is a major causative factor for the development of hypoxia, the association between blood hemoglobin concentration (cHb) and tumor oxygenation was examined in this study.Pretreatment O(2) tension (pO(2)) measurements were performed in 59 primary carcinomas of the uterine cervix in which a stringent histopathologic examination of the electrode tracks was mandatory in order to exclude measurements in necrotic, stromal or normal cervical tissue. In addition, pO(2) readings in twelve primary cancers and 17 local recurrences of vulvar cancers were included in this study. …

Pathophysiology of Solid Tumors

It is generally accepted that tumor blood flow, microcirculation, oxygen and nutrient supply, tissue pH distribution, lactate levels, and the bioenergetic status— factors that are usually closely linked and that define the so-called pathophysiological microenvironment (“tumor pathophysiome”)—can markedly influence the therapeutic response of malignant tumors to conventional irradiation, chemotherapy, other non-surgical treatment modalities, malignant progression, and the cell proliferation activity within tumors. Currently available information on the parameters defining the pathophysiological micromilieu in human tumors is presented in this chapter. According to these data, significant var…

Tumor microenvironmental physiology and its implications for radiation oncology.

Abstract The microenvironmental physiology of tumors is uniquely different from that of normal tissues. It is characterized, inter alia, by O 2 depletion (hypoxia, anoxia), glucose and energy deprivation, high lactate levels, and extracellular acidosis, parameters that are anisotropically distributed within the tumor mass. This hostile microenvironment is largely dictated by the abnormal tumor vasculature and heterogeneous microcirculation. Hypoxia and other hostile microenvironmental parameters are known to directly or indirectly confer resistance to irradiation leading to treatment failure. Hypoxia directly leads to a reduced "fixation" of radiation-induced DNA damage. Indirect mechanisms…

Endogenous Hypoxia Markers: Case Not Proven!

The pivotal role of hypoxia within the pathophysiological framework of solid malignant tumors is now considered to be indisputable. The fact that hypoxia can cause resistance to various cancer therapies and promote malignant progression is reflected in its adverse impact on prognosis which is repeatedly shown for various tumor entities. Knowledge in this area is based on direct assessment of the oxygenation status using O2-sensitive microsensors. However, weaknesses of this standard method are its invasiveness and limitation to accessible tumor entities. Hypoxia-inducible factor (HIF)-1α, the master transcriptional regulator of the hypoxic response, as well as certain downstream genes, e.g.…

Regional perfusion and oxygenation of tumors upon methylxanthine derivative administration

Abstract Purpose: The use of methylxanthine derivatives has been postulated as a means of increasing tumor perfusion and thus ameliorating tumor hypoxia. The aim of this study was to quantify and compare the effects of three methylxanthine derivatives: pentoxifylline (PX), torbafylline (TB), and HWA 138 (HW) on tumor perfusion and oxygenation. Methods and Materials: Anesthetized Sprague Dawley rats with DS-sarcomas implanted subcutaneously onto the hind foot dorsum were used in this study. Mean arterial blood pressure (MABP) was measured throughout experiments. Regional red blood cell (RBC) flux was monitored using a multichannel laser Doppler device and tumor oxygenation on a more global l…

Laser Doppler flux and tissue oxygenation of experimental tumours upon local hyperthermia and/or hyperglycaemia

Laser Doppler fluxmetry and oxygen partial pressure (pO2) histography have been applied to investigate the acute effects of hyperthermia (HT) and/or hyperglycaemia (HG) on microcirculatory function and tissue oxygenation of subcutaneous rat tumours growing on the dorsum of the hind foot. The experiments were performed to test whether, and to what extent, the two adjunct treatment modalities applied alone or in combination can modify these therapeutically relevant parameters. Local HT was performed in a saline bath (44 degrees C) for 2 h; HG was induced by i.v. infusion of 40% glucose solution for 2.5 h (blood glucose levels: 35-40 mM during heating). Laser Doppler flux (LDF) in superficial …

Relationship between hemoglobin levels and tumor oxygenation

Tissue hypoxia is a powerful and independent adverse prognostic factor in solid tumors. As outlined in Chapter 11, one major factor causing tumor hypoxia is a decreased O2 transport capacity of the blood resulting from tumor-associated and/or therapy-induced anemia, which is a frequent complication seen in cancer patients (Ludwig et al. 2004; Birgegard et al. 2005).

Impact of Various Thermal Doses on the Oxygenation and Blood Flow in Malignant Tumors Upon Localized Hyperthermia

Hyperthermia exhibits various direct cytocidal effects (Dickson, 1977; Overgaard, 1977; Suit, 1977). During heat treatment in vivo, several indirect mechanisms enhance the direct cell-killing capacity of hyperthermia. Therefore, the effective use of hyperthermia can overcome some of the well-known problems involved in modern radiation therapy at least in some malignant tumors.

Tumor Hypoxia: Causative Factors, Compensatory Mechanisms, and Cellular Response

Abstract Learning Objectives After completing this course, the reader will be able to: Explain the effect of hypoxia on resistance to treatment. Describe the causes of tumor hypoxia. Characterize cellular response to hypoxia. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Hypoxia is a characteristic feature of locally advanced solid tumors resulting from an imbalance between oxygen (O2) supply and consumption. Major causative factors of tumor hypoxia are abnormal structure and function of the microvessels supplying the tumor, increased diffusion distances between the nutritive blood vessels and the tumor cells, and reduced O2 tra…

l-glutamine: a major substrate for tumor cells in vivo?

From 65 human breast cancer xenografts investigated, a net glutamine uptake was found in 13 tumors (mean +/- SE: 15.7 +/- 4.5 nmol/g per min) whereas a net release (22.5 +/- 3.3 nmol/g per min) was observed in 40 tumors. In 12 tumors neither a significant net uptake nor a net release was obvious. There is experimental evidence that glutamine is taken up by cancer cells only at arterial concentrations greater than 0.5 mM. Another parameter determining glutamine utilization by tumor cells may be the tissue oxygenation. In hypoxic or anoxic tumor areas, glutamine oxidation is unlikely since oxygen is required for the reoxidation of coenzymes which are reduced in the course of this metabolic pa…

Revisiting the Warburg effect: historical dogma versus current understanding

Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary, permanent and universal consequence of dysfunctional or impaired mitochondria compensating for poor ATP yield per mole of glucose. Instead, in most tumours the Warburg effect is an essential part of a 'selfish' metabolic reprogramming, which results from the interplay between (normoxic/hypoxic) hypoxia-inducible factor-1 (HIF-1) overexpression, oncogene activation (cMyc, Ras), loss of function of tumour suppressors (mutant p53, mutant phosphatase and tensin homologue (PTEN), microRNAs and sirtuins with suppressor functions), activated (PI3K-Akt-mTORC1, Ras-Raf-MEK-ERK-cMyc, Jak-Stat3) or deactivated (LKB…

Laser Doppler flowmetry in subepidermal tumours and in normal skin of rats during localized ultrasound hyperthermia.

Laser Doppler flowmetry has been applied to normal skin and to subepidermal tumours during localized ultrasound hyperthermia in the rat. In normal skin, 40 degrees C hyperthermia only induced a marginal increase in the red blood cell flux. Significant increases occurred after 20 min at 42 degrees C and after 4 min at 44 degrees C. During 44 degrees C hyperthermia maximum fluxes were reached after 24 min. Thereafter, the flow declined and finally approached preheating values. In contrast, in subepidermal tumours 40 degrees C hyperthermia on the average induced a slight decrease of the flux. During 42 degrees C hyperthermia a significant flow decrease was found after 40 min of heating. Follow…

The Effect of Erythropoietin on Tumor Oxygenation in Normal and Anemic Rats

Anemia associated with malignancy is a common clinical problem. Its etiology is varied and includes nutritional causes, hemorrhage, hemolysis, bone marrow metastasis and hypoplasia, paraneoplastic syndromes, and chemotherapy1, with many patients presenting with anemia even before they receive cytotoxic therapy and even if their bone marrow is not invaded by tumor cells2. The response of tumors to standard radiotherapy and oxygen-dependent chemotherapy in these patients is often less satisfactory than in subjects with normal hemoglobin levels3. This is presumed to be due to the worsening of tumor oxygenation as a result of the decreased oxygen-carrying capacity of the blood in these anemic t…

The Role of Oxygen Tension Distribution on the Radiation Response of Human Breast Carcinoma

The response of tumors to radiation is heterogeneous even in animal tumor systems where tumors all originate from the same cell culture, are implanted in genetically similar age-matched animals in a constant anatomic locationl. Hence great heterogeneity of response exists even in situations where intrinsic genetic or epigenetic factors are minimally variable. Several metabolic factors are known to influence the probability of tumor control after radiation. These metabolic factors are also known to vary widely between tumors in humans2,3 and even in animal tumor models. Heterogeneous variables include tumor oxygen tension distribution, glutathione content, glucose delivery and utilization ra…

Expression pattern of the urokinase-plasminogen activator system in rat DS-sarcoma: Role of oxygenation status and tumour size

The urokinase plasminogen activator system plays a central role in malignant tumour progression. Both tumour hypoxia and enhancement of urokinase plasminogen activator, urokinase plasminogen activator-receptor and plasminogen activator inhibitor type 1 have been identified as adverse prognostic factors. Upregulation of urokinase plasminogen activator or plasminogen activator inhibitor type 1 could present means by which hypoxia influences malignant progression. Therefore, the impact of hypoxia on the expression pattern of the urokinase plasminogen activator system in rat DS-sarcoma in vivo and in vitro was examined. In the in vivo setting, tumour cells were implanted subcutaneously into rat…

Enhanced effects of aminolaevulinic acid-based photodynamic therapy through local hyperthermia in rat tumours.

The possibility of enhancing aminolaevulinic acid (ALA)-based photodynamic therapy (PDT) by simultaneous application of localised hyperthermia (HT) was evaluated. Treatments of rat DS-sarcomas included: (i) control, (ii) ALA administration (375 mg kg(-1), i.p.), no illumination, (iii) 'nonthermal' illumination, (iv) ALA-PDT: that is, ALA administration, 'nonthermal' illumination, (v) localised HT, 43 degrees C, 60 min (vi) ALA-PDT+HT: ALA administration with full spectrum irradiation resulting in ALA-PDT and HT. Tumour volume was monitored for 90 days or until a target volume (3.5 ml) was reached. No differences were seen between the first three groups, with all tumours reaching the target …

In vivo targets of recombinant human tumour necrosis factor-α: blood flow, oxygen consumption and growth of isotransplanted rat tumours

The impact of recombinant human tumour necrosis factor-alpha (1 microgram kg-1 to 1 mg kg-1; 6.6 x 10(6) U mg protein-1) on blood flow, oxygen consumption and growth of a moderately TNF-sensitive rat tumour (DS-carcinosarcoma) was studied. Tumour growth was stimulated at low TNF doses (1 and 10 micrograms kg-1) and significantly retarded at higher TNF dose levels (0.1 and 1 mg kg-1). Growth changes were concomitant with variations in oxygen consumption, lactate release and acidification of the metabolic micromilieu. Both single and repeated application of low TNF doses (1-10 micrograms kg-1 i.v.) increased tumour perfusion whereas single administration of high TNF dose levels (0.1-1 mg kg-1…

Oxygenation of Cervix Cancers: Impact of Clinical and Pathological Parameters

Current knowledge on the oxygenation status of carcinomas of the uterine cervix is mostly based on pretherapeutic data obtained in pre-and postmenopausal women. Mean and median 02 tensions (pO2) obtained from >20,000 p02-measurements in more than 400 squamous cell carcinomas of the uterine cervix observed by several research groups were, on average, distinctly lower than in normal tissues. Oxygen tensions measured in the normal cervix of nullipara patients revealed a median pO2 of 42 mmHg, whereas in conscious patients with locally advanced cancers of the cervix (stage FIGO lb-IVa), the median pO2 values were 10-20 mmHg. In patients under general propofol-anesthesia the median p02 values we…

Predictive Power of the Tumor Oxygenation Status

In most solid tumors the tissue pO2 status is poorer than in normal tissue at the site of tumor growth (for reviews see Vaupel et al., 1996, 1998; Vaupel and Hoeckel, 1998). Peculiarities of tumor tissue oxygenation can mainly be attributed to characteristic structural and functional abnormalities of the tumor microcirculation (perfusion-limited O2 delivery), to a deterioration of the diffusion-geometry (diffusion-limited O2 delivery), and—in some cases—to a reduced O2 carrying capacity of the blood due to tumor-associated anemia.

Tumor Blood Flow and O2 Availability during Hemodilution

An insufficient and heterogeneously distributed nutritive blood flow leads to an inadequate and nonuniform supply of O2 and substrates in many solid tumors (Vaupel, 1977, 1979, 1982). This deterioration of the supply conditions, which already occurs in very early growth stages and which is superimposed by a deterioration of diffusive transport during advanced growth stages, is paralleled by a decrease in the therapeutic efficacy of various cancer treatment modalities such as irradiation and chemotherapy with antiproliferative drugs. In the case of anticancer drugs, the efficiency may be reduced by affecting both pharmacokinetics and pharmacodynamics. In the latter case this is due to the de…

Glucose metabolism of malignant cells is not regulated by transketolase-like (TKTL)-1.

An isoenzyme of transketolase, transketolase-like (TKTL)-1, has been hypothesized to play a pivotal role in the pathophysiology of malignant tumors. Available data are based on the detection of the putative TKTL-1 protein with one particular mouse monoclonal anti-TKTL-1 antibody, clone JFC12T10. In this study it was demonstrated that a) JFC12T10 detects multiple unspecific bands in Western blots, b) a 75-kDa band hitherto referred to as TKTL-1 corresponds to a nuclear protein and c) immunohistochemical detection of TKTL-1 in benign leiomyomas yields an expression pattern identical to that found in a variety of malignant tumors. In RT-PCR assays, using three different primer pairs for transk…

Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix.

Abstract Purpose: Carbonic anhydrase IX (CA IX) can be induced by hypoxia in vitro and shows an immunohistochemical expression pattern that is predominantly found in perinecrotic tumor areas and correlates with exogenous markers of hypoxia, such as pimonidazole. CA IX might therefore serve as an endogenous marker of tumor hypoxia, although comparisons of CA IX immunostaining with direct oxygenation measurements using pO2 microsensors have thus far yielded contradictory results. Experimental Design: Because tumor heterogeneity may be among the factors responsible for the discrepancy between the two methods, CA IX expression in tissue samples originating from oxygen microelectrode tracks of l…

Interaction of Oxygen Partial Pressure and Energy Metabolism with the Relaxation Rate of Inorganic Phosphate: A 31P NMR Study

It is well known that oxygen molecules present in liquid or solid samples can shorten NMR spin-lattice relaxation times (T1) of the nucleus under investigation. Several studies have shown large decrements of 1H, 13C, and 19F relaxation times mediated by the O2 molecule (Lees and Muller, 1961; Ohuchi et al., 1979; Fishman et al., 1989). The positions of the 3lp atoms in phosphate compounds are stereometrically similar to some 13C atoms in organic compounds, and thus an effect of oxygen on the 31P T1 is expected. Recently, we have shown (Okunieff et al., 1988) that oxygen breathing can significantly reduce the T1 of 31p in the inorganic phosphate molecule (Pi). The degree to which this change…

Circulatory and metabolic responses of malignant tumors during localized hyperthermia

The effect of localized hyperthermia on the circulatory responses and on the oxygen and glucose supply has been evaluated in tissue-isolated rat tumors utilizing an in situ perfusion system. On the average, localized hyperthermia caused a significant increase in total tumor blood flow after raising of the mean tumor temperature from 37 degrees C to 39.5 degrees C. At higher temperatures (42 degrees C) total tumor blood flow decreased to a level somewhat below the flow during normothermia. However, there were great interindividual differences in the response of blood flow to temperature. The changes in blood flow were paralleled by variations of the O2-consumption and of the glucose uptake o…

Effectiveness of Respiratory Hyperoxia, of Normobaric and of Hyperbaric Oxygen Atmospheres in Improving Tumor Oxygenation

A restriction and an inhomogeneous distribution of diffusive and convective oxygen supply is considered the main cause for pronounced radioresistance in solid tumors (Thomlinson and Gray, 1955; Tannock, 1972). One way to alleviate this crucial problem in tumor therapy is the direct enhancement of oxygen delivery to the cancer cells. This can be performed either by the tumor host breathing pure O2 (respiratory hyperoxia, RHO) or by whole body exposure to pure O2 atmospheres at normobaric or hyperbaric pressures (normobaric oxygenation NMO, and hyperbaric oxygenation, HPO, respectively). Numerous investigations have been undertaken both in animals and in man using RHO, NMO, or HPO as an adjuv…

Tetrachlorodecaoxide Improves the Oxygenation Status of Multicellular Tumor Spheroids

Insufficient O2 supply to solid tumors has been recognized since many years to be a crucial problem in cancer therapy. Hypoxia and anoxia may increase the resistance of tumor cells to certain antiproliferative drugs or to ionizing radiation. Numerous approaches to overcoming this problem have been reported in the literature. Efforts have been made in mainly two basic directions: (1) the development of therapeutic means which are particularly efficient in hypoxic and nutrient-deprived tissue areas or which are at least independent of the tissue oxygenation, and (2) the development of methods for improving the oxygenation status of solid tumors. Among the former approaches, the cytotoxicity o…

Blood flow, oxygenation, metabolic and energetic status in different clonal subpopulations of a rat rhabdomyosarcoma.

Differentiation of a tumor plays an important role in terms of biological aggressiveness. The question arises as to whether this is reflected in differences in the metabolic and energetic status of solid tumors. The aim of this study was to analyze the influence of clonal tumor cell differentiation on the microenvironment of rat rhabdomyosarcomas. Two distinct lines of a rhabdomyosarcoma (BA-HAN-1) with different histomorphological properties were used (line F1, co-existence of mononuclear stellate cells and multinuclear myotube-like giant tumor cells; G8, polygonal, mononuclear tumor cells). Solid tumors were grown s.c. on the hind food dorsum of Lewis rats. Tumor oxygenation was measured …

Modulation of Spatial O2Tension Distribution in Experimental Tumors by Increasing Arterial O2Supply

Tumor oxygenation has been measured polarographically in s.c. implanted DS-sarcomas on the dorsum of the hind foot of male Sprague-Dawley rats. pO2 was determined in all 3 spatial dimensions and 3-dimensional pO2 distributions as well as the mean extent of confluent areas with pO25 mmHg were calculated. Finally, the effect of elevating arterial pO2 (by carbogen breathing) as well as of increasing tumor blood flow (by angiotensin infusion) on the spatial pO2 distribution was analyzed. Depending on the tumor volume, the spatial pO2 distribution is more or less anisotropic. In smaller tumors, areas with physiological pO2 values are found adjacent to large hypoxic areas whereas larger tumors ar…

Tumour tissue monitoring during photodynamic and hyperthermic treatment using bioimpedance spectroscopy.

Electrical bioimpedance spectroscopy is a fast and relatively easily applicable method for tissue characterization. In the frequency range up to 10 MHz, current conduction through tissue is mainly determined by tissue structure, i.e. the extra- and intra-cellular compartments and the insulating cell membranes. Therefore, changes in the extra- and intra-cellular fluid volumes are reflected in the impedance spectra. Investigations of tumours (DS sarcoma, implanted on the hind foot dorsum of rats) during treatment with localized hyperthermia (HT), photodynamic therapy (PDT) and the combination of these two components were carried out using impedance spectroscopy in the frequency range of 37 Hz…

Station�re Verteilung der O2-Drucke im Tumorgewebe (DS-Carcinosarkom) I. Messungen in vivo unter Verwendung von Gold-Mikroelektroden

Unter standardisierten Bedingungen wurden in vivo die O2-Drucke \(\left( {P_{{\text{0}}_{\text{2}} } } \right)\) in gewebsisolierten Impftumoren (DS-Carcinosarkom) der Rattenniere sowie zum Vergleich in den Nierenrinden gesunder Ratten gemessen. Fur die polarographische \(P_{{\text{0}}_{\text{2}} } \)-Messung im Gewebe fanden Gold-Mikroelektroden mit einem Spitzendurchmesser von 3–8 μm und einem Durchmesser der Goldkathode von 1 μm Verwendung. Bei kontinuierlichem oder diskontinuierlichem Vorschub der Elektrode wurden die \(P_{{\text{0}}_{\text{2}} } \)-Verteilungen in 9 Tumoren (37 Stichkanale, 3579 Einzelmessungen) und 3 Nierenrinden (14 Stichkanale, 2974 Einzelmessungen) ermittelt.

Hypoxia-stimulated expression of angiogenic growth factors in cervical cancer cells and cervical cancer-derived fibroblasts

It is generally accepted that local growth of solid tumors and their ability to establish distant metastases are dependent on the formation of new blood vessels arising from preexisting ones (angiogenesis). The angiogenic response of the host is mediated by angiogenic molecules that are released from cancer and normal stroma cells, especially fibroblasts. The goal of the present study was to quantitatively compare the expression of the two most important angiogenic growth factors (VEGF, angiogenin) of cervical cancer cells (HeLa and Me-180) with that of cervical cancer-derived fibroblasts (from one tumor/patient) under defined normoxic and hypoxic conditions in vitro. The growth kinetics of…

Effects of tumor necrosis factor-alpha on tumor blood flow and hyperthermic treatment.

The impact of recombinant human tumor necrosis factor-alpha (rhTNF-alpha), given alone or in combination with local hyperthermia, on perfusion and growth of a moderately rhTNF-alpha-sensitive rat tumor (DS-carcinosarcoma) was investigated. DS-carcinosarcomas were implanted into the hind foot dorsum of Sprague-Dawley rats. Tumor blood flow (TBF) was measured with the krypton-85 clearance technique. Treatment with either tumor necrosis factor-alpha (0.1-1.0 mg/kg) or hyperthermia (43.3 and 44.3 degrees C, 40 min) can decrease the perfusion of malignant tumors. The TBF reduction was fully established 2 h after rhTNF-alpha injection and lasted for at least 4 h. The application of local hyperthe…

Hypoxia, Lactate Accumulation, and Acidosis: Siblings or Accomplices Driving Tumor Progression and Resistance to Therapy?

This chapter briefly summarizes the most important processes by which hypoxia, lactate accumulation, and acidosis may influence malignant progression and therapeutic resistance of solid malignant tumors. While these phenomena are often elements of an integrated reaction, they may occur independently of each other under certain circumstances. The latter information may be of interest with regard to possible “targeted” therapeutic interventions.

Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy.

Hypoxic areas are a characteristic property of solid tumors. Hypoxia results from an imbalance between the supply and consumption of oxygen. Major pathogenetic mechanisms for the emergence of hypoxia are (1) structural and functional abnormalities in the tumor microvasculature; (2) an increase in diffusion distances; and (3) tumor- or therapy-associated anemia leading to a reduced O2 transport capacity of the blood. There is pronounced intertumor variability in the extent of hypoxia, which is independent of clinical size, stage, histopathologic type, and grade. Local recurrences have a higher hypoxic fraction than primary tumors. Tumor hypoxia is intensified in anemic patients, especially i…

Pathophysiology of Tumors in Hyperthermia

The response of tumor cells to hyperthermia is critically influenced by a number of pathophysiological factors both in vitro and in vivo. The most relevant factors in this context are tumor blood flow, tissue oxygenation, the energy status, and the pH distribution, which in turn define the cellular microenvironment.

Dynamics of tumor oxygenation and red blood cell flux in response to inspiratory hyperoxia combined with different levels of inspiratory hypercapnia.

Abstract Background and purpose : Increasing arterial oxygen partial pressure (pO 2 ) by breathing hyperoxic gases is an effective means of improving tumor oxygenation, although the efficacy of adding CO 2 to the inspiratory gas has been discussed controversially. This study aimed at analyzing the impact of different inspiratory CO 2 fractions on the time course of oxygenation and perfusion changes in experimental tumors during and after inspiratory hyperoxia. Material and methods : Perfusion and oxygenation of rat DS-sarcomas were studied during spontaneous breathing of pure oxygen or hyperoxic gas mixtures containing different CO 2 fractions (1, 2.5 or 5%). Red blood cell (RBC) flux was a…

Changes in Perfusion Pattern of Experimental Tumors Due to Reduction in Arterial Oxygen Partial Pressure

The role of hypoxia-induced factors in tumor progression.

Abstract Learning Objectives After completing this course, the reader will be able to: Describe hypoxia-induced mechanisms for cell survival. Discuss hypoxia-induced gene expression. Relate hypoxia and glucose metabolism. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit atCME.TheOncologist.com Hypoxia is a common characteristic of locally advanced solid tumors that has been associated with diminished therapeutic response and, more recently, with malignant progression, that is, an increasing probability of recurrence, locoregional spread, and distant metastasis. Emerging evidence indicates that the effect of hypoxia on malignant progression is mediated by a…

Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia.

The radiosensitivity of solid tumours in anaemic rats treated with recombinant human erythropoietin (rhEPO, epoetin beta) was studied. Anaemia was induced by a single dose of carboplatin (45 mg kg(-1) i.v.), resulting in a reduction in the haemoglobin concentration by 30%. In a second group, the development of anaemia was prevented by rhEPO (1000 IU kg(-1)) administered s.c. three times per week starting 6 days before the carboplatin application. Three days after carboplatin treatment, DS-sarcomas were implanted subcutaneously onto the hind foot dorsum. Neither carboplatin nor rhEPO treatment influenced tumour growth rate. Five days after implantation, tumours were irradiated with a single …

The influence of tumor blood flow and microenvironmental factors on the efficacy of radiation, drugs and localized hyperthermia.

It is generally accepted that tumor blood flow, microcirculation, oxygen and nutrient supply, tissue pH distribution, and the bioenergetic status-factors which are usually closely linked and which define the so-called metabolic microenvironment--can markedly influence the therapeutic response of malignant tumors to conventional irradiation, chemotherapy, other nonsurgical treatment modalities, and the cell proliferation activity within tumors. Currently available information on the parameters defining the metabolic micromilieu in human tumors is presented in this review. According to these data, significant variations in these relevant factors are likely to occur between different locations…

A Contribution Concerning the Unsettled Problem of Intrasplenic Microcirculation

From morphological studies it is well known that the vascular bed of the spleen consists of at least two different compartments. Figure one schematically shows how the splenic microcirculation can be subdivided. One compartment corresponds to the white pulp (pathways number 1 and 2), the other compartment to the red pulp, for which the existance of either an open or a closed type of terminal vascular bed is discussed. Futhermore there are references that the microcirculation in the red pulp is not homogeneous but composed of both types, as illustrated by the pathways marked by number 3 and 4.

Stoff- und Flüssigkeitstransport

Die Funktionen der Zellen und Gewebe — Stoffwechsel, Reproduktion, Wachstum, Regeneration, Sekretion, Resorption, Kontraktion und Erregbarkeit — erfordern einen standigen Transport von Stoffen und Flussigkeiten innerhalb des Organismus. Sauerstoff und Nahrstoffe mussen laufend den Zellen zugefuhrt, Kohlendioxid und andere Stoffwechselendprodukte an die Umgebung abgegeben werden. Voraussetzung fur den kontrollierten Ablauf der Stoffwechsel- und Erregungsprozesse sind ferner Konzentrationsgradienten bestimmter Ionen zwischen Intra- und Extrazellularraum. In Abhangigkeit von der Flussigkeitsaufnahme und -ausscheidung vollzieht sich schlieslich der Flussigkeitstransport im Organismus in enger K…

Physiological Effects of Hyperthermia

Hyperthermia as a modality for the treatment of malignant tumors, either alone or in combination with radiation or anticancer drugs, is rapidly becoming a clinical reality. Three different mechanisms of action have provided the rationale for considering the use of hyperthermia as an antitumor agent. At moderate hyperthermia (T=40˚ -42.5˚ C), heat can increase cell killing in a synergistic way following exposure of a tumor to ionizing radiation. This radiosensitization is probably based on, among other things, the inhibited repair of radiation-induced DNA lesions. Elevated tissue temperatures at 40˚ -42.5˚ C also sensitize tumor cells to certain chemotherapeutic drugs, particularly to alkyla…

Intensified oxidative and nitrosative stress following combined ALA-based photodynamic therapy and local hyperthermia in rat tumors.

Oxidative stress-related changes in tumors upon localized hyperthermia (HT), 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) and their combination (ALA+HT) were examined after the observation that the antitumor effects of ALA-PDT could be significantly enhanced upon simultaneous application of HT. Rats bearing s.c. DS-sarcomas (0.6–1.0 ml) on the hind foot dorsum were anesthetized and underwent one of the following treatments: (i) ALA-PDT (375 mg/kg 5-ALA i.v.); (ii) localized HT, 43°C for 60 min; (iii) combined ALA-PDT and HT [=ALA+HT]. Appropriate control experiments were also performed. After treatment, tumors were excised and rapidly frozen for later analysis of nitrosative s…

Pathophysiological approaches to identifying tumor hypoxia in patients

The present report summarizes observations of the authors on tumor oxygenation and on techniques for characterizing tumor hypoxia in patients. Cryospectrophotometric measurements of HbO2 saturations in tumor microvessels allow for estimates of the proportion of well oxygenated tissue regions. Labeling of tissue areas at oxygen (O2) tensions (pO2) less than 10 mm Hg with misonidazole may be used for a general characterization of the oxygenation status in patient tumors rather than for the determination of the radiobiologically hypoxic cell fraction. Quantitative bioluminescence and single photon imaging make it possible to determine ATP concentrations in absolute terms with a spatial resolut…

Tumor Oxygenation and Its Relevance to Tumor Physiology and Treatment

For many years, the identification of tumor hypoxia, its systematic characterization and the assessment of its clinical relevance were not possible due to lack of methods suitable for the routine measurement of intratumoral oxygen tensions in patients. In the late 1980s, a novel and clinically applicable standardized procedure was established enabling the determination of the tissue oxygenation status in primary tumors, local recurrences, and metastatic lesions in patients using a computerized polarographic needle electrode system. Within a relatively short period of time, the significance of tumor oxygenation for therapy outcome became evident in numerous experimental and clinical studies.

Hypoxyradiotherapy: lack of experimental evidence for a preferential radioprotective effect on normal versus tumor tissue as shown by direct oxygenation measurements in experimental sarcomas

Abstract Aim : In order to investigate possible pathophysiological mechanisms underlying the postulated preferential protective effect of hypoxia on normal tissue during radiotherapy, the impact of acute respiratory hypoxia (8.2% O 2 + 91.8% N 2 ) on tissue oxygenation was assessed. Methods : Tumor and normal tissue oxygenation was directly determined using O 2 -sensitive electrodes in two experimental rat tumors (DS and Yoshida sarcomas) and in the normal subcutis of the hind foot dorsum. Results : During respiratory hypoxia, arterial blood O 2 tension (pO 2 ), oxyhemoglobin saturation and mean arterial blood pressure decreased. Changes in the arterial blood gas status were accompanied by …

Blood flow and oxygenation status of human tumors. Clinical investigations.

There is a large body of evidence suggesting that blood flow and oxygenation of human tumors are important research topics which may explain, in particular, resistance to radiation and to many antineoplastic drugs, which can limit the curability of solid tumors by radiotherapy and chemotherapy.This manuscript reviews the clinical investigations which have been performed regarding blood flow and oxygenation status of human tumors in radiation oncology.The possible uses and limitations of the prognostic significance and the changes under therapy measuring blood flow and oxygenation in human tumors were discussed. In addition, several approaches were summarized, which can improve the microvasc…

Role of the tumor microenvironment in the activity and expression of the p-glycoprotein in human colon carcinoma cells.

The metabolic microenvironment of solid tumors is characterized by an oxygen deficiency and increased anaerobic glycolysis leading to extracellular acidosis and ATP depletion, which in turn may affect other energy-dependent cellular pathways. Since many tumors overexpress active drug transporters (e.g. the p-glycoprotein) leading to a multidrug-resistant phenotype, this study analyzes the impact of the different aspects of the extracellular microenvironment (hypoxia and acidosis) on the activity and expression of the p-glycoprotein (pGP) in the human colon carcinoma cell line LS513. For up to 24 h cells were exposed to hypoxia (pO2<0.5 mmHg), an acidic extracellular environment (pH 6.6), or…

HETEROGENEOUS OXYGEN TRANSPORT WITHIN MALIGNANT TUMORS

Publisher Summary This chapter discusses the heterogeneous oxygen transport within malignant tumors. Many solid tumors disturbances in the vascularization and in the microcirculation generally lead to distinct restrictions in the convective and diffusive transport. Beyond that, a heterogeneous distribution of the transport conditions develops causing an insufficient and heterogeneous substrate supply as well as an inadequate drainage of wastes. As one of the compulsory manifestations, a poor and heterogeneous oxygen supply becomes more extensively evident with increasing tumor size or age. The polarographic measurements of the local tissue pO 2 values in animal tumors show that very low oxy…

Oxygen Transport in Tumors

Experimental evidence suggests that the hypoxic fraction in solid tumors may influence its growth, may increase its malignant potential, and may reduce its sensitivity towards non-surgical treatment modalities (e.g., standard irradiation, certain anticancer drugs). The role of the tumor O2 status in radio-/chemotherapy and its impact on relevant tumor biological characteristics of tumors are summarized in Table 1.

Funktionen des Magen-Darm-Trakts

Herr U.K. leidet unter Arteriosklerose und hat bereits einen Herzinfarkt erlitten. Der Hausarzt verschreibt ihm daher den Prostaglandinsyntheseblocker Aspirin zur Hemmung der Thrombozytenaggregation. Einige Wochen spater fallt U.K. auf, dass sein Stuhl schwarz ist, sieht jedoch deswegen keinen Handlungsbedarf. Wenige Tage spater findet ihn seine vom Einkaufen zuruckkehrende Frau ohnmachtig am Boden liegend und ruft umgehend den Notarzt. Dieser kann jedoch nur noch den Tod feststellen. Die Obduktion deckt als Ursache eine Magenblutung auf. Die Hemmung der Prostaglandinsynthese hat einen wichtigen Schutzmechanismus der Magenschleimhaut unterbunden. Die aggressive Salzsaure des Magens hat dahe…

Verapamil Inhibits the Respiration Rate of Cancer Cells

Calcium antagonists have successfully been used in the treatment of hypertension, cardiac arrhythmias and coronary heart disease. Recent evidence has suggested that such agents may also play a role in the treatment of malignant tumors. Verapamil, a calcium entry blocker, has been reported to enhance the cytotoxicity of several anticancer drugs under in vitro- and in vivo-conditions [1–10]. The effects observed could be explained by an enhanced drug accumulation due to a Verapamil-induced inhibition of the drug efflux from the cancer cells.

O2 Supply Conditions in Tumor Tissue in Vivo

During the last few years O2 supply of tumor tissue has very carefully been investigated using GULLINO’ s model of a “tissue isolated” implantation tumor (GULLINO and GRANTHAM, 1961; GUNTHER et al., 1972; VAUPEL et al., 1971; VAUPEL, 1974). We analysed the O2 supply for a DS-Carcinosarcoma in the rat kidney by two methods: 1. direct measurement of O2 pressures in the tissue by means of gold micro-electrodes, 2. PO2 calculation according to diffusion laws considerring the experimentally determined parameters in the arterial and venous blood.

Abnormal Microvasculature and Defective Microcirculatory Function in Solid Tumors

Oxygenation of Mammary Tumors: From Isotransplanted Rodent Tumors to Primary Malignancies in Patients*

The role of oxygen in tumor cell proliferation, radiosensitivity, cytotoxicity of anticancer drugs and hyperthermia treatment has been the subject of a series of investigations (for reviews see Hall, 1988; Teicher et al., 1990, Vaupel et al., 1989a; Vaupel, 1990a,b). Despite the apparent importance of tumor oxygenation, data on pO2 values in solid tumors are mostly derived from experiments on rodents which might not necessarily reflect the variability of the clinical situation. Due to feasible techniques available now, considerable advances have been made in the past few years in the assessment of tumor hypoxia in patients (for reviews see Vaupel et al., 1989a; Vaupel, 1990a). The latter in…

Einflu� einer Hyperglyk�mie auf die Sauerstoff- und Glucoseaufnahme von Implantationstumoren (DS-Carcinosarkom) in vivo

Um den Einflus erhohter arterieller Glucosekonzentrationen auf die Glucose- und Sauerstoffaufnahme von Tumorgewebe unter in vivo-Bedingungen zu bestimmen, wurden Untersuchungen an gewebsisolierten Implantationstumoren von Ratten (DS-Carcinosarkom) durchgefuhrt.

Human Mammary Carcinomas in Nude Rats — A New Approach for Investigating Oxygen Transport and Substrate Utilization in Tumor Tissues

An understanding of tumor pathophysiology with respect to blood flow, oxygenation status, pH distribution and utilization of the relevant substrates which, all together, critically influence growth kinetics and the efficiency of nonsurgical therapeutic modalities in vivo requires information derived directly from human malignant tissues. At present, only inadequate knowledge of the relevant physiological factors in tumor tissues of patients are accessible. The little data available to date were obtained from clinical observations rather than from systematic studies, i.e., data were collected from various tumor types with differing staging and grading. For this reason generally valid stateme…

Intracellular acidosis in murine fibrosarcomas coincides with ATP depletion, hypoxia, and high levels of lactate and total Pi

Bioenergetic and metabolic status of murine FSaII tumours were evaluated using 31P MRS, acid extracts ('global' techniques) and quantitative bioluminescence ('microregional' assay). Data obtained from s.c. tumours of varying sizes (44-600 mm3) have been correlated with the oxygenation status evaluated using O2-sensitive needle electrodes. beta-NTP/Pi and phosphocreatine (PCr)/Pi ratios derived from 31P MRS were positively correlated to the median tissue pO2 values. pH declined during growth with intracellular acidosis being evident in tumours > 350 mm3. Whereas lactic acid formation greatly contributed to this decline in small- and medium-sized tumours, ATP hydrolysis and slowing down of th…

Vascularization, Blood Flow, Oxygenation, Tissue pH, and Bioenergetic Status of Human Breast Cancer

Many solid tumors are relatively resistant to conventional irradiation, chemotherapy and other non-surgical treatment modalities. A variety of factors are involved in the lack of responsiveness of these neoplasms, including (a) an intrinsic, genetically determined resistance and (b) physiological properties primarily created by inadequate and non-uniform vascular networks. Physiological factors which are usually closely linked encompass microcirculatory parameters (including transvascular and interstitial transport), tissue oxygen and nutrient supply, tumor pH and bioenergetic status. Despite the important role of physiological properties for tumor growth and metastasis, for early tumor res…

Blood Flow and Oxygen Supply to Human Mammary Carcinomas Transplanted into Nude Rats

Tumor blood flow (TBF), by itself, greatly influences the efficiency of nonsurgical therapeutic modalities, especially chemotherapy and hyperthermia. Furthermore, TBF is one of the most important determinants of tumor tissue oxygenation in vivo, thus playing a relevant role in tumor growth kinetics and in the development of regressive changes. In addition, the oxygenation of tumor tissue strongly determines the efficiency of radiation therapy and to a certain extent, pharmacodynamics of some antiproliferative drugs. Despite the considerable information available for rodent tumor systems, there are only sporadic ireports on blood flow (Beaney et al., 1984, Johnson, 1976, Mantyla, 1979, Manty…

Nifedipine improves blood flow and oxygen supply, but not steady-state oxygenation of tumours in perfusion pressure-controlled isolated limb perfusion.

Isolated limb perfusion allows the direct application of therapeutic agents to a tumour-bearing extremity. The present study investigated whether the dihydropyridine-type Ca2+-channel blocker nifedipine could improve blood flow and oxygenation status of experimental tumours during isolated limb perfusion. Perfusion was performed by cannulation of the femoral artery and vein in rats bearing DS-sarcoma on the hind foot dorsum. Perfusion rate was adjusted to maintain a perfusion pressure of 100–140 mmHg throughout the experiment. Following equilibration, nifedipine was continuously infused for 30 min (8.3 μg min−1 kg−1 BW). During constant-pressure isolated limb perfusion, nifedipine can signi…

Heterogeneous Oxygenation of Rectal Carcinomas in Humans: A Critical Parameter for Preoperative Irradiation?

The surgical treatment of rectal carcinoma in humans is often combined with irradiation. However, the efficacy of this latter treatment modality is crucially influenced by the oxygenation status of the tumor tissue to be treated. Therefore, the knowledge of the O2 supply to the tumor tissue is a decisive prerequisite for the assessment of the efficiency of radiotherapy.

Modulation of tumor oxygenation

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 deliver…

Blood Flow and Oxygenation Status of Head and Neck Carcinomas

Solid tumors contain a significant fraction of microregions which are chronically or transiently hypoxic. Experimental evidence is growing, showing that hypoxia may have a profound impact on malignant progression and on responsiveness to therapy [1–4].The clinical relevance of tumor oxygenation in human solid malignancies is under investigation (for a recent review see [5]). In this presentation, relevant clinical findings available to date on blood and oxygen supply of human head and neck carcinomas will be reviewed and emphasis will be given to the relevance of these factors in clinical oncology.

Funktion des Gastrointestinaltrakts

Die Hauptaufgabe des Gastrointestinaltrakts besteht in der Uberfuhrung der Nahrung in resorbierbare Bestandteile und in deren Aufnahme in den Korperkreislauf. Der erstgenannte Teilprozes, die Verdauung, wird durch mechanische Vorgange, durch Zerkleinerung, Transport und Durchmischung eingeleitet. In engem Zusammenhang damit erfolgt die Sekretion von Verdauungssaften. Die Einwirkung der Enzyme, die in den Verdauungssaften enthalten bzw. auf der inneren Darmwand lokalisiert sind, fuhrt dann zur hydrolytischen Spaltung der Eiweise, Kohlenhydrate und Fette. Im zweiten Teilprozes, der Resorption, werden die Endprodukte der Verdauung ebenso wie Wasser, Mineralstoffe und Vitamine aus dem Darmlumen…

Oxygenation and Bioenergetic Status of Murine Fibrosarcomas

The heterogeneity of cellular response to therapy is a major problem in non-surgical cancer therapy. This heterogeneity is influenced by both the genetic variability between different tumor cells and by epigenetic, physiological factors, such as the local metabolic milieu. A restriction of tumor microcirculation concomitant with regional hypoxia, nutrient depletion, accumulation of lactate, and an intensified tumor acidosis becomes evident during growth of many solid tumors1. These critical factors can greatly influence the efficiency of various non-surgical tumor therapies.

Blood Flow and Tissue Oxygenation of Human Tumors: An Update

It is generally accepted that tumor microcirculation, blood flow, oxygen and nutrient supply, tissue pH distribution, and the bioenergetic status (factors which are usually closely linked and which define the so-called cellular microenvironment) can markedly influence the therapeutic response of malignant tumors. Tumor blood flow is the major determinant for intra-tumor pharmacokinetics and (through modulation of the cellular microenvironment) of pharmacody-namics. The oxygen supply greatly determines the radiosensitivity of the tumors to be treated. The oxygen enhancement ratio, i.e., the ratio of doses with and without oxygen to produce the same biological effect is 2.7 to 3.0. O2 partial…

Intratumoral PO2 Histography as Predictive Assay in Advanced Cancer of the Uterine Cervix

Experimental evidence suggests that the hypoxic fraction in a solid tumor may increase its malignant potential and reduce its sensitivity towards nonsurgical treatment modalities such as standard irradiation and certain anticancer agents1–5. However, the clinical importance of tumor hypoxia remains uncertain since valid methods for the routine measurement of intratumoral O2-tensions in patients have so far been lacking.

Tumor hypoxia in pelvic recurrences of cervical cancer.

We have previously demonstrated in primary cancer of the uterine cervix that tumor hypoxia, as determined polarographically, is strongly associated with clinical malignant progression of the disease. Having applied a similar methodological approach to investigate loco-regional relapses, we found a pronounced shift to more hypoxic oxygenation profiles in the recurrent tumors than in the primary tumors. Median pO2 values in 53 pelvic recurrences were significantly lower than the median pO2 values of 117 primary tumors of comparable sizes (7.1 +/- 1.1 mmHg vs. 12.1 +/- 1.0 mmHg, p = 0.0013). The differences in tumor oxygenation between primary and recurrent tumors mirrored the differences in t…

GLUT-1 staining of squamous cell carcinomas of the uterine cervix identifies a novel element of invasion.

Perturbation of the normal tissue architecture in solid malignant tumors is perceived to be the consequence of actively migrating cancer cells which invade the adjacent normal host tissue. The opposite, invasion of cancer cell clusters by a vascularized stroma, has not been considered. The latter process should, however, be expected to occur since the hypoxic cores of tumor cell aggregates, under the control of HIF-1, are known to secrete cytokines (e.g., bFGF, VEGF) which attract fibroblasts and induce blood vessel formation. In this study, the expression of glucose transporter (GLUT)-1, a major HIF-1 target gene, was examined in 51 squamous cell carcinomas of the uterine cervix by immunoh…

Microcirculatory Function, Tissue Oxygenation, Microregional Redox Status and ATP Distribution in Tumors Upon Localized Infrared-A-Hyperthermia at 42°C

Since local hyperthermia (HT) affects microenvironmental parameters, the aim of the study was to analyze the impact of 42°C-HT on microcirculatory function, tumor pO2, microregional redox status and ATP distribution in experimental rat tumors. Subcutaneously growing DS-sarcomas were treated with localized HT using infrared-A radiation resulting in a mean tumor temperature of 42°C. The relative red blood cell (RBC) flux in the tumor was assessed using the laser Doppler technique and the mean tumor pO2 measured continuously using O2-sensitive catheter electrodes. In a second series of experiments, the microregional distribution of the mitochondrial redox status and ATP concentration was measu…

Evidence for and Against Hypoxia as the Primary Cause of Tumor Aggressiveness

In clinical trials, tumor hypoxia has consistently been associated with tumor aggressiveness. The evidence for an association between hypoxia and metastasis and more rapid tumor progression and death is seen in uterine cervical cancer, and sarcoma of soft tissue. Evidence is building in prostate, vulva, head and neck, and breast cancers. A major question is whether hypoxia precedes tumor aggressiveness or whether aggressive tumors incidentally are also hypoxic.

Oxygenation of malignant tumors after localized microwave hyperthermia

The oxyhemoglobin saturation (HbO2) of single red blood cells within tumor microvessels (diameter: 3-12 micrometers) of DS-Carcinosarcoma was studied using a cryophotometric micromethod. In untreated control tumors (mean tissue temperature approx. 35 degrees C) the measured values scattered over the whole saturation range from zero to 100 sat. %, the mean being 51 sat. %. Upon heating at 40 degrees C for 30 min, the oxygenation of the tumor tissue significantly improved as compared with control conditions. After 40 degrees C-hyperthermia a mean oxyhemoglobin saturation of 66 sat. % was obtained. In contradistinction to this, after 43 degrees C-hyperthermia the tumor oxygenation was signific…

Pathophysiological and vascular characteristics of tumours and their importance for hyperthermia: Heterogeneity is the key issue

Tumour blood flow before and during clinically relevant mild hyperthermia exhibits pronounced heterogeneity. Flow changes upon heating are not predictable and are both spatially and temporally highly variable. Flow increases may result in improved heat dissipation to the extent that therapeutically relevant tissue temperatures may not be achieved. This holds especially true for tumours or tumour regions in which flow rates are substantially higher than in the surrounding normal tissues. Changes in tumour oxygenation tend to reflect alterations in blood flow upon hyperthermia. An initial improvement in the oxygenation status, followed by a return to baseline levels (or even a drop to below b…

Relationship Between Size and Oxygenation Status of Malignant Tumors

During advanced phases of malignant growth, there are typical changes in the microvasculature pattern within the tissue of many solid tumors. Partly due to these peculiarities of tumor vascularization, a series of characteristic variations of tumor microcirculation occurs (for a review see 1). These alterations lead not only to marked restrictions and inhomogeneities of both convective and diffusive transport but also to an impairment of the efficiency of antitumor therapies.

Einfluß der Durchblutung auf den Atemgas- und Glucosestoffwechsel von Implantationstumoren (DS-Carcinosarkom)

Durchblutung, Sauerstoff- und Glucosestoffwechsel von Tumoren sind klinisch und pathophysiologisch von Interesse. Die Grose der Tumordurchblutung hat zum einen eine pharmakologische Bedeutung, da Cytostatika in schlecht durchbluteten Tumorarealen wahrscheinlich keine therapeutisch wirksamen Konzentrationen erreichen konnen. Zum anderen wurde von radiologischer Seite (Atkins u. Mitarb., 1965; Cater u. Silver, 1960; Gray u. Mitarb., 1953; Howard-Flanders u. Scott, 1960) berichtet, das die Strahlenempfindlichkeit von Tumoren von der z. Z. der Bestrahlung im Gewebe gelosten Sauerstoffmenge abhangig ist. Letztlich bestimmen die Versorgungsbedingungen des Tumorgewebes dessen Energiestoffwechsel u…

Hypoxia and radiation response in human tumors

This study demonstrates by an updated analysis of an ongoing prospective study that tumor oxygenation, as measured with a validated standardized polarographic needle electrode method before treatment, powerfully predicts the prognosis of patients receiving radiotherapy for intermediate and advanced stage cancer of the uterine cervix. First evidence for a host component in tumor oxygenation based on a significant correlation between median pO 2 values determined in normal subcutaneous fatty tissue and in cervical cancer is also presented. Further investigations are necessary to clarify whether tumor hypoxia is just a marker of intrinsic tumor aggressiveness or whether the negative impact of …

Professor Dr. Dr. Gerhard Thews: A Lifetime’s Dedication to Research on Oxygen Transport to Tissue and Academic Teaching

As President of ISOTT 1992, and on behalf of the ISOTT Executive Committee I wish to dedicate the 20th ISOTT meeting and this volume of Advances in Experimental Medicine and Biology arising from it to Professor Gerhard Thews, as a sign of sincere gratitude for his outstanding contributions to the world of science in the area of oxygen transport to tissues. His innovative and productive work over the last 40 years has been documented in more than 200 scientific papers. These publications are distinguished by their ability to present sophisticated ideas in a simple and precise way. As a result, many of Professor Thews’ works are recognized both nationally and internationally as “classics” in …

Oxygen diffusivity in tumor tissue (DS-Carcinosarcoma) under temperature conditions within the range of 20?40�C

The O2 diffusion constants D and K of tumor tissue (DS-Carcinosarcoma in the rat kidney) were determined at temperatures of 20, 30, 37, and 40 degrees C. The following mean values were obtained for the conditions of 37 degrees C: D = 1.75-10(-5) cm2/s and K = 1.9-10(-5) mlO2/cm-min-atm. Within the range of 20-40 degrees C, temperature variations in tumor tissue cause changes in the O2 diffusion coefficient D of 2.0-2.5%/C and in the Krogh O2 diffusion constant K of 0.5-1.5%/C. The measured O2 diffusion constants for tumor tissue correspond to values of normal tissue with similar water content. This indicates that the insufficient O2 supply in DS-Carcinosarcoma is due not to unfavorable O2 d…

Effect of Localized Hyperthermia on Tumor Blood Flow and Oxygenation

Hyperthermia has been shown to have a lethal effect in tumor cell cultures, particularly at temperatures above 42°C.1 Moreover, it has been demonstrated that hyperthermia retards the growth rate of certain types of malignant tumors and can be effective in completely eradicating some tumors without any major damage to normal tissue.2,3,4 The differential response of solid tumors in vivo to heat treatment in comparison to normal tissue probably results from several factors. Among these the in vivo micro-environment seems to play a decisive role. In general, the interstitial milieu of solid tumors is characterized by tissue hypoxia and anoxia5,6 and by severe tissue acidosis.7 These unfavorabl…

Proposal for Using a Standardized Terminology on Oxygen Transport to Tissue

The aim of the present proposal is to recommend some definitions of important and frequently used terms in the field of oxygen transport to tissue. The latest glossary on this topic is dated 1973 and was published by the International Union of Physiological Sciences (J. Appl. Physiol. 34, 549 – 558, 1973). In the meantime, some of these definitions are either outdated or are used in another sense.

Experimentelle und theoretische Untersuchungen der intralienalen Mikrozirkulation beim Kaninchen

1. Bei 57 spontanatmenden Kaninchen wird in Ketaminnarkose mit Hilfe der85Kr(β)-Auswaschtechnik nach Stosinjektion des gelosten Indikators in die Aorta die regionale Milzdurchblutung gemessen. 2. Bei der normalen, unbeeinflusten Milzin situ besteht im Bereich von 65–125 mm Hg eine lineare Abhangigkeit der regionalen Milzdurchblutung vom arteriellen Mitteldruck (2p < 0,001). Bei einem mittleren Druck von 97 mm Hg betragt die mittlere Milzdurchblutung 1,23 ml/g/min. 3. Nach totaler Obstruktion der offenen Strombahn durch Applikation rigider Spharocyten ist die Durchblutung im gleichen Blutdruckbereich unabhangig vom arteriellen Mitteldruck. Nach Ausschaltung der offenen Strombahn betragt die …

TISSUE OXYGENATION AND NORMAL AND HYPERTHERMIC CONDITIONS

Publisher Summary This chapter describes the tissue oxygenation and normal and hyperthermic conditions. The knowledge of the effect of hyperthermia on tumor and normal tissue blood flow is important not only for the effect of hyperthermia on hypoxic cells at the time of radiation, but also for differential tumor heating. There is considerable evidence from plethsmography that an elevation of normal tissue temperature to 41°C is accompanied by a considerable increase in blood flow. The chapter discusses studies that were conducted to examine changes in the microenvironment of normal and tumor tissue as measured directly with ultramicroelectrodes. In situ studies were carried out in fourth ge…

The Effect of Nicotinamide on Microcirculatory Function, Tissue Oxygenation and Bioenergetic Status in Rat Tumors

The failure of many attempts to improve tumor oxygenation - and thus the outcome of standard radiotherapy - may be due to the fact that the occurrence of hypoxia in tumors is not solely a result of diffusion-limited “chronic” hypoxia but is also due to temporary flow cessations in microregional tumor perfusion which have been shown to occur in tumor tissue1. As a result, attempts have more recently been made to reduce hypoxia in tumors through the reduction of tumor perfusion fluctuations. The benzamide analog nicotinamide is an agent which has recently received attention in this respect. It has been reported to be an effective, tumor-specific radiosensitizer in several tumor models, an eff…

The physician-patient relationship before cancer treatment: a prospective longitudinal study.

Abstract Objectives . To evaluate quality of life before surgery for genital cancer to determine risk factors that might influence the physician–patient relationship. Methods . From 1993 until 2003, 129 women with cervical cancer entered this prospective study. Patients were contacted 1 to 5 days before surgery by a psychologist or psychotherapeutically trained physician on the surgical ward. The semistructured interview included questions on the patient's psychosocial well-being according to criteria of the biographic interview technique. The preoperative anxiety level was evaluated by the STAI and quality of life by the Cancer Rehabilitation Evaluation System (CARES) and EORTC questionnai…

Impact of Reactive Oxygen Species on the Expression of Adhesion Molecules in Vivo

Many non-surgical tumor treatments induce reactive oxygen species (ROS) which result in cell damage. This study investigated the impact of ROS induction on the expression of adhesion molecules and whether alpha-tocopherol pre-treatment could have a protective effect. Experimental rat DS-sarcomas were treated with a combination of localized 44 degrees C-hyperthermia, inspiratory hyperoxia and xanthine oxidase which together lead to a pronounced ROS induction. Further animals were pre-treated with alpha-tocopherol. The in vivo expression of E- and N-cadherin, alpha-catenin, integrins alpha v, beta 3 and beta 5 as well as of the integrin dimer alpha v beta 3 was assessed by flow cytometry. The…

Effect of Cell Line and Differentiation on the Oxygenation Status of Experimental Sarcomas

Since the measurement of tumor oxygenation status and the fraction of hypoxia within tumor tissue by computerized pO2-histography [10] has become increasingly im-portant in the clinical setting, many studies on tumor oxygenation in different experimental malignancies as well as in various human tumors have been carried out. Because pO2-histography is an invasive technique, this method has been used in humans mostly in superficial primary tumors and lymph node metastases [1,3,10] (for a review see [9]). Experimental studies in animals have been carried out on a wide range of isotransplanted rodent sarcomas or carcinomas [2,4,6–8,11] and of xenotransplanted human tumors [6]. The results obtai…

Can Tumor Oxygenation be Improved by Reducing Cellular Oxygen Consumption?

Tumor hypoxia, which can be found in many experimental and human tumors is an important factor influencing the therapeutic efficacy of standard radiotherapy, O2-dependent chemotherapy and photodynamic therapy (Hall, 1994) and might be responsible for the development of aggressive tumor cell subpopulations (Graeber et al., 1996). Since this oxygen deficiency results from a disparity between O2 supply to the tumor tissue and the oxygen demand of the cells, several attempts have been undertaken to improve tumor oxygenation primarily by increasing the arterial oxygen supply. The O2 supply to the tumor cells can be improved by (a) increasing the arterial O2 content (by breathing hyperoxic gases …

Measurement of Human Tumor Blood Flow: A Positron Technique Using an Artifact of High Energy Radiation Therapy

For at least three decades (1–6) there has been an interest in measuring tumor blood flow (TBF) and in the determination of its relation to the response of human tumors to radiation, drug therapies, and to the probability of development of distant metastases. The proton activation method which will be described below allows daily measurements of blood flow, in only 7 minutes, in patients being irradiated by photons of ≥20 MV, or by protons and other heavy particles.

Recombinant human erythropoietin increases the radiosensitivity of xenografted human tumours in anaemic nude mice

Purpose: The effect of recombinant human erythropoietin (Epo) on the radiosensitivity of human tumour xenografts growing in anaemic nude mice was studied. Methods and materials: Anaemia was induced by total body irradiation (TBI) of mice prior to tumour transplantation. The development of anaemia was prevented by Epo (1000 U/kg s.c.) given 3 times weekly starting 2 weeks prior to TBI (5 Gy). Epo treatment did not influence the growth rate of the tumours, which were transplanted into the subcutis of the hind leg of mice. Thirteen days after TBI (tumour volume of approx. 40 mm3), a single-dose irradiation (12 Gy) of the tumour was performed resulting in a growth delay with subsequent regrowth…

Tumor Oxygenation in Anemic Rats: Effects of Erythropoietin Treatment Versus Red Blood Cell Transfusion

Anemia was induced in rats by the development of a hemorrhagic ascites. These animals also bore solid tumors (DS-sarcomas) on the hind foot dorsum. The effects of two methods for anemia correction on oxygenation in the solid tumors were compared in this study. Anemia was corrected either chronically by erythropoietin administration (1000 IU/kg) over 14 days (EPO) or acutely by transfusion with red blood cells (TR). Non-anemic and untreated anemic animals served as controls. Tumor oxygenation was determined in anesthetized animals using polarographic needle electrodes and pO2 histography. The reduction in hematocrit and hemoglobin content found in anemic animals could successfully be correct…

How to Improve the Uterotomy Healing

Abstract Suboptimal uterotomy healing following cesarean delivery or metroplastic operations may lead to considerable complications. New insights in the biology of wound healing and the availability of a variety of biologic response modifiers open the possibility to modulate the process of wound healing in order to gain clinical benefits. Can uterotomy healing be improved by local application of biosubstances? We developed an uterotomy model in the rat and measured the bursting pressure at defined times postwounding as a functional parameter of wound healing. In addition, the healing process was assessed by serial light microscopic histology. Uterotomy healing was investigated in the presen…

Splenic blood flow and intrasplenic flow distribution in rats

In 75 rats, anesthetized with pentobarbital and breathing spontaneously, regional splenic blood flow (rSBF) was measured by means of the85Kr(β)-clearance technique after an intraaortic slug injection of the dissolved indicator. In the normal and undisturbed spleen in situ rSBF is linearly related to the mean arterial blood pressure (MABP) within the range of 30–140 mm Hg. Mean rSBF is 0.71 ml/g/min, the mean arterial blood pressure being 105 mm Hg. In normal rats rSBF decreases significantly with increasing body weight or age. After total obstruction of the open circulation by application of rigid spherocytes, mean rSBF is reduced to 0.26 ml/g/min and is independent of the mean arterial blo…

Tumor Hypoxia and Malignant Progression

Publisher Summary This chapter discusses tumor hypoxia and malignant progression. Hypoxic (or anoxic) areas arise as a result of an imbalance between the supply and the consumption of oxygen. Whereas in normal tissues or organs the O2 supply matches the metabolic requirements, in locally advanced solid tumors the O2 consumption rate of neoplastic as well as stromal cells may outweigh an insufficient oxygen supply and result in the development of tissue areas with very low O2 levels. Major pathogenetic mechanisms involved in the emergence of hypoxia in solid tumors are (a) severe structural and functional abnormalities of the tumor microvessels (b) a deterioration of the diffusion geometry, …

O2 extraction is a key parameter determining the oxygenation status of malignant tumors and normal tissues

The aim of this study was to assess pivotal factors determining the oxygenation status of malignant tumors, and, for comparison, of normal tissues. For this purpose, microvascular patterns, blood flow data, O2 consumption rates and O2 extractions were correlated to the median pO2 values of isografted rodent and xenografted human tumors, and of various normal tissues. No correlations were found between median pO2 values and vascular patterns, O2 consumption rate or blood flow rate. When O2 extraction, however, was considered (a comprehensive parameter which encompasses all of the above factors), a strong inverse correlation was found between this parameter and the median pO2 values, both for…

Cervical carcinoma: standard and pharmacokinetic analysis of time-intensity curves for assessment of tumor angiogenesis and patient survival

Since detailed knowledge regarding the pathophysiological properties—which in turn are responsible for differences in contrast enhancement—remain fairly undetermined, it was the aim of this study (i) to examine the association of standard and pharmacokinetic analysis of time-intensity curves in dynamic MRI with histomorphological markers of tumor angiogenesis (microvessel density [MVD]; vascular endothelial growth factor [VEGF]) and (ii) to determine the ultimate value of a histomorphological and a dynamic MRI approach by correlation of those data with disease outcome in patients with primary cancer of the uterine cervix. Pharmacokinetic parameters (amplitude A, exchange rate constantk 21) …

Localized hypothermia: impact on oxygenation, microregional perfusion, metabolic and bioenergetic status of subcutaneous rat tumours.

The effect of localized hypothermia on microcirculatory and metabolic parameters in s.c. DS sarcomas on the hind foot dorsum of Sprague-Dawley rats was investigated. Tumours were cooled by superfusion of the tumour surface with cooled saline solution to 25 degrees C or 15 degrees C. Control tumours remained at 35 degrees C. These temperatures were maintained for 30 min. In tumour oxygenation measurements, hypothermia at 25 degrees C and 15 degrees C caused progressive decreases in the size of the fraction of pO2 measurements between 0 and 2.5 mmHg together with a reduction in pO2 variability. No significant changes in median or mean pO2 or in the fraction of pO2 measurements between 0 and 5…

Induction of dormancy in hypoxic human papillomavirus-positive cancer cells

Oncogenic human papillomaviruses (HPVs) are closely linked to major human malignancies, including cervical and head and neck cancers. It is widely assumed that HPV-positive cancer cells are under selection pressure to continuously express the viral E6/E7 oncogenes, that their intracellular p53 levels are reconstituted on E6/E7 repression, and that E6/E7 inhibition phenotypically results in cellular senescence. Here we show that hypoxic conditions, as are often found in subregions of cervical and head and neck cancers, enable HPV-positive cancer cells to escape from these regulatory principles: E6/E7 is efficiently repressed, yet, p53 levels do not increase. Moreover, E6/E7 repression under …

Nicotinamide exerts different acute effects on microcirculatory function and tissue oxygenation in rat tumors

Abstract Purpose : Nicotinamide has been reported to preferentially radiosensitize tumor tissue, supposedly through a reduction in tumor hypoxia. This may occur as a result of nicotinamide-induced changes in tumor blood flow and therefore the present study was undertaken to evaluate the effect of nicotinamide on circulatory parameters in skeletal muscle and tumor tissue (subcutaneously-implanted DS-sarcomas) of the rat. Methods and Materials : Mean arterial blood pressure (measured in the common carotid artery using a pressure transducer) and red blood cell flux (as measured by laser Doppler flowmetry) were continuously monitored for 120 min following a single intraperitoneal application of…

Lack of Association Between Tumor Oxygenation and Cell Cycle Distribution or Proliferation Kinetics in Experimental Sarcomas

In tumor cells, pronounced hypoxia induces an arrest of cell cycle in the late G1phase1−3. Since hypoxia is a common phenomenon in experimental and human tumors the hypoxia-induced disturbance of the cell cycle may play a role in the reduced efficacy of non-surgical treatment modalities resulting in a reduced long-term prognosis and a higher rate of local recurrences in hypoxic tumors4,5. It has been shown that a cell cycle arrest reduces the efficacy of standard radiotherapy6,7 and may alter the cytotoxic effects of various chemotherapeutic agents such as cisplatin, alkylating agents, doxorubicin or taxols8−12 and of cytokines13. If tumor hypoxia plays a relevant role in affecting the cell…

Acute changes of systemic parameters in tumour-bearing rats, and of tumour glucose, lactate, and ATP levels upon local hyperthermia and/or hyperglycaemia

Arterial blood pressure and relevant parameters of the arterial blood (O2 and CO2 tensions, pH, haematocrit, serum electrolytes and osmolality) were determined in tumour-bearing rats upon local hyperthermia (HT) and/or hyperglycaemia (HG). Tumour heating was performed in a saline bath (44 degrees C) for 120 min; hyperglycaemia was induced by i.v. infusion of 40% glucose solution for 150 min [blood glucose levels: 35-40 mM during heating; total amount of glucose: 1.19 g/100 g body wt.; infusion rates: 0.31 ml (100 g body wt.)-1 min-1 for 2 min, 0.02 ml (100 g body wt.)-1 min-1 for 88 min, and 0.01 ml (100 g body wt.)-1 min-1 for 60 min]. Immediately after treatment, glucose, lactate and ATP …

Die Verteilung von Na+ und K+ unter dem Einflu� von Temperaturgradienten

Der Ludwig-Soret-Effekt besagt, das Temperaturgradienten eine Verteilungsanderung von gelosten Teilchen bewirken. In Modellversuchen wird gepruft, wie sich dieser Effekt auf die Verteilung von Na+ und K+ auswirkt. Die Versuchsanordnung besteht aus einer Meszelle, deren Ruckwand aus isoliertem Kupfer und deren Vorderwand aus verschieden dicken Cellulosehydrat-Membranen (Dicke im getrockneten Zustand: 1–120 μm) bestehen. Die Kupferplatten konnen auf wahlweise einstellbaren Temperaturen gehalten werden. Die Tiefe der Meszelle ist variierbar (60–500 μm). Die Meszelle taucht in eine thermostatisierte Losung von NaCl und KCl (je 50 mVal/l) ein. Die Kationenkonzentrationen in Meszellen- und Ausenl…

Erythropoietin: effects on life expectancy in patients with cancer-related anaemia

ABSTRACTAnaemia is common in patients with cancer and has a detrimental impact on the quality of life. Anaemia has also been shown to reduce survival in patients with cancer. Tumour hypoxia resulting from the reduced oxygen carrying capacity of the blood in anaemic patients has been hypothesised to be a major contributor to this reduced survival. Several studies have shown that tumour hypoxia reduces the effectiveness of anticancer therapies including standard radiotherapy and some types of chemotherapy, and is associated with tumour progression. Moreover, preclinical data have demonstrated that erythropoietic protein therapy may delay tumour progression by improving tumour oxygenation. Mos…

Experimental evidence for a hyperthermia-induced breakdown of tumor blood flow during normoglycemia

A compilation of experimental data is presented indicating that hyperthermia alone can achieve a significant inhibition of tumor blood flow if appropriate heat exposure times and tissue hyperthermia levels are chosen.

Quantitative changes of metabolic and bioenergetic parameters in experimental tumors during fractionated irradiation.

Abstract Purpose: Previous studies with rat rhabdomyosarcomas indicate that during fractionated irradiation profound alterations of the tumor microvasculature and the oxygenation status occur when the total dose exceeds 45 Gy. At this dose a destruction which included all structures of the vessels and a significant worsening in tumor oxygenation were found. The aim of the present study was to analyze whether these effects of fractionated irradiation on the microvasculature and on tumor oxygenation also induce changes in the bioenergetic and metabolic status in the tumors during radiation treatment. Methods and Materials: R1H rhabdomyosarcomas of the rat implanted into the flank were irradia…

Vascularity, perfusion rate and local tissue oxygenation of tumors derived from ras-transformed fibroblasts.

Tumors derived from ras-transformed rat fibroblasts were investigated in order to gain insight into possible interrelationships between oncogenic transformations and therapeutically relevant parameters of the metabolic micromilieu of solid tumors in vivo. Tumors grew in nude mice after injection of in vitro-passaged cells. Growth rates, early stages of angiogenesis, perfusion and tissue oxygenation were assessed. Compared with the parental cell line, both ras transformants grew very rapidly and exhibited an early onset of angiogenesis. Perfusion rates of one ras-transformed tumor line were similar to those of the parental tumors whereas reduced flow values were detected in tumors of the oth…

Hypoxia in Breast Cancer: Pathogenesis, Characterization and Biological/Therapeutic Implications

Nearly 50% of locally advanced breast cancers exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumour mass. Hypoxia is predominantly caused by structural and functional abnormalities of the newly formed tumour vessels arising from neovascularization, by a disturbed microcirculation, by enlarged diffusion distances, and by tumour-associated or therapy-induced anaemia. The extent of pretherapeutically measured hypoxic tissue areas is independent of clinical tumour size and stage, and histological type and grade. Anaemia can substantially worsen tumour O2 depletion. Hypoxia is known to directly or indirectly confer resistance to irradiation and some ch…

Blut und Abwehrfunktionen

Blut stellt aus funktioneller Sicht ein „flussiges Korpergewebe“ dar. Es besteht aus Zellen, die in einer elektrolyt- und eiweishaltigen Losung, dem Plasma, suspendiert sind. Das Blut, dessen Zusammensetzung und Volumen normalerweise nur geringen Schwankungen unterliegen, dient vor allem als Transportmittel innerhalb des Organismus. Daneben ist es an der Aufrechterhaltung eines konstanten inneren Milieus (Homoostase) und an der Abwehr eingedrungener Fremdstoffe und Krankheitserreger beteiligt.

Effect of percentual water content in tissues and liquids on the diffusion coefficients of O2, CO2, N2, and H2.

Hot Topic Water-filtered infrared-A radiation: a novel technique for localized hyperthermia in combination with bacteriochlorophyll-based photodynamic therapy

A novel application of an infrared-A (IR-A) radiation source equipped with a water-filter in the radiation path is described, which allows for tumour treatment with a simultaneous combination of localized hyperthermia (HT) and bacteriochlorophyll-serine (Bchl-ser) based photodynamic therapy (PDT). Using this system, the IR-A radiation was used to heat tumours to 43 degrees C for 60 min, while at the same time activating the Bchl-ser which was injected i.v. at a dose of 20 mg/kg, 10 min following commencement of HT. The growth of tumours undergoing this combined therapy was compared to that of tumours undergoing HT alone or sham-treated controls. Within the 90 day observation period, 100% of…

Pathophysiological Aspects of Glucose Uptake by the Tumor Tissue under Various Conditions of Oxygen and Glucose Supply

Earlier examinations of the glucose uptake in neoplastic tissue by isolated DS- Carcinosarcoma implanted into the rat kidney had the results as follows (VAUPEL, 1974): 1. An increase of the tumor mass from 3 to 13 g wet weight caused an exponential decrease of the glucose consumption by the tumor tissue from 44.4 to 6.7/umoles per 100 g/min; very young tumors of 3 – 4 g bad uptake rates from 27.8 to 44.4/umoles/100 g/min. 2. Simultaneous measurements of the mean actual glucose concentrations in the tumor tissue showed that in the very young tumors the concentration still ranged from 1.75 to 2.25/umoles/g wet weight, whereas those in old tumors drop as low as 0 to 0.17/umoles/g.