Der Einfluß erhöhter arterieller CO2-Drucke auf die Sauerstoff- und Glucoseaufnahme des DS-Carcinosarkoms in vivo

An 14 Impftumoren (DS-Carcinosarkom) in Rattennieren wurde der Einflus erhohter arterieller CO2-Partialdrucke () auf die Durchblutung sowie die Glucose- und Sauerstoffaufnahme des Tumorgewebes untersucht.

Metabolic Imaging in Microregions of Tumors and Normal Tissues With Bioluminescence and Photon Counting

A method has been developed for metabolic imaging on a microscopic level in tumors, tumor spheroids, and normal tissues. The technique makes it possible to determine the spatial distribution of glucose, lactate, and ATP in absolute terms at similar locations within tissues or cell aggregates. The substrate distributions are registered in serial cryostat sections from tissue cryobiopsies or from frozen spheroids with the use of bioluminescence reactions. The light emission is measured directly by a special imaging photon counting system enabling on-line image analysis. The technique has been applied to human breast cancer xenografts, to spheroids originating from a human colon adenocarcinoma…

Response of tumour red blood cell flux to hyperthermia and/or hyperglycaemia.

Laser Doppler flowmetry has been applied to subepidermal rat tumours during localized ultrasound hyperthermia and/or moderate, short-term hyperglycaemia. Blood glucose levels were elevated 4-fold by continuous i.v. infusion of D-glucose (4.8 g/kg/60 min). To determine whether the effects of hyperglycaemia on tumour blood flow involved increased rates of glycolysis and lactic acid production, galactose, a sugar not metabolized by the tumour, was administered using the same dose schedule. Hyperglycaemia was accompanied by a 3-fold increase in blood lactate levels and a slight hypervolaemic haemodilution without any significant systematic changes of the arterial blood pressure or respiratory b…

OXYGENATION AND BIOENERGETIC STATUS OF HUMAN TUMORS

Abstract of the 68th Meeting (Spring Meeting) 6–9 March 1990, Heidelberg

Pathophysiological aspects of hyperthermia

Blood flow in many rapidly growing tumors is sluggish leading to an impairment of convective heat dissipation which facilitates tumor heating compared to normal tissues. In addition, the compromised microcirculation causes a hostile metabolic micromilieu which can modulate the therapeutic effect of heat. After clinically relevant heat doses, a shut-down of tumor microcirculation is often observed creating a “heat-reservoir” and aggravating tumor hypoxia, acidosis, and substrate and energy depletion, factors which are known to greatly enhance tumor cell killing by heat. Since the mechanisms described are mostly derived from experimental results on fast-growing animal tumors, the clinical rel…

Hypoxie beim Zervixkarzinom: Pathogenese, Charakterisierung und biologische/klinische Konsequenzen 1

Approximately 60% of locally advanced carcinomas of the uterine cervix exhibit hypoxic and/or anoxic tissue areas which are heterogeneously distributed within the tumor mass. Hypoxia is caused by structural and functional abnormalities of the newly formed tumor vessels arising from neovascularization, by a disturbed microcirculation, enlarged diffusion distances and by tumor- or therapy-associated anemia. The extent of pretherapeutically measured hypoxic tissue areas is independent of clinical size, FIGO stage and histopathological grade of squamous cell carcinomas of the uterine cervix. Anemia can intensify tumor hypoxia. O2-tensions in local recurrences are even lower than those in the pr…

Validit�t der pH-Messung mit der Mikro-pH-Einstabme�kette in Blut und anderen biologischen Fl�ssigkeiten

Die pH-Messung im Blut oder in eiweisbzw. polypeptidhaltigen Medien mit Mikro-pH-Einstabmesketten Type N 58 (Fa. Schott & Gen., Mainz) ergibt im pH-Bereich zwischen 5,3 und 8,3 einen systematischen Mesfehler, der durch die Regressionsgerade y=1,135 x−0,842 dargestellt wird. Die Abweichung vom tatsachlichen pH-Wert ist unabhangig von der Eiweiskonzentration und betragt 0,1–0,2 pH-Einheiten im physiologisch relevanten Bereich. Der Mesfehler tritt bei pH-Messungen in eiweisbzw. polypeptidfreien Medien nicht auf und wird durch einen Austausch der Elektrolytlosung in der Referenzelektrode (NaCl-Losung anstelle KCl-Losung) deutlich beeinflust. Die Ursache durfte daher in einer Anderung der Diffus…

Pyruvate kinase type M2: a crossroad in the tumor metabolome.

Cell proliferation is a process that consumes large amounts of energy. A reduction in the nutrient supply can lead to cell death by ATP depletion, if cell proliferation is not limited. A key sensor for this regulation is the glycolytic enzyme pyruvate kinase, which determines whether glucose carbons are channelled to synthetic processes or used for glycolytic energy production. In unicellular organisms pyruvate kinase is regulated by ATP, ADP and AMP, by ribose 5-P, the precursor of the nucleic acid synthesis, and by the glycolytic intermediate fructose 1,6-P2 (FBP), thereby adapting cell proliferation to nutrient supply. The mammalian pyruvate kinase isoenzyme type M2 (M2-PK) displays the …

Durchblutung und Sauerstoffverbrauch gewebsisolierter Impftumoren (DS-Carcinosarkom) in vivo

Nach einer von Gullino u. Grantham (1961) angegebenen Methode wurden DS-Carcino-Sarkomzellen in Rattennieren verimpft und gewebsisoliert gezuchtet. Nach im Mittel 11 Tagen hat der infiltrierend und destruierend wachsende Tumor das Nierengewebe meist vollig ersetzt und steht mit dem Wirtstier nur uber eine Arterie und eine Vene in Verbindung. Die Tumordurchblutungsmessungen erfolgten nach Kanulierung der Tumorvene druckkonstant mit Hilfe eines Rollenpumpen-Windkessel-Systems uber eine Mescapillare. Gleichzeitig konnten Mikroblutproben unter Luftabschlus aus Tumorvene und Aorta entnommen und pH, O2-Druck, CO2-Druck, Hb-Konzentration und Hamatokrit bestimmt werden. Aus der errechneten arterio-…

Blood flow and metabolic microenvironment of brain tumors

Summarizing thesein vivo data in the context of brain tumor therapy, the following aspects are of particular importance: Low and heterogeneous tumor blood flow may — in addition to the limiting effects of the blood-brain barrier — result in compromised delivery of drugs from blood to the tissue. Low tumor pO2 reduces sensitivity to standard radiation and ‘O2-dependent’ anticancer drugs. Treatment efficacy may be further altered by changes of tumor pH. Particularly acidosis can decrease radiation sensitivity and modulate the cytotoxicity of anticancer drugs. In the following presentations, these aspects will be discussed regardingin vivo data obtained with positron emission tomography.

Lactate-induced inhibition of tumor cell proliferation.

Abstract Culture medium that was recovered from tumor cell or fibroblast cultures during the plateau phase, and that was replenished by addition of glucose, glutamine, and serum and readjustment of pH had a distinct growth-inhibiting effect on monolayer cell cultures. The effect, which was not specific for a given cell strain, may be partially responsible for the "density inhibition" commonly observed in malignant cells grown in monolayer cultures. By modifying fresh growth media, it was shown that the growth inhibition observed can be partly attributed to the accumulation of lactate in the culture medium of plateau phase cells. This substance reduced the plating efficiency and the number o…

Interrelationship between mean arterial blood pressure, blood flow, and vascular resistance in solid tumor tissue of DS-carcinosarcoma

In vivo-Untersuchungen der Tumordurchblutung an Implantationstumoren eines DS-Carcinosarkoms in der Rattenniere zeigen eine deutliche Abhangigkeit der Durchblutungsgrosse vom Tumorgewicht. Bei Variation des arteriellen Mitteldrucks zwischen 40 und 135 mm Hg steigt die Durchblutung der einzelnen Tumoren linear mit zunehmendem Perfusionsdruck an. Eine zunehmende Rarefizierung der terminalen Strombahn mit ansteigendem Tumorgewicht wird belegt durch eine starke Zunahme des Stromungswiderstandes, der schon bei sehr jungen Tumoren wesentlich hohere Werte als bei verschiedenen Organen aufweist.

Growth-related changes of oxygen consumption rates of tumor cells grown in vitro and in vivo

Growth-related changes of oxygen consumption rates of tumor cells, grown in vitro or in vivo, were investigated. For in vitro investigations, L929 and DS-carcinosarcoma cells were cultured in artificial media. For in vivo studies, DS-carcinosarcoma cells were implanted into the abdominal cavity of Sprague-Dawley rats (ascites tumor, containing malignant cells, leukocytes, lymphocytes, and macrophages). Oxygen uptake was measured photometrically. Parameters of the extracellular medium judged to possibly influence the respiratory activity of tumor cells were monitored at different growth stages (glucose, lactate, and amino acid levels, oxygen and carbon dioxide partial pressures, and pH value…

Glucoseverbrauch gewebsisolierter Impftumoren (DS-Carcinosarkom) in vivo

Ziel der Untersuchungen war es, den Zusammenhang zwischen Durchblutung, Glucoseverbrauch und Alter gewebsisolierter Impftumoren (DS-Carcinosarkom) in vivo zu analysieren. Bei 15 reinen Tumoren und 11 Teiltumoren (Restnierenanteil 2–5% bzw. 50–60%) in Rattennieren als Wirtsorgan wurden die genannten Parameter bestimmt. Nach einer von Gullino u. Mitarb. (1961) angegebenen Methode konnten Impftumoren gewebsisoliert gezuchtet werden. Die Bestimmung des Glucoseverbrauchs und der Durchblutung erfolgte 9–13 Tage nach der Tumoruberimpfung. Bei einem mittleren Tumorgewicht von 6,5 g (Schwankungsbreite: 3,1–10,2 g) und einer mittleren Tumordurchblutung von 12,9 ml/100 g/min (2,9–34,8 ml/100 g/min) la…

TISSUE pH-DISTRIBUTION WITHIN MALIGNANT TUMORS AS MEASURED WITH ANTIMONY MICROELECTRODES

Publisher Summary Recent experiments using glass microelectrodes have demonstrated that very low tissue pH-values are prevalent in C3H mouse mammary carcinomas. The acidification of the tumor tissue is the result of an elevated lactic acid production and its inadequate removal. As a consequence of heterogeneities in tumor blood flow and in substrate supply, tissue pH values are distributed heterogeneously within solid tumors. Although glass microelectrodes with tip diameters of about 1 μm and a sensitive length of 10–50 μm have been used, the spatial resolution can be improved utilizing glass coated antimony microelectrodes the sensitive areas of that are restricted to their very tips. This…

Is there a critical tissue oxygen tension for bioenergetic status and cellular pH regulation in solid tumors?

Bioenergetic and metabolic status have been correlated with tissue oxygenation in murine fibrosarcomas (FSaII) of varying sizes (44-600 mm3). Ratios of beta-nucleoside triphosphates to inorganic phosphate (beta NTP/P) and phosphocreatine to inorganic phosphate (PCr/P(i)) ratios derived from 31P nuclear magnetic resonance spectroscopy (NMR) were positively correlated to median tissue O2 tension (pO2) values using O2-sensitive needle electrodes. pH declined during growth with intracellular acidosis being evident in tumors350 mm3. Whereas lactic acid formation greatly contributed to this decline in small and medium-sized tumors, adenosine triphosphate (ATP) hydrolysis and slowing down of the a…

Accumulation of purine catabolites in solid tumors exposed to therapeutic hyperthermia

Intensified adenosine triphosphate (ATP) degradation following therapeutic hyperthermia is often observed in solid tumors. As a result, accumulation of purine catabolites can be expected together with formation of protons at several stages during degradation to the final product, uric acid. Proton formation in turn can contribute to the development of heat-induced acidosis. Furthermore, oxidation of hypoxanthine and xanthine may result in generation of reactive oxygen species, which may lead to DNA damage, lipid peroxidation and protein denaturation, thus also contributing to heat-induced cytotoxicity. In hyperthermia experiments a tumor-size-dependent, significant increase in the levels of…

Tumor blood flow: The principal modulator of oxidative and glycolytic metabolism, and of the metabolic micromilieu of human tumor xenograftsin vivo

We have investigated therapeutically relevant pathophysiological parameters of human breast and lung cancer xenografts in nude rats. All lung cancers and one breast cancer exhibited rapid growth and high blood flow values paralleled by high metabolic rates. The tissue of these tumors was well oxygenated up to very advanced growth stages. Xenografts from other breast cancer cell lines grew much more slowly, were poorly perfused, and exhibited low metabolic rates. Here, tumor hypoxia and tissue acidosis were evident. These results indicate that significant differences in the metabolic micromilieu can be detected in human tumors; these are due to varying perfusion rates and may be partly respo…

Splenic respiratory gas exchange and glucose uptake in patients with splenomegaly in hypersplenism and Hodgkin's disease.

Blood samples are taken from the splenic artery, vein and pulp of patients suffering from Hodgkin's disease (n=10) or hypersplenism (n=7) and undergoing splenectomy. In these samples, the relevant parameters of the respiratory gas exchange as well as glucose and lactate concentrations are determined. In hypersplenism (mean splenic wet weight: 543 g) the mean oxygen consumption of the splenic tissue amounts to 0.9 ml O2/100 g/min taking into account a mean splenic blood flow of 80 ml/100 g/min. The glucose uptake and the lactate release are 9 mg/100 g/min and 5.5 mg/100 g/min, respectively. These values are in close agreement with the results obtained in the normal and undisturbed spleen in …

Atemgaswechsel und Glucoseaufnahme der menschlichen Milzin situ

Bei 16 Patienten mit lymphoproliferativen Erkrankungen, mit essentieller Thrombozytopenie oder hereditarer Spharocytose werden vor der Splenektomie Blutproben aus der Milzarterie, -vene und -pulpa entnommen und die relevanten Parameter des Atemgaswechsels sowie Glucose- und Lactatkonzentrationen bestimmt. Die eingehende Untersuchung der operativ entfernten Milzen zeigte in keinem Fall histopathologische Veranderungen. Unter Zugrundelegung einer mittleren Milzdurchblutung von 100 ml/100 g/min wahrend der Narkose errechnet sich ein mittlerer O2-Verbrauch des Milzgewebes von 1,1 ml/100 g/min. Die Glucose-Aufnahme und die Lactatfreisetzung betragen 9 mg/100 g/min bzw. 5,2 mg/100 g/min. Niedrige…

Tumor tissue oxygenation as evaluated by computerized-po2-histography

A computerized pO2 measurement system with a novel electrode motion pattern (Sigma-pO2-histography) was evaluated in vitro and in vivo. The system was found to be reliable in 0.9% saline and 10% hydroxyethylene starch solution and in fresh donor blood. Marked deviations were found in lipid and hemoglobin solutions and in fluorocarbon emulsions. Histograms obtained in rat liver, mouse muscle, and subcutis were similar to previously reported distributions. Direct comparison between Sigma-Eppendorf and self-constructed Whalen-type electrodes in hypoxic tumors gave similar results. A large series of measurements indicated that hypoxic and anoxic tissue areas were frequently found both in isogra…

Effect of Injectable or Inhalational Anesthetics and of Neuroleptic, Neuroleptanalgesic, and Sedative Agents on Tumor Blood Flow

Among other parameters, varying blood flow values may be responsible for tumor-to-tumor variabilities in the radiobiologically hypoxic cell fraction of experimental rodent tumors. To test whether changes in tumor blood flow may be caused by anesthetic agents often used in radiobiology, the effect of injectable and inhalational anesthetics and of neuroleptic, neuroleptanalgesic, and sedative agents on blood flow in subcutaneous DS-carcinosarcomas implanted in Sprague-Dawley rats has been investigated using the 85Kr clearance technique. In conscious rats, 20-100 min after animal instrumentation mean blood flow is 0.62 +/- 0.17 ml/g/min (mean +/- SD) in 0.75 +/- 0.15 g tumors at a mean arteria…