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…

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 …

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…

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…

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

Radiolabelling and preliminary evaluation of 68Ga-tetrapyrrole derivatives as potential tracers for PET

article i nfo Tetrapyrroles are multisided natural products which are of relevance in clinical medicine. Owing to their specific accumulation in tumour tissue, porphyrins, metalloporphyrins and chlorins have been used as in photodynamic therapy and optical imaging. Moreover, their specific uptake into inflammatory atheromatous plaques via LDL endocytosis has been reported. The present study is concerned with the synthesis of 68 Ga labelled porphyrin derivatives and an in vitro assessment of the utility of radiotracers in positron emission tomography. A set of five porphyrin derivatives were labelled using 68 Ga from a commercially obtained radionuclide generator. Dedicated post-processing o…

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…

Impact Of Hypoxic And Acidic Extracellular Conditions On Cytotoxicity Of Chemotherapeutic Drugs

In the microenvironment of solid growing tumors, pronounced hypoxia or extracellular acidosis is commonly found The aim of this study was the analysis of the cytotoxic effect of different chemotherapeutic agents (cisplatin, daunorubicin, docetaxel) under these conditions in vitro Prostate carcinoma cells (R3327-AT1) were exposed to hypoxia (pO 2 05 mmHg) or extracellular acidosis (pH=66) for 6h After 3h, cytotoxic drugs were added The cytotoxic effect was assessed by measuring caspase 3-activity (apoptosis), LDH release (necrosis) and repopulation of the cells after chemotherapy (cell death) Compared to aerobic control conditions, severe hypoxia over 6h per se led to a slight increase in ap…

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…

Transcriptional regulation of nucleoredoxin-like genes takes place on a daily basis in the retina and pineal gland of rats.

AbstractThe nucleoredoxin-like gene Nxnl1 (Txnl6) and its paralogue Nxnl2 encode the rod-derived cone viability factors (RdCVF and RdCVF2), which increase the resistance to photooxidative damage and have therapeutic potential for the survival of cones in retinitis pigmentosa. In this study, the transcription of Nxnl genes was investigated as a function of the day/night cycle in rats. The transcript levels of Nxnl1 and Nxnl2 were seen to display daily rhythms with steadily increasing values during the light phase and peak expression around dark onset in preparations of whole retina, photoreceptor cells and—but only in regard to Nxnl1—in photoreceptor-related pinealocytes. The cycling of Nxnl…

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…

Activity of Drug Efflux Transporters in Tumor Cells Under Hypoxic Conditions

Tumor cells exhibit mechanisms by which chemotherapeutic drugs can be actively pumped out of the cell (e.g., p-glycoprotein pGP, MRP1), resulting in a multidrug resistant phenotype. Many human tumors show pronounced hypoxia which can result in a local ATP depletion which in turn may compromise the efficacy of these transporters. The aim of this study was therefore to assess the transport activity and expression of drug transporters under hypoxic conditions. Prostate carcinoma cells (R3327-AT1) were exposed to hypoxia (pO2≶0.5 mmHg) for up to 24h and pump activity was determined by an efflux assay. The results showed that exposing cells to hypoxia for 3–6 h led to a moderate increase in pGP …

Comments on “Cellular response to infrared radiation involves retrograde mitochondrial signaling”

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…

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…

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…

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.

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…

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…

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 …

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…

Impact of Extracellular Acidity on the Activity of P-glycoprotein and the Cytotoxicity of Chemotherapeutic Drugs

AbstractThe expression and activity of P-glycoprotein (pGP) play a role in the multidrug resistance of tumors. Because solid-growing tumors often show pronounced hypoxia or extracellular acidosis, this study attempted to analyze the impact of an acidic environment on the expression and activity of pGP and on the cytotoxicity of chemotherapeutic agents. For this, prostate carcinoma cells were exposed to an acidic extracellular environment (pH 6.6) for up to 24 hours. pGP activity was more than doubled after 3 to 6 hours of incubation in acidic medium, whereas cellular pGP expression remained constant, indicating that increased transport rate is the result of functional modulation. In paralle…

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…

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

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 …

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…

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 …

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…

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…

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…

The Retinal Clock Drives the Expression ofKcnv2, a Channel Essential for Visual Function and Cone Survival

PURPOSE The gene Kcnv2 codes for the voltage-gated potassium channel subunit Kv8.2, which can coassemble with Kv2.1 subfamily members to constitute functional voltage-gated potassium channels. Mutations in the Kcnv2 gene result in a retinal disorder designated "cone dystrophy with supernormal rod response (CDSRR)," revealing that Kcnv2 is essential for visual processing and cone survival. The aim of this study was to determine whether expression of Kcnv2 and Kv2.1 is under circadian regulation and may thus contribute to the clock-driven adjustment of photoreceptor function. METHODS Expression of the genes was recorded in preparations of the whole retina and microdissected retinal neurons by…

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…

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…

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 …

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…

Phosphodiesterase 10A in the Rat Pineal Gland: Localization, Daily and Seasonal Regulation of Expression and Influence on Signal Transduction

The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in striatal spiny projection neurons and represents a therapeutic target for the treatment of psychotic symptoms. As reported previously [J Biol Chem 2009; 284:7606–7622], in this study PDE10A was seen to be additionally expressed in the pineal gland where the levels of PDE10A transcript display daily changes. As with the transcript, the amount of PDE10A protein was found to be under daily and seasonal regulation. The observed cyclicity in the amount of PDE10A mRNA persists under constant darkness, is blocked by constant light and is modulated by the lighting regime. It therefore appears to be driven by the master cloc…

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…

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…

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…

Effects of Infrared-A Irradiation on Skin: Discrepancies in Published Data Highlight the Need for an Exact Consideration of Physical and Photobiological Laws and Appropriate Experimental Settings

Skin exposure to infrared (IR) radiation should be limited in terms of irradiance, exposure time and frequency in order to avoid acute or chronic damage. Recommendations aimed at protecting humans from the risks of skin exposure to IR (e.g. ICNIRP, ACGIH) are only defined in terms of acute effects (e.g. heat pain and cardiovascular collapse), whereas the actual exposure conditions (e.g. spectral distribution, exposure geometry, frequency and number of exposures, thermal exchange with the environment, metabolic energy production and regulatory responses) are not taken into consideration. Since the IR component of solar radiation reaching the Earth's surface is mainly IR-A, and considering th…

Pgc-1α and Nr4a1 Are Target Genes of Circadian Melatonin and Dopamine Release in Murine Retina

Purpose The neurohormones melatonin and dopamine mediate clock-dependent/circadian regulation of inner retinal neurons and photoreceptor cells and in this way promote their functional adaptation to time of day and their survival. To fulfill this function they act on melatonin receptor type 1 (MT1 receptors) and dopamine D4 receptors (D4 receptors), respectively. The aim of the present study was to screen transcriptional regulators important for retinal physiology and/or pathology (Dbp, Egr-1, Fos, Nr1d1, Nr2e3, Nr4a1, Pgc-1α, Rorβ) for circadian regulation and dependence on melatonin signaling/MT1 receptors or dopamine signaling/D4 receptors. Methods This was done by gene profiling using qu…

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…