RESUMEN
OBJECTIVE: To assess the effects of dietary supplementation using two isomeric blends of conjugated linoleic acid (CLA) on immune function in healthy human volunteers. DESIGN: Double-blind, randomised, placebo-controlled intervention trial. SUBJECTS AND INTERVENTION: A total of 55 healthy volunteers (n=20 males, n=35 females) were randomised into one of three study groups who received 3 g/day of a fatty acid blend containing a 50:50 cis-9, trans-11: trans-10, cis-12 CLA isomer blend (2 g CLA), and 80:20 cis-9, trans-11: trans-10, cis-12 (80:20) CLA isomer blend (1.76 g CLA) or linoleic acid (control, 2 g linoleic acid) for 8 weeks. RESULTS: Supplementation with the 80:20 CLA isomer blend significantly (P< or =0.05) enhanced PHA-induced lymphocyte proliferation. CLA decreased basal interleukin (IL)-2 secretion (P< or =0.01) and increased PHA-induced IL-2 and tumor necrosis factor alpha (TNF(alpha)) production (P< or =0.01). However, these effects were not solely attributable to CLA as similar results were observed with linoleic acid. CLA supplementation had no significant effect on peripheral blood mononuclear cells IL-4 production, or on serum-soluble intercellular adhesion molecule-1 (sICAM-1) or plasma prostaglandin E2 (PGE2) or leukotreine B4 (LTB4) concentrations. CONCLUSIONS: This study shows that CLA supplementation had a minimal effect on the markers of human immune function. Furthermore, supplementation with CLA had no immunological benefit compared with linoleic acid.
Asunto(s)
Citocinas/biosíntesis , Inmunidad Celular/efectos de los fármacos , Ácidos Linoleicos Conjugados/farmacología , Activación de Linfocitos/efectos de los fármacos , Adulto , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Inmunidad Celular/fisiología , Interleucina-2/biosíntesis , Isomerismo , Leucocitos Mononucleares/inmunología , Ácido Linoleico/administración & dosificación , Ácido Linoleico/química , Ácido Linoleico/farmacología , Ácidos Linoleicos Conjugados/administración & dosificación , Ácidos Linoleicos Conjugados/química , Masculino , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
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 the median oxygen partial pressure (pO(2)) dramatically (1 vs 10 mmHg in controls), whereas in chronically hypoxic tumours the pO(2) was significantly improved (median pO(2)=4 mmHg), however not reaching the control level. These findings reflect the changes in tumour perfusion where acutely hypoxic tumours show a dramatic reduction of perfused tumour vessels (maybe the result of a simultaneous reduction in arterial blood pressure). In animals under chronic inspiratory hypoxia, the number of perfused vessels increased (compared to acute hypoxia), although the perfusion pattern found in control tumours was not reached. In the chronically hypoxic animals, tumour cell proliferation and tumour growth were significantly reduced, whereas no differences in VEGF expression and vascular density between these groups were observed. These results suggest that long-term adaptation of tumours to chronic hypoxia in vivo, while not affecting vascularity, does influence the functional status of the microvessels in favour of a more homogeneous perfusion.
Asunto(s)
Hipoxia de la Célula/fisiología , Neoplasias Experimentales/patología , Enfermedad Aguda , Animales , División Celular , Enfermedad Crónica , Replicación del ADN , ADN de Neoplasias/análisis , Modelos Animales de Enfermedad , Cinética , Masculino , Neoplasias Experimentales/metabolismo , Consumo de Oxígeno , Ratas , Ratas Sprague-DawleyRESUMEN
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 subsequent experiments identified the pathophysiological basis for this effect. Red blood cell flux in tumour microvessels declined rapidly upon Bchl-ser-PDT+HT, reaching approximately 10% of initial values by the end of treatment. Similarly, tumour oxygenation worsened, reaching almost anoxic levels by the end of the treatment period. Assessment of metabolic parameters showed a pronounced increase in lactate levels and a decrease in ATP concentrations after combined treatment. The results presented suggest that vascular collapse and flow stasis resulting in a deterioration of tumour oxygenation and a switch from oxidative to glycolytic glucose turnover are key elements in the tumour eradication seen with this novel approach in which an antivascular PDT and HT are combined and simultaneously applied.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Bacterioclorofilas/farmacología , Hipertermia Inducida/métodos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Sarcoma Experimental/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Bacterioclorofilas/uso terapéutico , División Celular/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Terapia Combinada , Masculino , Modelos Animales , Neovascularización Patológica/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
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 volume by 8-11 days. A total of 13 and 15% of tumours did not reach the target volume by day 90 following HT or ALA-PDT treatment, respectively. ALA-PDT+HT showed the greatest antitumour effect (P=0.0001), with 61% of the tumours not reaching the target volume. Viability and in vitro growth were also assessed in cells from tumours excised after treatment. ALA-PDT+HT reduced the fraction of viable tumour cells by 85%, and in vitro culture showed pronounced growth delay compared to control cells. These results demonstrate an enhanced antitumour effect upon ALA+HT, which appears to involve direct cell toxicity rather than solely vascular damage.
Asunto(s)
Ácido Aminolevulínico/farmacología , Hipertermia Inducida , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Sarcoma/tratamiento farmacológico , Animales , Muerte Celular , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-Dawley , Sarcoma/veterinaria , Resultado del TratamientoRESUMEN
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 to 3.7 MHz. Data collected reveal totally different, but characteristic, behaviour patterns for the three treatments. HT caused a slow increase in conductance at high frequencies (G(HF)) and in the extracellular space index (ECSI), indicating an increase in extracellular fluid volume and in total fluid content. With PDT, G(HF) increased immediately upon commencement of irradiation and was accompanied by a distinct decrease in ECSI, indicating the development of a pronounced intracellular oedema.
Asunto(s)
Impedancia Eléctrica , Hipertermia Inducida , Sarcoma/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Análisis Espectral/métodos , Animales , Líquidos Corporales/fisiología , Edema/diagnóstico , Edema/terapia , Miembro Posterior , Masculino , Trasplante de Neoplasias , Fotoquimioterapia , Ratas , Ratas Sprague-Dawley , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapiaRESUMEN
Isolated limb perfusion allows the direct application of therapeutic agents to a tumour-bearing extremity. The present study investigated whether the dihydropyridine-type Ca(2+)-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 microg min(-1) kg(-1) BW). During constant-pressure isolated limb perfusion, nifedipine can significantly increase perfusion rate (+100%) and RBC flux (+60%) through experimental leg tumours. "Steal phenomena" in favour of the surrounding normal tissue and oedema formation were not observed. Despite the increased oxygen availability (+63%) seen upon application of this calcium channel blocker, nifedipine does not result in a substantial reduction of tumour hypoxia, most probably due to an increase in O(2) uptake with rising O(2) supply to the tumour-bearing hind limb. Nifedipine application during isolated limb perfusion can enhance tumour microcirculation and may therefore promote the delivery (pharmacokinetics) of anti-cancer drugs to the tumour and by this improve the efficacy of pressure-controlled isolated limb perfusion.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Quimioterapia del Cáncer por Perfusión Regional , Nifedipino/farmacología , Oxígeno/metabolismo , Sarcoma Experimental/irrigación sanguínea , Animales , Respiración de la Célula , Infusiones Intravenosas , Flujometría por Láser-Doppler , Masculino , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Sarcoma Experimental/metabolismoRESUMEN
In an investigation of the antitumor effects of 2-methoxyestradiol (2-ME) in combination with other reactive oxygen generating treatments, 2-ME (0.5 microM) was found to completely inhibit cell proliferation of rat DS-sarcoma cells in vitro, with 71% of cells dying after exposure to 5 microM 2-ME. Concentration-dependent increases in ROS-formation, lipid peroxidation and mitochondrial changes were also observed, and an elevation in caspase-3 activity resulted in DNA fragmentation and apoptosis. Combination of 2-ME with hypoxanthine and xanthine oxidase enhanced in vitro cytotoxicity. In vivo, 2-ME caused a slight inhibition of tumor growth, with no tumors cured. Combination of 2-ME treatment with localized 44 degrees C hyperthermia, respiratory hyperoxia and xanthine oxidase caused a tumor growth delay with 51% of tumors cured. These results suggest that amplifying the levels of reactive oxygen species within tumor tissue with substances such as 2-ME may prove to be a promising strategy for adjuvant treatment of solid tumors.
Asunto(s)
Antineoplásicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Superóxidos/metabolismo , 2-Metoxiestradiol , Animales , Antineoplásicos/uso terapéutico , Apoptosis , Caspasa 3 , Caspasas/efectos de los fármacos , Caspasas/metabolismo , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Estradiol/análogos & derivados , Estradiol/farmacología , Estradiol/uso terapéutico , Hiperoxia , Hipertermia Inducida , Hipoxantina/uso terapéutico , Peroxidación de Lípido/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Ratas , Ratas Sprague-Dawley , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Células Tumorales Cultivadas , Xantina Oxidasa/uso terapéuticoRESUMEN
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 drugs resulted in a dose-dependent decrease in MABP. In parallel, tumor perfusion was reduced linearly with falling MABP resulting in a decrease in RBC flux by approximately 40%. Resistance to flow did not change during the infusion indicating that these drugs have no impact on tumor vessel diameter. With decreasing tumor perfusion, tumor pO2 was reduced parallel to the MABP drop. This effect was more distinct with Na+-nitroprusside than with nifedipine due to the more pronounced fall in MABP. The vasodilator drugs studied are not suitable for dilation of tumor vessels either because the tumor vasculature lacks contractile wall elements or because the vessels are already maximally dilated.
Asunto(s)
Nifedipino/farmacología , Nitroprusiato/farmacología , Oxígeno/metabolismo , Sarcoma Experimental/irrigación sanguínea , Vasodilatadores/farmacología , Animales , Infusiones Intravenosas , Flujometría por Láser-Doppler , Masculino , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
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 in tumors with low perfusion rates. Tumor hypoxia is a therapeutic problem, as it makes solid tumors resistant to sparsely ionizing radiation and some forms of chemotherapy. Hypoxia also may modulate the proliferation and cell cycle position of tumor cells and, in turn, the amount of cells destroyed following therapy. Recent clinical studies suggest that hypoxia can enhance malignant progression and increase aggressiveness through clonal selection and genome changes. As a result, loss of differentiation and apoptosis, chaotic angiogenesis, increased locoregional spread, and enhanced metastasis can further increase resistance to therapy and affect long-term prognosis. Hypoxia is a powerful, independent prognostic factor in cervix cancers, carcinomas of the head and neck, and in soft-tissue sarcomas.
Asunto(s)
Hipoxia de la Célula , Neoplasias/fisiopatología , Carcinoma de Células Escamosas/fisiopatología , Hipoxia de la Célula/fisiología , Femenino , Humanos , Neoplasias/terapia , Consumo de Oxígeno , Pronóstico , Neoplasias del Cuello Uterino/fisiopatologíaRESUMEN
The aim of this study was to examine the impact of anemia prevention by recombinant human erythropoietin (rHuEPO) treatment on the cytotoxicity of cyclophosphamide in solid experimental tumors. Anemia was induced using a single dose of carboplatin (50 mg/kg i.v.) resulting in a long-lasting reduction (30%) of the hemoglobin concentration. In a second group, the development of anemia was prevented by rHuEPO (1000 IU/kg) administered s.c. three times/week starting 7 days before carboplatin application. Four days after carboplatin treatment, tumors (DS-sarcoma of the rat) were implanted s.c. onto the hind food dorsum. Neither carboplatin nor rHuEPO treatment influenced tumor growth rate per se. When tumors were treated with a single dose of cyclophosphamide (60 mg/kg i.p.) 5 days after implantation, a growth delay with a subsequent regrowth of the tumors was observed. In the anemia group, the growth delay was significantly shorter compared with nonanemic controls (13.3 days versus 8.6 days). In the group where anemia was prevented by rHuEPO treatment, growth delay was comparable with that of nonanemic controls (13.3 days). These results suggest that chemotherapy-induced anemia reduces cytotoxicity of cyclophosphamide in tumors, whereas correction of anemia by rHuEPO treatment (epoetin alpha) increases the sensitivity, probably as a result of an improved oxygen supply to tumor tissue.
Asunto(s)
Anemia/prevención & control , Antineoplásicos Alquilantes/toxicidad , Ciclofosfamida/toxicidad , Eritropoyetina/farmacología , Anemia/inducido químicamente , Animales , Carboplatino/toxicidad , División Celular/efectos de los fármacos , Masculino , Trasplante de Neoplasias , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes , Sarcoma Experimental/tratamiento farmacológico , Sarcoma Experimental/patologíaRESUMEN
Perfusion and oxygenation of experimental tumours were studied during angiotensin II (AT II) administration whereby the rate of the continuous AT II infusion was chosen to increase the mean arterial blood pressure (MABP) by 50-70 mmHg. In subcutaneous DS-sarcomas the red blood cell (RBC) flux was assessed using the laser Doppler technique and the mean tumour oxygen partial pressure (pO2) was measured polarographically using O2-sensitive catheter and needle electrodes. Changes in RBC flux with increasing MABP depended mainly on tumour size. In small tumours, RBC flux decreased with rising MABP whereas in larger tumours RBC flux increased parallel to the MABP. As a result of these volume-dependent effects on tumour blood flow, the impact of AT II on tumour pO2 was also mainly tumour volume-related. In small tumours oxygenation decreased with increasing MABP during AT II infusion, whereas in large tumours a positive relationship between blood pressure and O2 status was found. This disparate behaviour might be the result of the co-existence of two functionally distinct populations of tumour vessels. In small tumours, perfusion decreases presumably due to vasoconstriction of pre-existing host vessels feeding the tumour. In larger malignancies, newly formed tumour vessels predominate and seem not to have this vasoresponsive capability (lack of smooth muscle cells and/or AT receptors), resulting in an improvement of perfusion which is not tumour-related per se, but is due to the increased perfusion pressure.
Asunto(s)
Angiotensina II/farmacología , Neoplasias Experimentales/irrigación sanguínea , Oxígeno/metabolismo , Vasoconstrictores/farmacología , Animales , Modelos Animales de Enfermedad , Flujometría por Láser-Doppler , Masculino , Neoplasias Experimentales/metabolismo , Perfusión/efectos adversos , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
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 tumours in sham-treated animals, 80% in HT-treated animals and only 17% in HT + Bchlser-treated animals reached the end point target volume of 3.5 ml. Thus, the tumour growth inhibition effect of HT can be substantially enhanced by combination with Bchl-ser-PDT. This novel technique has proved to be well-tolerated, easy to apply and should be suitable for treatment of superficial malignancies, especially where hypoxic tumour areas are present.
Asunto(s)
Bacterioclorofilas/administración & dosificación , Hipertermia Inducida/métodos , Rayos Infrarrojos , Neoplasias Experimentales/terapia , Fotoquimioterapia , Animales , Terapia Combinada , Masculino , Neoplasias Experimentales/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , AguaRESUMEN
The biology of human breast milk, and the policy of encouraging breastfeeding, continue to be the object of much scientific inquiry. The past year has seen several advances in these fields of nutrition, and this article reviews some of the most interesting and pertinent studies. Four general themes have been apparent in the recent literature: 1) the role of breastfeeding and breast milk in the incidence of infectious diseases; 2) the effect of breastfeeding on neurodevelopmental outcome; 3) the nutritional composition of breast milk; and 4) the determinants of breastfeeding among adolescents and ethnic minority mothers. Review of these studies will assist the office-based pediatrician in knowing the scientific rationale, and the best methodology, for the promotion of breastfeeding.
Asunto(s)
Lactancia Materna , Leche Humana , Logro , Lactancia Materna/etnología , Desarrollo Infantil , Cognición , Conocimientos, Actitudes y Práctica en Salud , Humanos , Lactante , Leche Humana/química , Leche Humana/inmunologíaAsunto(s)
3-Yodobencilguanidina/uso terapéutico , Antineoplásicos/uso terapéutico , Oxígeno/metabolismo , Radiofármacos/uso terapéutico , Sarcoma Experimental/metabolismo , Animales , Masculino , Consumo de Oxígeno/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sarcoma Experimental/tratamiento farmacológicoRESUMEN
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 delivery. Reducing cellular respiration rate should be of benefit in both pathophysiological conditions. Because both types of O2 limitation coexist in solid tumors, appropriate combinations should be aimed at eradicating tumor hypoxia which is present in at least one third of cancers in the clinical setting.
Asunto(s)
Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Consumo de Oxígeno/fisiología , Anemia/terapia , Animales , Carboxihemoglobina/metabolismo , Hipoxia de la Célula/fisiología , Transfusión de Eritrocitos , Predicción , Hemoglobinas/metabolismo , Humanos , Oxigenoterapia Hiperbárica , Microcirculación , Neoplasias/terapia , Oxígeno/administración & dosificación , Oxígeno/sangre , Presión ParcialRESUMEN
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 level was assessed polarographically using an O2-sensitive catheter electrode. The methylxanthine derivatives were administered as a single dose intraperitoneally (for PX 50 mg/kg; for TB and HW 75 mg/kg). RESULTS: Following drug administration, initial decreases in MABP down to 75% of baseline values were observed for all three substances. PX, HW, and TB caused initial transient reductions in mean RBC flux followed by gradual increases to values of 137 +/- 27%, 139 +/- 14%, and 122 + 14% respectively at t = 60 min. Following a small initial decrease upon drug administration, O2 partial pressure (pO2) rose to 160 +/- 31%, 153 +/- 34%, and 121 +/- 11% for PX, HW, and TB, respectively at t = 60 min. At the end of the observation period (t = 90 min), increases in RBC flux and pO2 were still evident. When individual tumors were considered, a variety of patterns (including opposing effects) for changes in RBC flux were seen, not necessarily reflected in the mean values. Thus, while the methylxanthine derivatives caused an increased average tumor perfusion, there is evidence suggesting that a redistribution of tumor blood flow occurs which may amplify preexisting heterogeneity. CONCLUSIONS: Substantial improvements in tumor oxygenation and perfusion were observed after administration of the methylxanthine derivatives. These substances may therefore be of use during tumor therapies in which the outcome may be detrimentally affected by the presence of hypoxia.
Asunto(s)
Neoplasias Experimentales/irrigación sanguínea , Consumo de Oxígeno/efectos de los fármacos , Pentoxifilina/análogos & derivados , Pentoxifilina/farmacología , Animales , Masculino , Neoplasias Experimentales/metabolismo , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Sarcoma Experimental/irrigación sanguínea , Vasodilatadores/farmacologíaRESUMEN
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 non-curative dose (10 Gy), resulting in a growth delay with a subsequent regrowth of the tumours. In the rhEPO-treated group, the growth delay lasted significantly longer (9.5 days vs. 4.5 days) and the regrowth was slower (6.0 days vs. 4.1 days) compared with the anaemic group. These data suggest that the correction of chemotherapy-induced anaemia by rhEPO (epoetin beta) treatment increases tumour radiosensitivity, presumably as a result of an improved oxygen supply to tumour tissue.
Asunto(s)
Anemia/prevención & control , Eritropoyetina/uso terapéutico , Sarcoma Experimental/radioterapia , Anemia/sangre , Anemia/inducido químicamente , Anemia/tratamiento farmacológico , Animales , Antineoplásicos/efectos adversos , Carboplatino/efectos adversos , Hemoglobinas/efectos de los fármacos , Humanos , Masculino , Trasplante de Neoplasias , Tolerancia a Radiación , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes , Sarcoma Experimental/sangreRESUMEN
The effects of respiratory hyperoxia (RH) and xanthine oxidase (XO) during localized hyperthermia (HT) were investigated by determining markers of oxidative damage to lipids and proteins and tumor growth. Anesthetized rats with s.c. DS-sarcomas underwent one of the following treatments: (a) localized saline-bath HT (60 min, 44 degrees C); (b) HT + RH (100% O2); and (c) HT + RH + XO (15 units/kg i.v.). Sham-treated animals served as controls. Tumors were investigated for: (a) thiobarbituric acid-reactive substance formation and protein-bound 4-hydroxynonenal, as indicators of lipid peroxidation; (b) reactive oxygen-mediated protein modifications; (c) apoptosis; and (d) tumor volume growth. Upon treatment, increases in thiobarbituric acid-reactive substances, protein-bound 4-hydroxynonenal, protein-associated carbonyl functions, and number of cells undergoing apoptosis were found in tumor tissue, together with an inhibition of tumor growth. When treatment groups were compared, effects in the group HT + RH + XO were generally most pronounced. These findings indicate that the antitumor effect of HT is at least partially mediated through the selective induction of lipid peroxidation and oxidative injury in tumor cells, leading to apoptosis. This effect was enhanced by adding RH or RH + XO, presumably due to enhanced tissue damage following an increased formation of reactive oxygen species, with higher levels of lipid peroxidation and protein oxidation.