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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The response of SCK tumor cells in vivo and in vitro to heat was compared, and the relationship between the kinetics of cell death and vascular function in tumors in vivo after hyperthermia was studied. The number of clonogenic cells in tumors excised immediately after heating was significantly less than that in the in vitro culture treated with the same heat doses. This suggested that the tumor cells in vivo are far more sensitive to direct damage by heat than are the cells in vitro. When the tumors were left in situ after hyperthermia at 43.5 degrees for 30 min, there was a progressive decrease in cell survival until 6 to 12 hr after the heating. The study of intravascular volume using the 51Cr-labeled red blood cell method indicated that severe vascular occlusion occurs in the tumor after hyperthermia. It therefore appeared that delayed cell death in tumors in vivo after hyperthermia resulted from an insufficient supply of oxygen and nutrients and an increase in acidity due to the vascular occlusion. Both the direct damage to tumor cells and the indirect damage to tumor cells as a consequence of vascular occlusion may play important roles in the eradication of tumors by hyperthermia.
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PMID:Role of vascular function in response of tumors in vivo to hyperthermia. 735 44

Blood flow in rat skin and muscle increased three- to fourfold during heating at 43 degrees C for one hour, while that in Walker tumors did not change significantly; however, blood flow in the tumors decreased a few hours after heating at 45 degrees C. The temperature of Walker tumors was significantly higher than in the muscle during heating, probably due to inefficient heat dissipation caused by the sluggish blood flow. Severe vascular occlusion occurred in SCK tumors in mice after heating at 41.5-45.0 degrees C. Upon heating, the pH in the tumors significantly decreased, while that in the muscle increased. The clonogenic cell number continuously decreased when SCK tumors were left in situ after hyperthermia. The vascular occlusion and increase in acidity may account for the progressive death of tumor cells after heating.
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PMID:The effect of hyperthermia on vascular function, pH, and cell survival. 744 64

The tumor interstitial pH and its modification play a significant role in cancer treatment. Current in vivo pH measurement techniques are invasive and/or provide poor spatial resolution. Therefore, there are no data on perivascular interstitial pH gradients in normal or tumor tissue. We have optically measured interstitial pH gradients with high resolution in normal and tumor (VX2 carcinoma) tissue in vivo by combining a fluorescence ratio imaging microscopy technique and the rabbit ear chamber preparation. The strengths of our approach include the ability to follow pH in the same location for several weeks and to relate these measurements to local blood flow and vascular architecture. Our results show: (a) tumor interstitial pH (6.75 units; N = 6 animals, n = 324 measurements) is significantly (P < 0.001) less than normal interstitial pH (7.23; N = 5, n = 274). This increased acidity in the tumor interstitium is in agreement with the previously reported data on this tumor; (b) with respect to pH spatial gradients in normal tissue, the interstitial pH decreased by approximately 0.32 pH units over a distance of 50 microns away from the blood vessel, while in tumor tissue, interstitial pH decreased by approximately 0.13 units over the same distance. Although the pH gradient near the vessel wall was steeper in normal tissue compared to tumor, the proton concentration gradient in normal tissue was less than that in the tumor. The approximate increase in proton concentration from 0-50 microns from the vessel was 4.5 x 10(-8)M in normal versus 5.7 x 10(-8)M in tumor tissue; (c) a simple one-dimensional diffusion-reaction model suggested that tumor tissue was producing protons at a rat 65-100% greater than normal tissue; (d) feasibility studies of temporal dynamics resulting from hyperglycemia (6 g/kg) or hypercapnia (10% CO2) led to significant (P < 0.05) interstitial pH reductions. During hyperglycemia, pH dropped by more than 0.2 pH units in about 90 min in tumor tissue but remained constant in normal tissue. Hypercapnia dramatically reduced pH by approximately 0.3 pH units in tumor tissue. Our limited studies on hyperglycemia and hypercapnia are in agreement with the previously published studies and demonstrate the capability of fluorescence ratio imaging microscopy to measure spatial as well as temporal changes in interstitial pH. Fluorescence ratio imaging microscopy should permit noninvasive evaluation of new pH-modifying agents and offer unique mechanistic information about tumor pathophysiology in tissue preparations where the surface of the tissue can be observed.
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PMID:Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. 792 15

To further understand the control of brain tumor fluid balance and pH, the following studies were undertaken. The transport of a water soluble molecule across the brain and tumor capillary endothelium was studied during glucocorticoid and radiation treatment. The brain and brain-tumor acidity (pH) was evaluated as a single measurement in patients receiving a low maintenance dose of glucocorticoid. Transport changes and pH were measured in 61 patients with cerebral tumors using 82Rubidium (82Rb) and 11C-Dimethyloxa-zolidindione (11C-DMO), respectively, and Positron Emission Tomography (PET). Supplementary studies of tumor and contralateral brain blood flow and blood volume using the C15O2/PET and C15O/PET technique, respectively, were included to validate the 82Rb/PET model and obtain further information. A total of 125 PET scans were performed. Supplementary studies were undertaken to estimate delay of blood registration and form distribution of arterial blood isotope activity curves. Blood-to-tumor barrier transport was outlined at baseline and at 6 and 24 hours after the start of glucocorticoid treatment, finding a significant decrease in the transport. Radiation treatment (2-6 gray) did not alter the blood-to-tumor barrier transport when restudied within one hour in patients receiving glucocorticoid. In accordance with others, we observed pH values in gray and white matter in the range of 6.74-7.09 and 6.77-7.03 respectively. The pH in brain tumors was as high as 6.88-7.26, suggesting that tumors are more alkalotic than the normal brain. The permeability surface area product and the permeability coefficient were determined from the 82Rb/PET transport and C15O2/PET flow studies. Baseline permeability values were comparable to the literature values both for 82Rb and potassium. No difference in tissue blood volume was seen between 82Rb/PET and C15O/PET models and was of the same magnitude in the tumor and the contralateral tissue. The pH and fluid control in human brain tumors are perceived as metabolically controlled rather than, as previously believed, a result of simple passive exchange of alkalotic or osmotic active molecules between plasma and tumor interstitial space. Aspects of tumor alkalosis, tumor edema production, glucocorticoid edema clearance, and relationship between the anti-edema effect of glucocorticoid and the shown transport changes to 82Rb will be reviewed in the light of metabolic control mechanisms.
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PMID:Pathophysiological aspects of malignant brain tumors studied with positron emission tomography. 794 66

Solid tumors have been observed to develop an acidic extracellular environment, which is believed to occur as a result of lactic acid accumulation produced during aerobic and anaerobic glycolysis. Experiments using glycolysis-deficient ras-transfected Chinese hamster lung fibroblasts have been performed to test the hypothesis that lactic acid production within solid tumors is responsible for the development of tumor acidity. The variant cells have defects in glucose transport and in the glycolytic enzyme phosphoglucose isomerase with 1% activity compared to parental cells. Consequently, the in vitro rate of lactic acid production by variant cells was < 4% compared to parental cells. An in vitro correlation between lactic acid production and acidification of exposure medium was observed for parental and variant cells. Implantation of both cell lines into nude mice led to tumors with minimal difference in growth rate. As expected, variant cells died when exposed to hypoxic conditions in culture, and parental tumors were observed to have a larger fraction of cells resistant to radiation due to hypoxia (27%) than variant tumors (2%). Using pH microelectrodes, parental (n = 12) and variant (n = 12) tumors were observed to have extracellular pH (pHe) values of 6.65 +/- 0.07 and 6.78 +/- 0.04 (mean +/- SE, P = 0.13), respectively, whereas normal muscle had a pHe of 7.29 +/- 0.06 (P < 0.0001 for both cell lines). The lactic acid content of variant tumors was found to be similar to that in serum, whereas parental tumors had lactic acid content that was higher than in serum (P < 0.0001). We conclude that there was no correlation between lactic acid content and acidosis for these tumors derived from ras-transfected fibroblasts. These results provide evidence that the production of lactic acid via glycolysis is not the only mechanism responsible for the development of an acidic environment within solid tumors.
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PMID:Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. 843 84

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor implicated in many pathological processes. We investigated the regulation of 4 alternatively spliced isoforms (121, 165, 189 and 206 amino acids) by hypoxia, hypoglycemia, acidity, female reproductive hormones and vitamin D in breast carcinoma cell lines representing different tumor phenotypes. There was a 17-fold difference in total VEGF mRNA expression across the cell lines. The isoform expression, 121 > 165 > 189, was unchanged by different culture conditions. Hypoxia was the most potent stimulus, and the cell lines demonstrated a 1.4- to 6.9-fold range of VEGF induction, maintained when other hypoxically regulated genes (phosphoglycerate kinase 1 and glucose transporter 1) and a HIF-1-dependent reporter gene were examined. The relative inducibility of the genes was maintained in each cell line, but basal expression was independent of -fold induction. VEGF expression decreased under acidic conditions in 2 cell lines, but the hypoxia stimulus remained effective under acidic conditions. Hypoglycemia, female reproductive hormones and vitamin D exerted no effect on expression, nor did inhibitors of mutant ras. Our results show that VEGF expression varies widely between cell lines and that capacity to respond to hypoxia is also cell specific, relating mostly to the hypoxic sensing of the cell and the signal transduction mechanism. Such characteristics, if maintained in vivo, have implications for the angiogenic potential of different tumor cells under normal and hypoxic conditions.
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PMID:Role of the hypoxia sensing system, acidity and reproductive hormones in the variability of vascular endothelial growth factor induction in human breast carcinoma cell lines. 949 38

Helicobacter pylori acquisition is the main cause of chronic gastritis in humans. In up to half of the infected subjects, chronic gastritis progresses to atrophic gastritis and intestinal metaplasia. During this course, various mechanisms are triggered that may contribute to the pathogenesis of gastric cancer. Such mechanisms include the inflammation-related cascades of cytokine and free radical reactions, up- and downregulation of growth factors and their receptors, and the atrophy-related impairment of acid output and intraluminal acidity. An array of other factors may also have become significant including overgrowth of bacteria other than H. pylori in the hypochlorhydric or achlorhydric stomach, a high dietary consumption of salt, nitrate, or nitrite, smoking, deficiency of vitamins or micronutrients, influence of sex hormones, or an inherited liability of the dividing epithelial cells to gene errors. These factors may vary in effect between populations and individuals but, if active, may affect the cell genome which may further influence the course and progression of chronic gastritis, and can finally result in overt gastric neoplasia. The molecular biology of gastric cancer has revealed a spectrum of gene errors which vary in type and extent between different histological types of cancer, and between individual cases. There now is evidence that the intestinal metaplasia or the gastric epithelium in atrophic gastritis reveal signs of abnormal expression of various regulatory genes well before the appearance of gastric neoplasia. It is possible that the mechanisms leading to mutation of the genes in epithelial cells are triggered very early in the H. pylori gastritis cascade, and that atrophic gastritis and intestinal metaplasia result from these processes.
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PMID:Review article: Pathogenesis of the transformation from gastritis to malignancy. 970 Oct 4

Since the conception of the pentavalent technetium polynuclear complex of dimercaptosuccinic acid, Tc(V)-DMS, a great number of papers published on its clinical applicability forced us to question "how tumor tissue appropriates the Tc(V)-DMS." Preliminary in vitro studies with Ehrlich ascites tumor cells (EATC) indicated the pH-sensitive character of this tumor agent. From this finding and the well-established notion that malignant tumors are more acidic than normal tissue, the in vivo correlation of Tc(V)-DMS accumulation in tumor tissue with its tissue acidification was considered of interest. The systemic lowering of tumor tissue pH by the stimulation of aerobic glycolysis has been well reported. In the present paper, the response of Tc(V)-DMS tumor accumulation to acidification induced by the glucose administration was explored in EATC-bearing mice. Measurement of tumor tissue pH was carried out by direct microelectrode technique and by histochemical umbelliferone technique in tumor tissue excised from EATC bearing mice. The regional acidity distribution is correlated with the regional radioactivity distribution registered by autoradiography. Evidence related to the pH sensitiveness of Tc(V)-DMS in response to glycolytic acidification was gathered; the pH measurement and the in vivo biodistribution of the double-tracer macroautoradiography with C-14 deoxyglucose (C-14-DG) demonstrated that the regional tissue distribution of Tc(V)-DMS was superimposed to that of C-14-DG. The glucose interventional modality offers the premier foundation for the interpretation of Tc(V)-DMS accumulation in diagnostic studies of malignant tumors.
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PMID:Tc(V)-DMS tumor localization mechanism: a pH-sensitive Tc(V)-DMS-enhanced target/nontarget ratio by glucose-mediated acidosis. 975 22

Mammalian cells in culture were used to study the genotoxic potential of coke oven emissions constituting a complex mixture of chemicals. For this purpose, particle extracts and some polycyclic aromatic and nitroaromatic hydrocarbons (PAH and nitro-PAH) occurring in these mixtures were assayed for DNA adduct formation using the -postlabeling technique. In primary cultures of rat hepatocytes, benzo[a]pyrene (B[a]P), benz[a]anthracene (B[a]A) and benzo[b]fluoranthene (B[k]F) caused DNA adduct levels in the range of 1 adduct/108 nucleotides. 4-Nitropyrene (4-NP), 6-nitrochrysene (6-NC), 3-nitrofluoranthene (3-NF) caused DNA adduct levels that were by one to two orders of magnitude higher. The crude particle extract and its fractions differing in acidity and polarity induced the formation of DNA reactive material within diagonal radioactive zones (DRZ) on the autoradiograms. On a weight base, the neutral aromatic fraction contributed by more than 80% to the total adduct level in hepatocytes. To examine whether the PAH- and nitro-PAH-DNA derived adducts can be further differentiated, hepatocyte cultures were preincubated with 2,3,7,8-tetrachloro-p-dioxin (TCDD) to induce the activity of cytochrome P450 1A1. TCDD pretreatment strongly increased the levels of PAH-DNA adducts, whereas, the levels of nitro-PAH adducts were markedly decreased. NCI-H322 cells, a human lung tumor cell line derived from Clara cells, exhibited PAH-DNA adduct levels between 10 and 100, and nitro-PAH-DNA adducts at levels between 0.2 to about 30 adducts per 108 nucleotides, respectively. In contrast to hepatocytes, incubations with extractable organic matter (EOM) and the neutral aromatic EOM fraction displayed several distinct spots in the chromatograms of NCI-H322 cells. The major spot was assigned by cochromatography to be identical with the major DNA adduct formed by incubation with B[a]P alone. In V79NH cells, a Chinese hamster lung cell line expressing nitro-PAH activating enzymes, but virtually no cytochrome P450 activity, PAH-derived DNA adducts were not detectable. Nitro-PAH-derived DNA adducts, however, were formed at levels between 10 and 300 adducts/108 nucleotides. The slightly and the moderately polar EOM fraction caused the formation of distinct adduct spots suggesting the occurrence of nitro-PAH in these fractions. GC/MS analyses revealed the presence of twelve PAH in the aromatic fraction, at a total amount of about 10% (w/w), and of four nitro-PAH in the slightly polar and the acidic fraction amounting to about 0.2% (w/w). In conclusion, our results indicate that PAH and nitro-PAH contribute to the genotoxicity of coke oven emissions. Using DNA adduct analysis in rat hepatocytes (+/-pretreatment with TCDD) and in NCI-H322 and in V79NH cells offers a promising approach to determine the genotoxic activity of PAH and nitro-PAH in any complex environmental samples.
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PMID:DNA adduct formation in mammalian cell cultures by polycyclic aromatic hydrocarbons (PAH) and nitro-PAH in coke oven emission extract. 980 6

Multidrug-resistant cells are believed to contain a plasma-membrane-efflux pump which is hypothesized to expel anticancer drugs from the cytosol to the cell exterior. Many of these drugs are classified as weak bases whose binding to intracellular targets is pH-dependent. Slight alterations in intracellular pH gradients have been shown to affect accumulation, endocytosis and secretion of drugs. In this study, we developed a new method based on confocal spectral imaging analysis to determine intracellular pH gradients in sensitive and MDR tumor cells. Fluorescein isothiocyanate (FITC) and tetramethylrhodamine conjugated to dextran (FRD) and SNAFL-calcein-AM were used to determine pH in acidic compartments. Carboxy-SNARF1-AM was used to examine cytosolic pH. We observed that sensitive (HL60, K562, CEM and MCF7) cells exhibit lower acidity of the subcellular organelles than that corresponding to drug-resistant derivatives. Moreover, results obtained with carboxy-SNARF1-AM show that resistant cells display a more alkaline cytosolic pH. This results in a considerably larger pH gradient between the vesicular compartments and the cytosol of resistant cells than of sensitive cells. The lower pH gradient observed in sensitive cells may be related to a disruption in the organization of the trans-Golgi network (TGN). In drug-resistant cells, the organization of TGN appears compact. In addition, confocal microscopic analysis of cells labelled with FRD and SNAFL-calcein showed that sensitive cells contain a lower number of acidified vesicles. This suggest a diminished capacity of these cells to remove protonated drugs from the cytoplasm to secretory compartments followed by their secretion through the activity of the secretory and recycling pathways.
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PMID:Characterization of intracellular pH gradients in human multidrug-resistant tumor cells by means of scanning microspectrofluorometry and dual-emission-ratio probes. 1007 57


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