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

Photoradiation therapy with porphyrins and light offers an alternative approach to the management of certain types of cancer. The mechanism of tissue destruction mediated by this modality is poorly understood. In this study, epidermal microsomes incubated in vitro with Photofrin-I (Pf-I) and Photofrin-II (Pf-II) followed by exposure to radiation (approximately 400 nm) resulted in increased (180%) NADPH-supported (enzymatic) as well as ADP/iron-supported (140%) (nonenzymatic) lipid peroxidative damage as measured by malondialdehyde formation. Lipid peroxidation by Pf-I and Pf-II was found to be differentially affected by quenchers of singlet oxygen (2,5-dimethylfuran, histidine, beta-carotene, ascorbic acid, and sodium azide), superoxide anion (superoxide dismutase), and the hydroxyl radical (sodium benzoate, mannitol, and ethanol). Catalase, a quencher of hydrogen peroxide, afforded significant protection only against Pf-II-enhanced lipid peroxidative damage while it had little effect against the Pf-I-mediated reaction. Deuterium oxide, which is known to increase the half-life of singlet oxygen, was found to enhance Pf-I-mediated lipid peroxidation but produced insignificant effects upon Pf-II-mediated photosensitization. Our results indicate that Pf-I and Pf-II, which are employed for the photodynamic therapy of malignant tumors, evoke membrane damage by generating different reactive oxygen species. The Pf-I-mediated photodestruction mainly involves a type II mechanism via singlet oxygen formation, whereas Pf-II-mediated photodestruction preferentially involves a type I mechanism by generating superoxide anions and hydroxyl radicals. Our data indicate that tumor necrosis evoked by porphyrins and light is likely due to the generation of reactive oxygen species.
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PMID:Differential role of reactive oxygen intermediates in photofrin-I- and photofrin-II-mediated photoenhancement of lipid peroxidation in epidermal microsomal membranes. 283 56

The binary toxin produced by Clostridium botulinum, also known as type C2 toxin, was examined for its ability to alter the structure and function of Y-1 cells, a murine adrenocortical tumor line. The toxin produced time- and concentration-dependent changes in morphology, characterized by retraction of cell extensions and by rounding of the cell body. These changes were not accompanied by increases or decreases in tissue levels of c-AMP or c-GMP, although there was an increase in the release of total steroids. When cells were exposed to toxin for 24 hr there was no evidence of cell death or lysis. Total nucleic acid content and the rate of incorporation of 14C-leucine into protein were comparable in control cells and intoxicated cells. The toxin has been shown to possess mono(ADP-ribosyl)ating activity, and actin is the presumed substrate. When Y-1 cells were ruptured and then exposed to the toxin in the presence of 32P-NAD, actin was ADP-ribosylated. When cells were exposed to the toxin before being ruptured, there was a subsequent loss in the amount of actin that was available for ADP-ribosylation (32P-NAD) in the broken cell assay. The data suggest that Y-1 cells can survive challenge with the botulinum binary toxin, and thus they are a suitable tissue in which to use the toxin as a pharmacological tool.
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PMID:Actions of the Clostridium botulinum binary toxin on the structure and function of Y-1 adrenal cells. 284 29

Both forskolin, the activator of adenylate cyclase, and 8-bromocyclic (cAMP) increase cytosolic calcium levels (measured using Quin 2) and adrenocorticotropin (ACTH) release from a tumor cell line of the mouse anterior pituitary (AtT-20/D16-16). Somatostatin (SRIF) blocks the ACTH release response to each secretagogue but only inhibits forskolin-stimulated calcium mobilization suggesting that SRIF prevents the formation of cAMP rather than blocking the ability of cAMP to raise intracellular calcium concentrations. SRIF itself lowers intracellular calcium levels. The ACTH release response but not the rise in cytosolic calcium levels induced by the membrane-depolarizing agent K+, is blocked by SRIF, indicating that SRIF can interfere with some intracellular event, other than calcium mobilization or cAMP formation, to reduce ACTH secretion. Pertussis toxin uncouples SRIF receptors from adenylate cyclase by catalyzing the ADP-ribosylation of an inhibitory guanine nucleotide binding protein (Ni) in AtT-20 cell membranes. Pretreatment of AtT-20 cells with pertussis toxin abolishes the inhibition by SRIF of the ACTH release response and of the rise in cytosolic calcium induced by forskolin. In addition, the ability of SRIF to inhibit basal calcium levels is prevented by pertussis toxin treatment. Pertussis toxin treatment also reduced the ability of SRIF to inhibit K+-evoked ACTH release. SRIF receptor binding studies using the ligand 125I-CGP-23996 revealed that pertussis toxin treatment greatly diminished the affinity of the SRIF receptor for SRIF and its structural analogs. These results indicate that, in addition to coupling SRIF receptors to adenylate cyclase, Ni is also involved in the lowering by SRIF of resting calcium levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pertussis toxin blocks somatostatin inhibition of calcium mobilization and reduces the affinity of somatostatin receptors for agonists. 286 3

The effect of Adriamycin on mitochondria of the rat heart, liver, and Ehrlich ascites tumor mitochondria has been evaluated. The results may be summarized as follows: Adriamycin reduces both ADP- and FCCP-stimulated respiration, inhibits oxidative phosphorylation, decreases mitochondrial ATP-ase activity, and affects the redox state of respiratory carriers. These alterations are common to all types of mitochondria tested with almost similar patterns. However, the severe cardiotoxicity of the drug cannot be ascribed only to an effect on mitochondrial energy-yielding processes. The addition of hexokinase to phosphorylating heart mitochondria does not increase the sensitivity of succinate oxidation to Adriamycin. Experiments to determine the site of action were not able to detect a specific point of attack. It is conceivable, therefore, that the modifications induced by Adriamycin on the functional parameters of mitochondria may be ascribed to alterations of the physical state of some components of the inner mitochondrial membrane, e.g., lipids, which regulate the kinetic properties of the membrane-associated enzymes.
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PMID:Effect of adriamycin on electron transport in rat heart, liver, and tumor mitochondria. 287 39

The extracellular pH (pHe) in many solid tumors is often lower than the pH of normal tissues. The K+/H+ ionophore nigericin is toxic to CHO cells when pHe is below but not above 6.5, and thus it has potential for selective killing of tumor cells in an acidic environment. This study examines the pH-dependent effects of nigericin on the response of CHO cells to radiation and heat treatment. Cells held for 4 h in Hank's balanced salt solution, after 9 Gy irradiation, exhibit potentially lethal damage recovery (PLDR) which is maximal at pHe 6.7-6.8. Addition of nigericin, postirradiation, not only inhibits PLDR when pHe is below 6.8, but interacts synergistically with radiation to reduce survival below that of cells plated immediately after irradiation when pHe is 6.4 or lower. Nigericin enhances heat killing of CHO cells perferentially under acidic conditions, and where neither heat nor drug treatment alone is significantly toxic. Survival of cells held for 30 min at 42.1 degrees C in the presence of 1.0 microgram/ml nigericin is 0.6, 0.08, 0.003, and 0.00003 at pHe 7.4, 6.8, 6.6, and 6.4, respectively, relative to survival of 1.0 in untreated cultures. The biochemical effects of nigericin at pHe 7.4 vs pHe 6.4 have been investigated. Nigericin inhibits respiration, stimulates glucose consumption, and causes dramatic changes in intracellular concentrations of Na+ and K+ at pHe 7.4 as well as 6.4. The drug reduces intracellular levels of ATP, GTP, and ADP but has more pronounced effects under acidic incubation conditions. Others have shown that nigericin equilibrates pHe and intracellular pH (pHi) only when pHe is 6.5 or lower. Our observations and those of others have led us to conclude that lowering of pHi by nigericin is either the direct or indirect cause of enhancement of radiation and heat killing of cells in an acidic environment.
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PMID:pH-dependent effects of the ionophore nigericin on response of mammalian cells to radiation and heat treatment. 292 73

The energy status, radiobiological hypoxic cell fraction, and hyperthermic sensitivity of a spontaneous murine fibrosarcoma, FSa-II, have been evaluated as a function of tumor size. Tumors were evaluated over the size range of 70 to 800 mm3. The concentration of the high-energy phosphate reservoir creatine phosphate progressively decreased by a factor of 5 with increasing tumor volume, and was matched by an increase in creatine. The concentration of ATP also decreased with increasing tumor size, although this decrease was substantially less pronounced. The sum of ATP, ADP, and AMP did not vary with tumor size, suggesting that the necrotic fraction remained constant. The decrease in energy status occurred in parallel with an increase in the size of the hypoxic cell fraction and with increasing thermal sensitivity. The results suggest that energy status may be an important modifier of hyperthermic sensitivity in vivo and reflect tissue oxygen concentration.
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PMID:Relationship between energy status, hypoxic cell fraction, and hyperthermic sensitivity in a murine fibrosarcoma. 292 69

The effect of hyperthermia (1 hr, 41 degrees C) on the functional properties of Ehrlich ascites tumor mitochondria was investigated. Mitochondria isolated from Ehrlich ascites tumor after exposure of whole cells to 41 degrees C for 1 hr still phosphorylate and maintain a normal acceptor control ratio (ACR). The temperature decreases state 4 and ADP-and FCCP-stimulated respiration on various substrates entering at three energy-conserving sites of the respiratory chain. The inhibition of oxygen consumption by NAD- and FAD-linked substrates was 40% for state 4 and 70% for ADP- or FCCP-stimulated respiration. State 4 and FCCP-stimulated respiration of mitochondria on TMPD + ascorbate was affected 38% and 45%, respectively. ATPase activity was unaffected by hyperthermia, indicating that under these experimental conditions, the inhibition of ADP-stimulated respiration does not depend on an effect on either Fo F1-ATPase or adenine translocase, the activity of which is required for ATP entry prior to ATPase activity. Because of the inability to detect a specific site of action of temperature, it is conceivable that hyperthermia might inhibit substrate oxidation by altering some components of the inner mitochondrial membrane, which regulates the kinetic properties of the membrane-associated enzymes.
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PMID:Effect of hyperthermia on electron transport in Ehrlich ascites tumor mitochondria. 295 47

Lipophilic cations, such as rhodamine 123, have selective anticarcinoma activity both in epithelial-derived tumor cells and in tumor cells injected into mice. The mechanism by which rhodamine 123 and safranin have their effect on mitochondrial function was examined. Rhodamine 123 and safranin inhibit the stimulation of mitochondrial respiration by ADP in a similar concentration range. This inhibition occurs whether the mitochondria are respiring on succinate as a substrate or on ascorbate plus tetramethylphenylenediamine. ATP hydrolysis was stimulated twofold by high lipophilic cation concentration. These results demonstrate that rhodamine 123 and safranin affect oxidative phosphorylation in a similar fashion.
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PMID:Functional impairment induced by lipophilic cationic compounds on mitochondria. 296 37

Effects of various inhibitors on motility, heat, and lactate production of ejaculated bovine sperm were determined in the presence of antimycin A and rotenone. erythro-9-[3-(2-Hydroxynonyl)]adenine (EHNA) and polyvinylpyrrolidone (PVP-360) stopped motility and reduced heat or lactate production by 30-50%. Carbodiimides resulted in loss of motility and a reduction of metabolism by 60-75%. Quercetin treatment, which enhanced rather than inhibited motility, depressed heat and lactate production by 50-60%. Since mechanical immobilization reduced heat production by only 30%, the question arises as to what other cellular processes are major contributors to the energy budget. Inhibitors of ion flux had little-to-no effect on heat or lactate production, suggesting that neither mitochondrial nor Na+/K+ ATPases were major ATP-requiring processes. Calcium flux at the plasma membrane also was minimal and previous reports eliminated glycolytic substrate cycling as major consuming processes for ATP. Although quercetin inhibited lactate production in intact cells, no effect of quercetin on cell-free glycolysis and the ATPase activities of isolated dynein was detected. Quercetin did, however, inhibit ATPase activity of plasma membrane, suggesting that this unidentified ATPase may contribute to the formation of ADP and Pi required for lactate production by the intact cell. We propose (a) that the bioenergetic costs of motility are divided between regulatory events and dynein-microtubule interaction (dynein ATPase), (b) that some of the membrane-related processes may be "inefficient," and (c) that quercetin may render these steps more "efficient," in a manner analogous to its action on the Na+/K+ pump of Ehrlich ascites tumor cells.
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PMID:Motility, heat, and lactate production in ejaculated bovine sperm. 297 56

The tumor promoter phorbol-12-myristate-13-acetate (PMA) induces rapid poly ADP-ribosylation and a drop in cellular NAD concentration in human monocytes. The antioxidants CuZn-superoxide dismutase, catalase, glutathione peroxidase and butylated-hydroxytoluene inhibit the reaction indicating that active oxygen species produced in the PMA-induced oxidative burst represent intermediates. The inhibitor of ADP-ribosyl-transferase, 3-amino-benzamide, inhibited poly ADP-ribosylation but did not prevent the drop in NAD-levels. PMA also causes the slow accumulation of DNA strand breaks in monocytes. The difference in the kinetics of poly ADP-ribosylation and DNA breakage argues against a simple relationship between the two reactions.
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PMID:Tumor promoter phorbol-12-myristate-13-acetate induces poly ADP-ribosylation in human monocytes. 298 3


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