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

Murine resident macrophages can proliferate in vitro when they are grown in coculture on a layer of mesothelial or endothelial type feeder cells. Resident macrophages were obtained from lung explants of C57Bl/6 lpr/lpr mice and from spleen explants or peritoneal washing of Balb/c mice; the cells were seeded without further washing. After 3-4 weeks of culture, the macrophages began to proliferate on a confluent layer of feeder cells. The macrophages then could be collected in the fluid phase and reseeded for permanent culture after generation of a new feeder layer. These cells were characterized as macrophages by the following criteria: 1) their morphology, ultrastructure, and adherence properties; 2) more than 90% of the macrophages phagocytized yeasts compared with less than 1% of the feeder cells; 3) the presence of functional Fc and mannose receptors, nonspecific cytoplasmic esterases, and membrane ectoenzymes such as nicotinamide adenine dinucleotide (NAD) glycohydrolase and nucleotide pyrophosphatase; 4) by cytofluorographic phenotype analysis with monoclonal antibodies, characterizing a normal macrophage population (MAC1+, Fcrec+, H-2K+, THY1-, LYT2-, L3T4-). 5) by functional studies proving that the expanded macrophages could function as accessory cells in the induction of lymphocyte proliferation in response to concanavalin A (Con A), that they generated reactive oxygen radicals and that they were cytotoxic for tumor cells. During coculture, growth or activating factors such as macrophage colony-stimulating factor or gamma-interferon were released in the medium. Long-term cultured macrophages had chromosomal abnormalities. Our study suggests that tissue macrophages can proliferate in vitro and hence that it is possible to establish long-term cultured cell lines of macrophages of defined and reproducible characteristics.
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PMID:Establishment and characterization of long-term cultured cell lines of murine resident macrophages. 314 41

To assess a suitable model for the study of the mechanisms of development of insulin resistance in vivo, liver and muscle glycogen levels (as a metabolic index of tissue insulin sensitivity) were investigated in rats with functioning islet cell adenomas induced by streptozotocin and nicotinamide. These rats have basal moderate hyperinsulinemia and hypoglycemia and show a remarkable increase in insulin secretion after glucose administration. Plasma glucagon concentrations are normal. Nevertheless, in tumor-bearing rats, a reduction of tissue glycogen stores occurs, related to plasma glucose concentrations, and liver glycogen fails to increase even after a glucose load. The lack of excess fat in tumor-bearing rats also suggests a certain insulin insensitivity of the adipose tissue and distinguishes this model of chronic hyperinsulinism from other reported models, such as genetically obese animals.
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PMID:Reduction of glycogen stores in a rat model of chronic hyperinsulinism. 330 83

Colonic levels of nitrite and circulating levels of nitrate are elevated in subjects with chronic diarrhea. The role of colonic epithelial cells in oxidation-reduction of nitrite and consequent control of nitrite and nitrate levels is unknown. Isolated rat colonocytes and isolated loops of colon were used to study oxidation and reduction of nitrate and nitrite. Colonocytes oxidized nitrite to nitrate at a rate of 162 +/- 33 nmol/min.g (dry wt) (n = 6) over 0-20 min, a value increased by addition of 5 mM glucose and 1 mM nicotinamide adenine dinucleotide (p = less than 0.01), but not altered by antibiotics. Nitrite oxidation correlated linearly with the dry weight of isolated colonocytes (r = 0.92), indicating a cellular reaction. Nitrite was absorbed at a rate of 0.28 nmol/min.cm2 (n = 9) from the colonic lumen, which reflected 74% absorption of the available nitrite. Of the absorbed nitrite, 14.3% reappeared in the colonic lumen as nitrate. Colonocytes may be important in oxidizing nitrite to nitrate, thus preventing excess nitrite from entering into the circulation and returning some nitrate to the colonic lumen for respiration by anaerobic bacteria. The interaction of nitrites and colonocytes deserves further study with regard to the oxidation-reduction of nitrite and to the development of colonic neoplasia in chronic diarrheal conditions.
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PMID:Role of nitrite and nitrate as a redox couple in the rat colon. Implications for diarrheal conditions. 334 92

The presence of 50 microM t-butyl hydroperoxide induces the oxidation of intramitochondrial pyridine nucleotides and release of accumulated Ca2+ from rat liver but not AS-30D hepatoma mitochondria in the presence of succinate (plus rotenone) as a respiratory substrate. The effects of t-butyl hydroperoxide are mediated by the activities of glutathione peroxidase and reductase, which are less than 20 and 50% as active, respectively, in hepatoma than in normal liver mitochondria. However, the differences in the activities of these enzymes are not responsible for the insensitivity of succinate-energized tumor mitochondria to t-butyl hydroperoxide, since Ca2+ release and pyridine nucleotide oxidation can be elicited when ascorbate plus tetramethyl-p-phenylenediamine are used as alternative respiratory electron donors. In the presence of succinate alone, rat liver mitochondria generate malate exclusively, whereas AS-30D hepatoma mitochondria produce pyruvate and reduced nicotinamide adenine dinucleotide phosphate as well as malate due to the activity of a nicotinamide adenine dinucleotide phosphate-dependent malic enzyme which is not present in normal rat liver mitochondria. These results indicate that the maintenance of pyridine nucleotides in their reduced form by malic enzyme is responsible for the lack of t-butyl hydroperoxide-induced Ca2+ efflux by tumor mitochondria respiring on succinate. This altered pattern of mitochondrial metabolism may also influence the regulation of other reduced nicotinamide adenine dinucleotide phosphate-sensitive activities in addition to that of Ca2+ transport.
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PMID:Hydroperoxide-stimulated release of calcium from rat liver and AS-30D hepatoma mitochondria. 370 77

The activity of the malate-aspartate shuttle for the reoxidation of reduced cytosolic nicotinamide adenine dinucleotide (NADH) by mitochondria was studied in a line of human myeloid leukemia cells (K-562). The tumor cells showed mitochondrial reoxidation of cytosolic NADH, as evidenced by the accumulation of pyruvate, when incubated aerobically with L-lactate. The involvement of the respiratory chain in the reoxidation of cytosolic NADH was demonstrated by the action of rotenone, antimycin A, and oligomycin which strongly inhibited the formation of pyruvate from added L-lactate. Moreover, pyruvate production was greatly inhibited by the transaminase inhibitor, aminooxyacetate. Under glycolytic conditions, in the presence of aminooxyacetate, the rate of pyruvate production was also markedly inhibited, the rate of lactate accumulation was stimulated, and at 60 min the cytosolic NADH/nicotinamide adenine dinucleotide (NAD) ratio had increased progressively about 5-fold with respect to untreated cells. The maximal rate of the malate-aspartate shuttle has also been established by addition of arsenite to inhibit mitochondrial oxidation of the pyruvate formed from added L-lactate.
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PMID:Oxidation of reduced cytosolic nicotinamide adenine dinucleotide by the malate-aspartate shuttle in the K-562 human leukemia cell line. 375 5

Exposure of target cells to a bolus of H2O2 induced cell lysis after a latent period of several hours, which was prevented only when the H2O2 was removed within the first 30 min of injury by addition of catalase. This indicated that early metabolic events take place that are important in the fate of the cell exposed to oxidants. In this study, we described two early and independent events of H2O2-induced injury in P388D1 macrophagelike tumor cells: activation of the glutathione cycle and depletion of cellular NAD. Glutathione cycle and hexose monophosphate shunt (HMPS) were activated within seconds after the addition of H2O2. High HMPS activity maintained glutathione that was largely reduced. However, when HMPS activity was inhibited--by glucose depletion or by incubation at 4 degrees C--glutathione remained in the oxidized state. Total pyridine nucleotide levels were diminished when cells were exposed to H2O2, and the breakdown product, nicotinamide, was recovered in the extracellular medium. Intracellular NAD levels fell by 80% within 20 min of exposure of cells to H2O2. The loss of NADP(H) and stimulation of the HMPS could be prevented when the glutathione cycle was inhibited by either blocking glutathione synthesis with buthionine sulfoximine (BSO) or by inhibiting glutathione reductase with (1,3-bis) 2 chlorethyl-1-nitrosourea. The loss of NAD developed independently of glutathione cycle and HMPS activity, as it also occurred in BSO-treated cells.
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PMID:Glutathione cycle activity and pyridine nucleotide levels in oxidant-induced injury of cells. 384 Jan 76

In contrast to thymine and 5-fluorouracil (FUra) which were cleared from the bloodstream within 2-4 h after their i.p. administration (200 mumol/kg) to rat, (E)-5-(2-bromovinyl)uracil (BVUra) maintained a concentration of 50-70 microM for at least 6 h and was still present in the plasma 24 h after its administration. In vitro experiments with rat liver extracts indicated that BVUra was not a substrate but an inhibitor for the reductive step in pyrimidine degradation catalyzed by dihydrothymine dehydrogenase. Kinetic and dialysis experiments suggested that BVUra was an irreversible inhibitor of this enzyme. The binding of BVUra to the enzyme depended on the presence of reduced nicotinamide adenine dinucleotide phosphate in the reaction mixture. Dihydrothymine dehydrogenase activity was also inhibited in the dialysed 105,000 X g supernatant fraction of livers from rats that had previously been treated with BVUra. Such inhibitory effects also occurred in vivo; previous administration of BVUra increased the plasma half-lives of thymine and FUra by 10- and 5-fold and their area under the curve by 9- and 8-fold, respectively. The effect of BVUra on the antitumor activity of FUra was evaluated in DBA/2 mice inoculated with 10(6) P388 leukemia cells. The mean survival times for the control and FUra-treated mice (5 mg/kg at 1, 3, 5, and 7 days after tumor cell inoculation) were 9.7 and 12.4 days, respectively. When BVUra (200 mumol/kg) was administered 1 h before each injection of FUra, the mean survival time was extended to 17.1 days. BVUra alone did not affect the mean survival time. When the dose of FUra was increased to 20 mg/kg, the mean survival time was 15.3 days; upon a preceding injection of BVUra the mean survival time decreased to 9.2 days. The latter effect probably resulted from an increased toxicity of FUra. Similar results were obtained if FUra was replaced by 5-fluoro-2'-deoxyuridine and BVUra by (E)-5-(2-bromovinyl)-2'-deoxyuridine. The enhancement of both the antitumor and toxic effects of FUra by BVUra were most probably due to an inhibition of FUra degradation, since, like in rats, BVUra increased the plasma half-life of FUra in DBA/2 mice. Hence BVUra appears to be an interesting compound, increasing the potency of FUra by decreasing its degradation.
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PMID:Effect of (E)-5-(2-bromovinyl)uracil on the catabolism and antitumor activity of 5-fluorouracil in rats and leukemic mice. 394 86

AspCNU and SarCNU are two amino acid amide congeners (L-asparaginamide and sarcosinamide congeners) of chloroethylnitrosoureas. The in vitro myelotoxicity of these agents compared with BCNU at 1-8 micrograms/ml was determined in bone marrow cells from normal volunteers in the CFU-C assay. AspCNU and SarCNU were significantly (P less than 0.05) less myelotoxic than BCNU at equivalent microgram concentrations. SarCNU or AspCNU at 3 micrograms/ml demonstrate equivalent in vitro myelotoxicity to BCNU 1 microgram/ml. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained four specimens of malignant glioma and one specimen of meningioma from patients not previously treated with chemotherapy. AspCNU and SarCNU were significantly (P less than 0.05) more active than BCNU at 1-3 micrograms/ml concentrations in the HTSCA in all four malignant glioma specimens. In the one meningioma specimen, BCNU was significantly (P less than 0.05) more active than either AspCNU or SarCNU at all concentrations studied. These results suggest that AspCNU or SarCNU at doses that should produce less myelotoxicity than BCNU may be more active than BCNU against gliomas.
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PMID:Utilization of the HTSCA and CFU-C assay to identify two new 2-chloroethylnitrosourea congeners of amino acid amides with increased in vitro activity against human glioma compared with BCNU. 397 80

Specific lysis of tumor cells by thymus-derived lymphocytes from alloimmunized mice (T-effector specific lysis) was studied with target cells labeled with isotopes attached to both small ((14)C-labeled nicotinamide) and large ((51)Cr-labeled) molecules. The results confirm and extend previous reports that target cells release small molecules considerably earlier than large molecules during T-effector specific lysis. After interruption of T-effector specific lysis by specific antibody and complement directed against the killer cells, or by ethylenediaminetetraacetic acid, release of both isotopes continued, eventually reaching identical levels of specific release, the value of which represents the fraction of the target cell population which had been committed to die at the time these treatments were applied. On the other hand, release of both isotopes during T-effector specific lysis stops immediately when the cultures are cooled to 0 degrees . Thus, while ethylenediaminetetraacetic acid or specific complement-mediated lysis of the killer cells merely prevents the initiation of any new damage to target cells, cooling to 0 degrees also stops the lytic process in already-damaged target cells. The colloid osmotic phase of target cell lysis induced by specific antibody and complement was similarly stopped at 0 degrees in tumor cells, but not in erythrocytes. Thus, in tumor target cells, both T-effector specific lysis and complement cause a sequential release of progressively larger molecules which can be immediately stopped at any point by cooling to 0 degrees .
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PMID:Interruption of the sequential release of small and large molecules from tumor cells by low temperature during cytolysis mediated by immune T-cells or complement. 435 27

In these preliminary experiments, we have found enhanced cell killing by the bifunctional alkylating agent L-phenylalanine mustard (L-PAM) in the presence of inhibitors of poly (ADP-ribose) polymerase (ADPRP) in vitro. In vivo enhancement of the tumoricidal effects of L-PAM was observed with the ADPRP inhibitor nicotinamide (1000 mg/kg), although enhanced myelosuppression was also demonstrated. Nicotinamide also increased the plasma elimination half-life of L-PAM by a factor of at least 2. This alteration of L-PAm pharmacokinetics makes it difficult to assess the role that ADPRP inhibition plays in the enhancement of L-PAM tumor cell killing in vivo.
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PMID:Enhancement of melphalan cytotoxicity in vivo and in vitro by inhibitors of poly (ADP-ribose) polymerase. 609 Mar 66


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