Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemical synthesis of adenosine(5') [alpha-thio]diphospho(5')ribofuranosyl-nicotinamide (NAD[S]) is described. The product occurs as a pair of diastereomers with different configuration at the sulfur-bearing phosphorus atom. The diastereomers were separated by high-performance liquid chromatography and their absolute configuration was determined after chemical degradation to the ADP[alpha S] diastereomers and chromatographic comparison with enzymically synthesized ADP[alpha S] diastereomers of known absolute configuration. Additional support for this assignment is based on different rates in the phosphodiesterase-catalyzed hydrolysis. Furthermore the synthesis of [14C]NAD[S] is described. The coenzyme activity of NAD[S] in the reaction with alcohol dehydrogenase from baker's yeast and lactate dehydrogenase from pig heart is very similar to that of beta-NAD. Also, NAD and NAD[S] serve equally well as substrates for NAD glycohydrolase from calf spleen. In contrast, no reaction was detected with NAD pyrophosphorylase, and hydrolysis of the separated NAD[S] diastereomers with snake venom phosphodiesterase showed a 26-fold and a 33-fold slower reaction rate than that of NAD. Nucleotide pyrophosphatase was less sensitive to the S substitution, hydrolyzing NAD[S] 14-times slower than NAD. Poly(ADP-ribose) polymerase from Ehrlich ascites tumor cell nuclei accepted NAD[S] as a substrate but the reaction was significantly slower and approached saturation at much lower values than with NAD. Alkaline hydrolysis of the products insoluble in trichloroacetic acid yielded AMP[S] as the main derivative. It is concluded that with NAD[S] as a substrate the nuclear acceptors were nearly exclusively mono(ADP-ribosyl) ated .
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PMID:NAD[S], an NAD analogue with reduced susceptibility to phosphodiesterase. Chemical synthesis and enzymic properties. 614 44

Since it is known that tumor cell membranes have lost the capacity to undergo lipid peroxidation, it seemed of interest to investigate whether the loss of susceptibility to lipid peroxidation represents a tumoral marker appearing in preneoplastic cells together with the other known tumoral markers. A histochemical technique was developed to detect lipid peroxidation in individual cells of liver sections exposed to effective prooxidants. The technique was based on the detection of protein-bound aldehydes (alkenals) with the use of the Schiff's reagent. The latter reagent can also detect carbonyl function present in acyl residues of peroxidized phospholipids of cellular membranes. Liver preneoplastic foci were obtained in rats by the i.p. administration of diethylnitrosamine and of 2-acetylaminofluorene in the diet. Frozen sections of the liver, incubated in the presence of reduced nicotinamide adenine dinucleotide phosphate:iron revealed the presence of areas in which lipid peroxidation had not been induced (Schiff-negative areas). These areas corresponded strictly, in serial sections, to areas that were strongly positive to gamma-glutamyltranspeptidase.
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PMID:Loss of lipid peroxidation as a histochemical marker for preneoplastic hepatocellular foci of rats. 614 8

Following the parenteral administration of tiazofurin, 2-beta D-ribofuranosylthiazole-4-carboxamide (thiazole nucleoside, TR), a potent but reversible inhibitor of IMP dehydrogenase is generated in subcutaneous nodules of the P388 leukemia. The compound responsible for this effect has been isolated from homogenates of the tumor by ion-exchange HPLC, and its presence monitored by enzyme-inhibition assay. The inhibitor has also been prepared by incubation of tiazofurin with P388 cells in culture. Chromatographically, the inhibitory principle exhibits a moderately strong set negative charge at pH 3, and elutes in the general vicinity of the nucleoside-5'-diphosphates; its absorption maximum in aqueous solution (pH 7) lies at 252 nm. Exposure of the molecule to snake-venom phosphodiesterase or to nucleotide pyrophosphatase destroys its inhibitory potency, whereas other phosphodiesterases are either less effective or inert. Since these results suggested that the anabolite might be a dinucleotide with a phosphodiester linkage of the kind found in NAD, attempts were made to synthesize such an analogue from the 5'-monophosphate of thiazole nucleoside and ATP-Mg2+, using a purified preparation of NAD pyrophosphorylase; modest yields were obtained of a compound with chromatographic, spectral and enzyme-inhibitory properties identical to those of the material isolated from P388 tumor nodules. This enzyme-synthesized material was radioactive when [3H]ATP was used as cosubstrate, and yielded both AMP and thiazole nucleoside-5'-monophosphate on treatment with phosphodiesterase. It resisted attack by NAD glycohydrolase. An apparently identical dinucleotide was also synthesized chemically by means of the Khorana condensation. Mass spectral analysis and nuclear magnetic resonance studies with homogeneous preparations of both the enzymically and chemically synthesized compound were compatible with its being a dinucleotide in which the nicotinamide of NAD has been replaced by thiazole-4-carboxamide. Versus IMP dehydrogenase, the dinucleotide exhibited a K1 of approximately 2 X 10(-7) M and was non-competitive with NAD as the variable substrate. Other NAD utilizing enzymes, including representative dehydrogenases and poly ADP ribose polymerase, were, by comparison to mammalian IMPD, resistant to inhibition by TAD. The properties of this novel dinucleotide are compared and contrasted with those of analogs of NAD containing modifications in the pyridine, adenine or ribofuranose rings, as well as in the pyrophosphate bridge.
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PMID:Studies on the mechanism of action of tiazofurin metabolism to an analog of NAD with potent IMP dehydrogenase-inhibitory activity. 615 29

Diabetic mouse serum was found to be toxic to F-10 melanoma cells in vitro. However, when F-10 cells were injected intravenously into streptozotocin-induced diabetic mice there was a significant increase in the number of lung tumors. Contrarily, when streptozotocin was injected after F-10 cells there was a 5-fold decrease in lung metastases. Reversal of the diabetes in these mice by nicotinamide or insulin injection did not increase the lung metastases. Solid tumors (resulting from the subcutaneous injection of F-10 cells) grew at similar rates in both control and diabetic mice. Streptozotocin injected after F-10 cells resulted in a 6 day delay in the appearance of solid tumors. Triglycerides, the toxic factors in vitro, were elevated to similar extents in both tumor-bearing control and diabetic mice. Most of the differences in tumor growth between control and streptozotocin injected mice were attributable to the antitumor activity of streptozotocin, rather than the diabetic state.
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PMID:Differential effects of streptozotocin and streptozotocin-induced diabetes mellitus on tumor metastases and growth in mice. 623 Sep 83

Special diets that were extremely low in protein (5.5%) and high in carbohydrate were used to test the effect of nicotinamide on N-nitrosodimethylamine-induced carcinogenesis in Holtzman albino rats. The level of nicotinamide in the three diets ranged from 0 mg/kg of food to 50 mg/kg to 500 mg/kg. During the treatment with these diets (5 weeks) and the carcinogen (18 days), the renal and hepatic concentrations of nicotinamide adenine dinucleotide-reduced nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate-reduced nicotinamide adenine dinucleotide phosphate were measured. In the liver, the concentration of these coenzymes fell well below normal levels, and significant differences between the two extreme diets (0 and 500 mg/kg) were found in the hepatic content of nicotinamide adenine dinucleotide-reduced nicotinamide adenine dinucleotide. In the kidney, the treatment with special diets and carcinogen had less effect. The content of nicotinamide adenine dinucleotide phosphate-reduced nicotinamide adenine dinucleotide phosphate remained normal, and the only significant drop in the concentrations of nicotinamide adenine dinucleotide-reduced nicotinamide adenine dinucleotide phosphate occurred in the animals on the nicotinamide-deficient diet. After the treatment, all of the animals were returned to the same standard diet. During the remainder of the experiment, 85 weeks, it was found that the initial treatments had not affected tumor incidence levels or tumor type, but had altered the rate of tumor incidence. These differences could be seen by comparing the results for the rats that had been given the nicotinamide-deficient diet to the results for the animals receiving an excess of the vitamin.
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PMID:N-nitrosodimethylamine carcinogenesis in nicotinamide-deficient rats. 623 Oct 98

The distribution of cytosolic activity of nicotinamide:S-adenosylmethionine methyltransferase (nicotinamide methylase, EC 2.1.1.1) in normal tissues from adult rat and mouse and in tumors and the change in the enzyme activity during the development of rat tissues were studied. (1) Rat liver exhibited the highest nicotinamide methylase activity among all adult tissues tested; other rat tissues, like adrenal, pancreas, kidney, brain and mouse tissues, had only less than 15% of the adult rat liver activity. (2) 3 days before birth, fetal liver showed a very low nicotinamide methylase activity (2% of adult rat liver), which, however, increased already 1 day before birth and reached the adult level on the day 28 after birth. (3) In a variety of hepatomas and ascites tumors, an inverse correlation, with some exceptions, between tumor growth rate and nicotinamide methylase activity could be seen. In all hepatomas, with the exception of Morris hepatoma 5123tc, nicotinamide methylase activity was significantly decreased in comparison to normal adult rat liver. The highly malignant Zajdela hepatoma, Yoshida sarcoma, sarcoma 180 and Ehrlich ascites tumor methylated nicotinamide only at a negligibly low rate. (4) Cultured RLC cells (an established rat liver cell line) from the stationary growth phase or G1-arrested RLC cells had about half of the adult rat liver activity, yet the activity was 70% higher than that of the logarithmically growing RLC cells.
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PMID:Nicotinamide methylation. Tissue distribution, developmental and neoplastic changes. 623 53

A serially transplantable, chemically induced pancreatic islet cell tumor was developed in Lewis rats. The original tumor was induced by the administration of streptozotocin and nicotinamide. It was subsequently maintained by ip or sc transplantation of tissue fragments into recipient animals. Tumors generally grew to 0.5--2.0 cm in diameter within 3--4 months of transplantation. They were well encapsulated, without gross evidence of metastasis. Peroxidase immunocytochemical staining revealed a predominance of insulin-positive cells. Somatostatin-positive cells were also present and varied widely in numbers between different tumors. In addition, small numbers of glucagon-positive cells were observed in all of the tumors. On electron microscopy, cells containing secretory granules, indistinguishable from nonneoplastic beta-cells, were most abundant. Other granulated cells were also observed, but the granule morphology was not identical to that of any of the other classically described islet cell types. Tumor extracts contained an average of 3260 micrograms insulin, 22.6 micrograms somatostatin, and 0.84 micrograms glucagon per g wet wt of tissue. Tumors caused marked, progressive hypoglycemia in recipients, with plasma glucose levels frequently falling below 30 mg/dl before death. Furthermore, the recipients' islets were markedly reduced in size due to a decreased beta-cell volume.
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PMID:Serially transplantable chemically induced rat islet cell tumor. 625 Aug

Total superoxide dismutase (SOD) and manganese superoxide dismutase (Mn SOD) specific activities were measured in tissue homogenates and in isolated mitochondria from normal rat liver and three Morris hepatomas of different growth rates. Total SOD and Mn SOD specific activities were decreased in all tumor homogenates when compared to normal liver; the lowest activity was associated with the fastest growing tumor. These results are consistent with the hypothesis that total Mn SOD specific activity is decreased in all tumors. The Mn SOD specific activity was similar to the total SOD specific activity of isolated mitochondria, indicating that mitochondrial SOD is almost entirely manganese containing. This activity was decreased in the fast- and medium-growth-rate hepatomas but was slightly increased in the tumor with the slowest growth rate when compared to liver. The normal or higher than normal mitochondrial Mn SOD specific activity indicates that decreased mitochondrial SOD specific activity is not a characteristic of all tumors. Superoxide radical (O2-.) formation was measured in submitochondrial particles obtained by sonication of isolated mitochondria and subsequent washings to remove the SOD. The difficulty encountered in reducing the SOD activity suggests that at least part of the mitochondrial SOD might be associated with the mitochondrial membrane. In liver submitochondrial particles, O2-. was formed only when succinate and antimycin A were used together, as substrate and inhibitor of the electron transport chain, respectively. In the hepatomas studied for O2-. production (slow- and fast-growth rates), the formation of the radical was detected in the presence of succinate even when no inhibitor was present. Antimycin A stimulated the production of O2-. in normal rat liver and slow-growth-rate tumor, but not in fast-growth-rate tumor submitochondrial particles. Reduced nicotinamide adenine dinucleotide did not lead to the production of O2-. by normal liver or hepatoma submitochondrial particles. Mitochondrial membrane damage was seen in micrographs of the medium- and fast-growing hepatomas. This could be a consequence of low mitochondrial SOD concomitant with a flux of superoxide, if the radical is produced in vivo by these mitochondria.
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PMID:Superoxide dismutase and superoxide radical in Morris hepatomas. 625 38

Morphological and biochemical studies were performed in pancreatic islet cell tumors found in rats given alloxan (40 mg/kg) and nicotinamide (305 mg/kg). Complete serial sections of the whole pancreas, combined with planimetric analysis, uncovered islet cell tumors in 5 of 7 rats which were killed 10 to 14 months after treatment. Hypoglycemia associated with hyperinsulinemia was found in a rat which developed a tumor which consisted of cells which reacted lightly with aldehyde fuchsin. Another rat developed a gross tumor which was composed of cells stained deeply with aldehyde fuchsin. However, flat insulin response to glucose associated with glucose intolerance was found in this rat. In addition to B cells, a few A and D cells were found within the two tumors. The present study suggests that pancreatic islet cell tumors found in rats given alloxan and nicotinamide are composed of at least three endocrine cell populations, although the majority of tumor cells are insulin-producing B cells.
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PMID:Pancreatic islet cell tumors found in rats given alloxan and nicotinamide. 625 53

Young male Holtzman rats injected with nicotinamide and streptozotocin develop grossly visible tumors of pancreatic islet tissue. Using an i.v. glucose tolerance test, some tumor-bearing animals exhibited a vigorous (or fast) response to glucose loading (Diabetic Index = 0.47), whereas others showed a subdiabetic (or slow) response (Diabetic Index = 2.34). In vitro perifusion studies demonstrate that tumor pieces from both groups of rats released immunoreactive insulin (IRI) in response to glucose; tumors from fast responding rats showed a rapid monophasic release of IRI (i.e., rapid transient release with little secondary phase), while tumors from slow responders released IRI in a biphasic pattern resembling that of normal islets. A population of large islet masses (or microscopic tumors), isolated from drug-treated rats by collagenase digestion of the pancreas of tumor-containing rats, exhibited glucose-stimulated IRI release that resembled the pattern of the tumor from the same animal. Isolated islets of Langerhans of ordinary size from the pancreas of tumor-bearing rats, on the other hand, usually exhibited a normal (biphasic) IRI release pattern in response to glucose. Analysis by gel filtration suggests that the predominant form of IRI released from perifused tumor preparations, under either basal or glucose-stimulated conditions, eluted at a rate corresponding to rat insulin.
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PMID:Insulin release in vitro from islet tissues and adenomas of rats treated with nicotinamide and streptozotocin. The effects of glucose. 625 6


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