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

Liver microsomes of the rat contain a group of hydroxylating enzymes which are coupled to a greater or lesser degree to the electron flow system. In our studies, enzymes believed to be directly associated with the electron flow chain of NADPH, ferricyanide reduction, cytochrome c, cytochrome P-450 and substrate hydroxylation have been observed in livers obtained from normal, tumor-bearing and whole body irradiated rats as well as in Morris hepatoma 7777 and dimethyl-amino-biphenyl induced breast tumors.A significant difference appeared to exist in the activity of NADPH oxidase, NADP-ferricyanide reductase and benzopyrene hydroxylase when normal liver was compared with the liver obtained from a breast-tumor-bearing animal. Both cytochrome P-450 and cytochrome b(5) were decreased in the tumor-bearing animal.Tissue distribution of benzopyrene hydroxylase in normal, lactating and tumor-bearing Wistar rats has been studied.With the exception of NADPH oxidase, the activities of NADP-cytochrome c reductase, NADPH-ferricyanide reductase, benzopyrene hydroxylase and P-450 were markedly different in liver from Morris hepatoma 7777-bearing Buffalo rat when this was compared with homologous tissue obtained from normal Buffalo rat.Whole-body irradiated animals showed increased P-450 and NADPH oxidase activity in liver as a function of irradiation and there further appeared to be a correlation with decreased ferricyanide reductase activity.
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PMID:Mixed-function oxidation in tumors. 439 26

The glycerol portion of lipids may be derived biosynthetically by reduction of dihydroxyacetone phosphate to glycerolphosphate, and then be acylated with fatty acids or, alternatively, dihydroxyacetone phosphate may first be acylated and then reduced to 1-acyl sn glcerol-3-phosphate. Since the former pathway utilizes NADH for reduction of the C-2 carbonyl, while the latter requires NADPH, we were able to compare the relative participation of the two pathways for phospholipid synthesis by measuring the incorporation of radioactivity from tritiumlabeled NADH and NADPH into C-2 of lipid glycerol. The acyl-dihydroxyacetone phosphate pathway plays a significant role in glycerolipid synthesis in mouse liver homogenates and a clearly dominant one in Ehrlich ascites tumor cell homogenates. This finding is related to a reported lack of glycerol-3-phosphate dehydrogenase in tumor cells and to their high glycerol ether lipid content.
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PMID:The acyl dihydroxyacetone phosphate pathway for glycerolipid biosynthesis in mouse liver and Ehrlich ascites tumor cells. 527 94

Effects of adenosine and related compounds on the regulation of steroid production by isolated Leydig cells have been investigated. Steroid production by freshly isolated Leydig cells from testes of immature or mature rats and mice, or from Leydig tumor tissue could not be stimulated with adenosine, nicotinamide-adenine dinucleotide (phosphate) [NADPH, NAD(P)] or N6-(1-2-phenylisopropyl)-adenosine (PIA) (50 microM), whereas luteinizing hormone (LH) stimulated steroid production more than 10-fold. After 24 h incubation all adenosine-related compounds, but not inosine, stimulated steroid production to 20-100% of the maximal LH-stimulated activity. LH- or 22R -hydroxycholesterol-stimulated steroidogenesis in Leydig cells from immature rats did not decrease during the 24-h culture period, whereas ATP levels increased. The first significant effect of adenosine on steroid production in these cells was found after an incubation period of 3 h. In cells incubated for 1 h and 24 h, LH stimulated cyclic adenosine 3':5'-monophosphoric acid (cAMP) production 10-fold. Significant effects of adenosine and PIA on cAMP production or protein phosphorylation could only be shown in cells incubated for 24 h. Effects of adenosine on Leydig cells in intact testis tissue of immature rats could not be determined. The results suggest that after isolation of Leydig cells, specific alterations in the cell membrane occur, causing increased sensitivity to adenosine and related compounds. Adenosine apparently does not play a role in the role of steroid production in Leydig cells in vivo.
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PMID:Development of adenosine responsiveness after isolation of Leydig cells. 632 34

Several kinds of neoplastic diseases have been described in mollusks collected from the field. The etiology of these lesions is unknown; however, the involvement of chemical carcinogens has been suggested. Experimental models for chemically-induced neoplasia in bivalves have yet to be developed. We have obtained data which suggest that aromatic amines may be more appropriate candidates than polycyclic aromatic hydrocarbons for putative molluscan carcinogens. Digestive gland enzymes from a bivalve mollusk, Mercenaria mercenaria, were found to be able to convert aromatic amines to frameshift mutagens as detected by the Ames Salmonella tester strains. Extensive mutagenesis was obtained with 2-aminoanthracene, 2-aminofluorene, 2-acetylaminofluorene and 4-amino-trans-stilbene which are all mammalian procarcinogens. Mutagenic activation of benzo[a]pyrene and 3-methylcholanthrene was minimal. Low levels of aromatic amine-activating enzyme(s) were found in all tissues examined, but activity was greatest in the digestive gland. Enzymatic activity was heat-labile, NADPH-dependent, and apparently not inducible by polychlorinated biphenyls (Aroclor 1254).
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PMID:Activation of mammalian carcinogens to bacterial mutagens by microsomal enzymes from a pelecypod mollusk, Mercenaria mercenaria. 633 94

Earlier evidence, in Part I of this paper, has shown that cytotoxic and antitumor 1-nitroacridines did not primarily exert their potent inhibitory effects on cultured mammalian cells by physicochemical binding with DNA, although it undoubtedly occurred (Chem.-Biol. Interact., 43 (1983) 131). As a result it was investigated (i) whether 9-14C- or 1'-14C-labeled derivatives of their representative, 1-nitro-9-/3'-dimethylamino-n-propylamino/acridine (Ledakrin or Nitracrine), were capable of covalent binding with nucleic acids and other suitable macromolecules in target cells in vivo and/or (ii) whether activation of the agent in the cell was a necessary prerequisite for such binding. Using the criteria of resistance to exhaustive extractions with trichloroacetic acid and/or organic solvents, [14C]Ledakrin was found to bind covalently, with relatively little discrimination, with: (i) intracellular macromolecules, including DNA, of cultured tumor HeLa cells (370-2500 DNA base pairs/one Ledakrin molecule; (ii) experimental animal tumor Ehrlich ascites (Eat) cells in vivo (650-5880 DNA base pairs/one Ledakrin molecule); (iii) bacterial Bacillus subtilis SB 1058 cells (7000-33 000 Ledakrin links/one cell genome); (iv) NADPH-fortified rat liver homogenates in vitro (25.6 nmol/mg microsomal protein under air). These results far exceed the common levels reported for alkylating agents or chemical carcinogens. Unlike [ethyl-14C]quinacrine, compared in vitro, covalent macromolecules binding with Ledakrin in vitro, and most probably in vivo, can be equated to NADPH-dependent activation(s) by oxidoreductase systems and the presence of DNA alone was not satisfactory in itself to attain Ledakrin binding. Fractionation of the enzymatic digest of 14C-associated DNA, isolated from Eat cells exposed in vivo to [9-14C]Ledakrin, by Sephadex LH-20 column chromatography followed by mass spectrometry analyses of modified nucleosides, indicated that both mono- and dinucleosidical Ledakrin metabolites were the products of an in vivo reaction. This implied that the lethal reaction of the drug could be its cross-linking of the target macromolecules and/or its monofunctional attack on vitally important cellular components.
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PMID:The mode of action of cytotoxic and antitumor 1-nitroacridines. II. In vivo enzyme-mediated covalent binding of a 1-nitroacridine derivative, Ledakrin or Nitracrine, with dna and other macromolecules of mammalian or bacterial cells. 640 14

Isoenergetic diets containing 20% corn oil, 20% beef tallow, or an equal mixture of 10% corn oil and 10% beef tallow (mixed fat) were fed to 30 rats per diet for 28 weeks following weaning. DMBA [7,12-dimethylbenz(a)anthracene] was administered (1.75 mg/100 g body weight) in a single oral dose after 4 weeks of feeding. After 28 weeks, 70% of the rats fed corn oil had mammary tumors versus 47% for mixed fat and 30% for tallow. Diet had no effect on the number of tumors per tumor-bearing rat or the proportion of tumors that were adenocarcinomas. Other rats assigned to each of the three diets were killed at the time corresponding to DMBA administration for examination of hepatic mixed-function oxidase activity. NADPH cytochrome c reductase activity and cytochrome P-450 content were higher in rats fed corn oil or mixed fat rather than tallow. However, no significant differences in aryl hydrocarbon hydroxylase, glutathione transferase, and uridine-diphosphoglucuronide transferase activities were observed. The effects of dietary fat saturation on enzyme activity failed to show a clear association with DMBA carcinogenesis. In other rats assigned to the three dietary treatments for 4 or 16 weeks, lipid saturation did not change serum prolactin (PRL) concentrations during diestrus or proestrus. PRL secretion was examined following a provocative stimulus (perphenazine) in rats fed the experimental diets for 4 or 10-22 weeks. Although perphenazine increased serum PRL and depleted the pituitary of PRL, differences in dietary lipid saturation caused no significant changes in these indices. These data show that the incidence of mammary tumors in rats fed high fat diets (20% by weight) was greater in those fed corn oil compared to beef tallow. The effect of dietary lipid source on tumorigenesis was not associated with changes in carcinogen-metabolizing enzyme activity or PRL secretion.
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PMID:Effects of dietary lipid saturation on prolactin secretion, carcinogen metabolism and mammary carcinogenesis in rats. 643 76

Although it is well known that the development of uterine myoma is influenced by estrogen, the details of its remain unknown. In this study, estrogen biosynthesis (androstenedione aromatase activity) was investigated in the myoma tissue (the central, surface and middle parts of the tumor) and in the myometrial tissue of the same uterus (5 cases). The tissue homogenate (500 mg w. w.) was incubated with [6,7-3H]-androstenedione (100pmol) and NADPH (1.5mg) at 37 degrees C for 1h in air. After stopping the enzyme reaction with ethyl acetate, [4-14C]-estrone and [4-14C]-estradiol-17 beta (10,000dpm, 250 micrograms, respectively) were added to the incubated sample. The sample extracted with ethyl acetate was subjected to Bio-Rad AG1-X2 column, thin layer chromatography and co-crystallization to constant specific activity and 3H/14C ratio. Estrogen formed in the incubated sample was calculated from the 3H/14C ratio of the final crystal. The myoma tissues (14 samples) converted from androstenedione to estrone (36-466 fmol/h/g), while the myometrial tissues of the same uterus did to a lesser extent (22-78 fmol/h/g), while the myometrial tissues of the same uterus did to a lesser extent (22-78 fmol/h/g). Thus, aromatase activity was significantly higher in the myoma tissue rather than in the myometrial tissue of the same uterus. Less estradiol was formed than estrone in both tissues. The distribution of aromatase activity in the tumor was also investigated, and it was found that the enzyme activity tends to become greater away from the center and towards the surface of the tumor. These results suggest that aromatase activity for androgen contributes to the development of uterine myoma.
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PMID:[Estrogen biosynthesis in human uterine myoma tissue. The distribution of androstenedione aromatase activity in uterine myoma tissue]. 650 68

Thalidomide metabolites inhibited the attachment of tumor cells to concanavalin A coated polyethylene surfaces. Thalidomide, itself, was non-inhibitory. Thalidomide activation to inhibitory products required hepatic microsomes, an NADPH-generating system, and molecular oxygen. Production of inhibitory metabolites was unaffected by either epoxide hydrolase or 1,2-epoxy-3,3,3-trichloropropane (TCPO), an inhibitor of epoxide hydrolase endogenous to hepatic S9 fraction. Therefore, the attachment inhibitor was probably not an arene oxide. Inhibition was not accompanied by cytotoxicity, as judged by trypan blue exclusion. Although uninduced hepatic microsomes from mice, rats and dogs had similar abilities to activate thalidomide, microsomes from Aroclor 1254 induced rats were relatively inactive in the system. Inhibitory metabolites were generated from the thalidomide analogues EM8 , EM12 , EM16 , EM87 , EM136 , EM255 , E350 , phthalimide, phthalimido-phthalimide, indan, 1- indanone and 1,3- indandione . Glutarimide , glutamic acid and phthalic acid did not activate to inhibitory products.
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PMID:Teratogen metabolism: activation of thalidomide and thalidomide analogues to products that inhibit the attachment of cells to concanavalin A coated plastic surfaces. 673 64

Teroxirone is an experimental triepoxide antitumor agent currently undergoing evaluation in clinical trials. We have developed an assay based on derivatization with diethyldithiocarbamate followed by normal-phase high-performance liquid chromatographic analysis. When 14C-labeled teroxirone is administered to rabbits by rapid i.v. infusion, plasma disappearance of parent drug is very rapid (t1/2 less than 5 min), while plasma 14C-labeled drug equivalents are eliminated at a much slower rate (t1/2 greater than 60 min). Twenty-four-hr urinary recovery of parent drug is less than 1%, while recovery of 14C total radioactivity is 60 to 70%. Rapid plasma elimination (t1/2 less than 5 min) and total body clearance (greater than 5 liters/min) are observed following rapid i.v. administration of teroxirone to humans. When teroxirone is administered to humans at constant rates of infusion, plateau concentrations are rapidly achieved and maintained during infusion. Plasma concentrations rapidly decrease upon cessation of infusion. Less than 1% parent drug is recovered in 24-hr urine. Teroxirone is relatively stable in fresh human plasma and whole blood. Teroxirone is metabolized by rat liver, but not lung, microsomal preparations by an NADPH-independent pathway. Epoxide hydrolysis metabolites are detected in microsomal incubations, and cyclohexene oxide inhibits teroxirone metabolism, suggesting that epoxide hydrase may be responsible for teroxirone biotransformation. Cytotoxicity of teroxirone against continuous human tumor cell lines is abolished in the presence of 9000 X g rat liver supernatant preparations but partially restored when cyclohexene oxide is added to incubation mixtures.
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PMID:Pharmacological characterization of teroxirone, a triepoxide antitumor agent, in rats, rabbits, and humans. 674 26

Bioreductive alkylating agents require reductive activation prior to exerting their cytotoxic actions. This property results in preferential toxicity to hypoxic cells. Previous data have demonstrated that mitomycin C is activated by hypoxic tumor cells and is selectively cytotoxic to these oxygen-deficient cells. The biotransformation of mitomycin C was studied in liver microsomes and nuclei and in a reconstituted, partially purified cytochrome P-450 drug-metabolizing system to provide information on these reductive processes. Both the metabolism of mitomycin C, measured by disappearance of the quinone portion of the substrate, and the formation of an alkylating metabolite(s), determined by employing 4-(p-nitrobenzyl)pyridine as a trapping agent, required anaerobic conditions and an NADPH-generating system, and were inhibited by O2 and CO in both microsomes and nuclei. A reconstituted enzyme system consisting of NADPH, NADPH-cytochrome P-450 reductase, phospholipid and cytochrome P-450 converted mitomycin C to a reactive metabolite(s) under hypoxic conditions. Omission of N2 or any component of the system decreased the metabolic activation of mitomycin C. These findings support the concept that the cytochrome P-450 system is capable of activating mitomycin C under hypoxic conditions to the alkylating metabolite(s) that is responsible for antineoplastic activity.
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PMID:Metabolic activation of mitomycin C by liver microsomes and nuclei. 681 Aug 99


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