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)

Although the antitumor effects of chloroethylnitrosoureas have been shown to be due primarily to DNA-DNA cross-linking by the alkylating moieties of these agents, the basis of the often accompanying bone marrow toxicity has been more controversial. We report on the relative bone marrow toxicity of four model nitrosoureas with different alkylating and carbamoylating activities: 1,3-bis(2-chloroethyl)-1-nitrosourea; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea; chlorozotozin, (2-[3-(2-chloroethyl)-3 -nitrosoureido]-2-deoxy-D-glucopyranose); and -3-(beta-D-glucopyranosyl)-1-nitrosourea. Inhibitions of DNA, RNA, and protein synthesis in murine bone marrow cells and of colony growth of myeloid precursor cells (granulocyte-macrophage colony-forming units) were used as in vitro end points of myelotoxicity. Further, we determined the antiglioma activity of the four nitrosoureas on two human gliomas in a clonogenic tumor cell assay and studied the effect of the non-nitrosourea carbamoylators potassium cyanate, chloroethyl isocyanate, cyclohexyl isocyanate, ethyl isocyanate, and ethyl isothiocyanate on granulocyte-macrophage colony-forming units. The results show that, at equivalent drug exposures, clonogenic glioma cell kill was significant and comparative for 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, and chlorozotocin; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea showed little activity. In contrast, granulocyte-macrophage colony-forming unit toxicity was low with chlorozotocin and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea and very high with 1,3-bis(2-chloroethyl)-1-nitrosourea and 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea. Of the isocyanates, bone marrow toxicity was highest with chloroethyl isocyanate and cyclohexyl isocyanate, intermediate with ethyl isocyanate, and lowest with KOCN and ethyl isothiocyanate. Our results indicate that (a) bifunctional alkylation is essential for antiglioma activity of nitrosoureas and (b) myelosuppression is at least partly linked with carbamoylation but that structural entities in the carbamoylating isocyanate rather than a quantitative degree of carbamoylation determine the degree of potential myelotoxicity.
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PMID:Chemical structure of carbamoylating groups and their relationship to bone marrow toxicity and antiglioma activity of bifunctionally alkylating and carbamoylating nitrosoureas. 241 98

Mucins produced by breast carcinoma have been shown to be neutral and sialomucins. Colonic mucins were found to be sulfated with an o-acylated sialomucin component that was reported by Culling to be specific to normal colonic epithelium and colonic adenocarcinoma. This type of molecule gives a positive staining after potassium hydroxide/periodate borohydride (KOH/PBT) treatment. We studied the types of mucin in five medullary carcinomas, 10 infiltrating duct carcinomas, and 10 infiltrating lobular carcinomas of the breast. Twenty-two of 25 cases were positive for neutral mucins; 14 of 25 were positive for sialomucin. Sulfated mucins were found in five of 10 cases of infiltrating lobular carcinoma, and in six of 10 cases there was a positive periodic acid-Schiff reaction following KOH/PBT. This study illustrates the presence of sulfated mucin and o-acylated sialomucin in infiltrating lobular carcinoma of the breast. Thus, mucin stains cannot be used in differentiating metastatic breast carcinoma from colonic carcinoma. The significance of this finding and its relation to tumor histogenesis, typing, and biologic behaviors require further analysis.
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PMID:Mucins in breast carcinoma. 244 6

Stimulation of phosphatidylinositol metabolism by neurotransmitters produces diacylglycerol, an activator of protein kinase C, which may be involved in hormone-mediated contractions. We studied the effect of a tumor-promoting phorbol ester, 12-deoxyphorbol 13-isobutyrate 20-acetate (DPBA), on contraction of caudal artery rings of Wistar-Kyoto control (WKY) and spontaneously hypertensive rats (SHR) in order to examine whether protein kinase C-mediated mechanisms are increased in SHR. Although DPBA alone did not produce contractions of either WKY or SHR caudal artery rings, it greatly potentiated the contractions evoked by norepinephrine, norepinephrine, vasopressin, potassium, and calcium ionophore A23187. The potentiation of contractile response to these agents by DPBA was dependent on extracellular calcium. The DPBA potentiation of contractions evoked by norepinephrine, vasopressin, and potassium was significantly greater (p less than 0.05) in SHR than in WKY, while no differences were observed between strains for the contractions evoked by calcium ionophore A23187. These results indicate that the protein kinase C-mediated responses are increased in SHR caudal artery rings, and this effect appears to be due to increased calcium influx through cell membrane calcium channels.
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PMID:Contractile response of spontaneously hypertensive rat caudal artery to phorbol esters. 245 63

Au(DPPE)+2 (bis[1,2-bis(diphenylphosphino)ethane] gold(I] is an organo-gold antineoplastic agent that has anti-tumor activity in a variety of in vitro cell lines and in vivo rodent tumor models. Preliminary studies suggested that this compound represented a novel class of inhibitors of mitochondrial function. The purpose of this study was, therefore, to determine the mechanism of mitochondrial dysfunction induced by Au(DPPE)+2. Au(DPPE)+2 induced a rapid, dose-related collapse of the inner mitochondrial membrane potential (EC50 = 28.0 microM) that was not potentiated by Ca2+ preloading. Au(DPPE)+2-induced dissipation of mitochondrial membrane potential was accompanied by an efflux of Ca2+ from mitochondria upon exposure to Au(DPPE)+2. Ca2+ efflux in these experiments was via a reversal of the Ca2+ uniporter as efflux could be inhibited with ruthenium red. Au(DPPE)+2 did not increase the permeability of mitochondria to oxalacetate, indicating that the collapse of membrane potential may not be a result of gross increased inner membrane permeability. However, Au(DPPE)+2 may mediate an increased permeability of the inner membrane to cations and protons. Au(DPPE)+2 caused passive swelling in potassium acetate buffer in the absence of valinomycin, suggesting Au(DPPE)+2 facilitated the exchange of H+ and K+. Ca2+ cycling was not extensive and did not contribute to the decrease in membrane potential. These data suggest that one possible mechanism of Au(DPPE+2-induced uncoupling of mitochondrial oxidative phosphorylation is via increased permeability of the inner mitochondrial membrane to cations. The disruption of mitochondrial function may be a key process leading to hepatocyte cell injury by this drug.
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PMID:Mechanism of alterations in isolated rat liver mitochondrial function induced by gold complexes of bidentate phosphines. 245 18

Ehrlich ascites tumor cells were permeabilized using low concentrations of digitonin, 8 micrograms/10(6) cells. Permeabilization was monitored by the assay of lactate dehydrogenase released into the incubation medium and of hexokinase partially bound to mitochondria. Integrity of the cellular organelles was unaffected as determined by assay of the mitochondrial enzyme glutamate dehydrogenase. Cells were stained with rhodamine 123 as a mitochondrial specific dye and propidium iodide/mithramycin as DNA specific dyes. The green fluorescence of bound rhodamine 123 versus red fluorescence of DNA in individual cells was analysed by dual parameter flow cytometry. Incubation of cells with inhibitors of mitochondrial energy metabolism, such as, potassium cyanide and carbonyl cyanide m-chlorophenylhydrazone abolished binding of rhodamine 123. Flow cytometric data allowed a correlation between cell position in the mitotic cycle with total mitochondrial activity. In addition, comparison of the characteristics of propidium iodide and ethidium bromide staining further elucidated the molecular basis of the staining with the positively-charged fluorescent dye rhodamine 123.
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PMID:Simultaneous analysis of mitochondrial activity and DNA content in Ehrlich ascites tumor cells by dual parameter flow cytometry. 248 81

The fluorescence intensity of the dye 1,1'-dipropylox-adicarbocyanine (DiOC3-(5] has been measured in suspensions of Ehrlich ascites tumor cells in an attempt to monitor their membrane potential (Vm) under different ionic conditions, after treatment with cation ionophores and after hypotonic cell swelling. Calibration is performed with gramicidin in Na+-free K-/choline-media, i.e., standard medium in which NaCl is replaced by KCl and cholineCl and where the sum of potassium and choline is kept constant at 155 mM. Calibration by the valinomycin "null point" procedure described by Laris et al. (Laris, P.C., Pershadsingh, A., Johnstone, R.M., 1976, Biochim, Biophys. Acta 436:475-488) is shown to be valid only in the presence of the Cl- -channel blocker indacrinone (MK196). Distribution of the lipophilic anion SCN- as an indirect estimation of the membrane potential is found not to be applicable for the fast changes in Vm reported in this paper. Incubation with DiOC3-(5) for 5 min is demonstrated to reduce the Cl permeability by 26 +/- 5% and the NO3- permeability by 15 +/- 2%, while no significant effect of the probe could be demonstrated on the K+ permeability. Values for Vm, corrected for the inhibitory effect of the dye on the anion conductance, are estimated at -61 +/- 1 mV in isotonic standard NaCl medium, -78 +/- 3 mV in isotonic Na+-free choline medium and -46 +/- 1 mV in isotonic NaNO3 medium. The cell membrane is depolarized by addition of the K+ channel inhibitor quinine and it is hyperpolarized when the cells are suspended in Na+-free choline medium, indicating that Vm is generated partly by potassium and partly by sodium diffusion. Ehrlich cells have previously been shown to be more permeable to nitrate than to chloride. Substituting NO3- for all cellular and extracellular Cl- leads to a depolarization of the membrane, demonstrating that Vm is also generated by the anions and that anions are above equilibrium. Taking the previously demonstrated single-file behavior of the K+ channels into consideration, the membrane conductances in Ehrlich cells are estimated at 10.4 microS/cm2 for K+, 3.0 microS/cm2 for Na+, 0.6 microS/cm2 for Cl- and 8.7 microS/cm2 for NO3-. Addition of the Ca2+-ionophore A23187 results in net loss of KCl and a hyperpolarization of the membrane, indicating that the K+ permeability exceeds the Cl- permeability also after the addition of A23187. The K+ and Cl- conductances in A23187-treated Ehrlich cells are estimated at 134 and 30 microS/cm2, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Membrane potential, anion and cation conductances in Ehrlich ascites tumor cells. 248 60

The paper critically analyzes available data on the nutritional and metabolic effects of total parenteral nutrition (TPN) and enteral nutrition (EN) in cachectic cancer patients. Only papers dealing with adult cancer patients and providing data regarding type of tumor, duration of the nutritional support, and administration rate of calories and amino acids, validated by statistical analysis of the results, are included. The main conclusions are the following: (1) No nutritional variable worsened in cancer patients receiving TPN or EN, in conditions in which progressive deterioration of the nutritional status is the rule. (2) The nutritional variables improved by TPN and EN were body weight, fat mass, and some indicators of lean body mass (nitrogen balance and whole body potassium). Thyroxin-binding prealbumin and retinol-binding protein increased only with TPN, whereas some immunologic indexes (complement factors and lymphocytes) improved only with EN. (3) The daily regimens which improved lean body mass and visceral proteins ranged from 35 to 55 kcal/kg and from 1.2 to 2.0 g of amino acids/kg for TPN; for EN it was 35 kcal/kg and 1.3 g of amino acids/kg. However, the enteral regimen capable of improving some immune responses included at least 42 kcal/kg and 2.3 g of amino acids/kg. (4) Only three randomized studies were performed to compare TPN and EN, and conflicting results were obtained. Only TPN showed some significant advantages with regard to weight gain, nitrogen balance, maintenance of serum albumin levels and some mineral balances. However, the advantage of TPN was not clear enough to recommend its indiscriminate use. The choice between TPN and EN should always consider the functionality of the GI tract, the need for hospitalization to start a TPN regimen, and the higher cost of intravenous feeding. (5) When comparing TPN to a standard oral diet, the following variables improved with the nutritional support: body weight, nitrogen balance, 3-methylhistidine, urinary excretion, and serum levels of transferrin, cholinesterase, thyroxin-binding prealbumin, and retinol-binding protein. (6) When comparing TPN with glucose vs TPN with glucose-lipids, no major difference was found with regard to most nutritional variables. In conclusion, nutritional support alone probably has a small role in managing a limited number of advanced cancer patients dying primarily because of malnutrition or mainly suffering from nutritional deterioration. It can also have a "permissive" role in those patients potentially candidate to an oncologic treatment which cannot be delivered because of a poor nutritional status.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of artificial nutrition on the nutritional status of cancer patients. 250 78

VIP-secreting tumors are rare, but they produce a dramatic clinical picture, the most prominent feature of which is profuse, watery diarrhea and hypokalemia. A definitive diagnosis is aided by the determination of plasma VIP concentrations through the use of the sensitive radioimmunoassays that are now available. Intestinal secretion resulting from the direct action of VIP on the intestinal epithelial cell receptors accounts for the loss of fluid and electrolytes in patients with VIPoma. The hypokalemia is the result of passive and VIP-induced active secretion of potassium by colonic epithelial cells. Surgery is the most definitive treatment of VIPoma; pharmacotherapy is extremely important in controlling symptoms and stabilizing the patient prior to surgery. Sandostatin and glucocorticoids are well established agents in the management of the secretory diarrhea; other pharmacologic agents, including clonidine, indomethacin, phenothiazines, lithium carbonate, and propranolol, may be helpful in selected patients but require further study. The most potent and promising drug for the treatment of VIPoma is a new peptidomimetic agent--Sandostatin. This metabolically stable synthetic analogue of somatostatin appears, in part, to inhibit the release of VIP from the tumor and the secretion of chloride by the intestine. In addition to controlling the diarrhea, it may have a direct effect on the tumor in reducing its size.
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PMID:Medical therapy of VIPomas. 254 44

Toxin B, an exotoxin produced by Clostridium difficile, induces the rounding-up and arborization of cultured mammalian cells, a typical effect which resembles that provoked by cytochalasins. In this study, the effect of toxin B was examined on astroglial cells grown in primary culture. A specific antiserum to toxin B was used to investigate its mechanisms of action. We found that the toxin exerts its effects on cell morphology after its incorporation into cells. The internalization of toxin B requires the presence of calcium ions in the extracellular medium. Replacement of NaCl with sucrose or with potassium glutamate prevents the internalization of the toxin. The direct introduction of calcium ions into cells by the calcium ionophore A23187 stimulates toxin-induced morphological changes. In contrast, toxin-induced morphological transformations were prevented in cells treated with tumor-promoting phorbol. esters or with dibutyryl-cAMP, although such treatment did not abolish the internalization of the toxin. As in the other cell types, the earliest effect of toxin B on astrocyte cytoskeleton is the disruption of actin filaments, without no visible alteration of intermediate filament nor microtubule networks. As astrocytes with toxin-induced stellate morphology survive toxin treatment, the progression of cell morphology and cytoskeleton organization were followed for several weeks. Twenty-six days after exposure to toxin B, stellate astrocytes have processes which were markedly longer and much more branched than those of cells freshly exposed to toxin. At that time, cells are still devoid of F-actin as assessed with rhodamine-conjugated phalloidin and only 70% contain vimentin while all astrocytes present in control cultures express vimentin. Some flat epithelioid astrocytes with prominent bundles of microfilaments reappear during the second week after toxin treatment. Our results show that Clostridium difficile toxin B is internalized into brain astrocytes in culture where it acts by modifying cytoskeletal elements. Its cytopathic effects are reversible. Although actin-related components of the cytoskeleton are the major target of toxin B, other cytoskeletal elements also seem to be affected.
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PMID:Mechanism of action of Clostridium difficile toxin B: role of external medium and cytoskeletal organization in intoxicated cells. 254 47

Previous experimental evidence indicates that immunogenicity of mouse tumor cells can be increased by treatment with dacarbazine and other triazene compounds. The present studies have been conducted on the human cell lines H125 (lung cancer), 1246 (melanoma), X3 (EBV-immortalized B cells) subjected to in vitro treatment with 4 (3-methyl-1-triazeno) benzoic acid potassium salt (MTBA). Untreated or drug-treated sublines were tested for susceptibility to allogeneic NK effector cells, either non-stimulated or pretreated with beta-Interferon. In the case of X3 cell line and its MTBA-treated subline the expression of the EBV-associated antigens and the capability of eliciting autologous cytotoxic T lymphocytes (CTL) were also investigated. The results suggest that a modification of membrane antigenic pattern could be induced by MTBA treatment in terms of changes of cell susceptibility to cell-mediated lysis, expression of EBV-related antigens and capability to elicit autologous CTL.
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PMID:Changes of immunological patterns of human cancer cells treated in vitro with a triazene compound. 254 62


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