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)

Membrane-associated tumor necrosis factor (TNF) and soluble TNF were compared as to their lytic activities, and as to the kinetics of their expression by macrophages activated with LPS and/or IFN-gamma in the presence or absence of cycloheximide. EL 4 tumor cells, resistant and sensitive to lysis by recombinant TNF or membrane-associated TNF (paraformaldehyde (PF)-fixed activated macrophages) were used as targets. In the presence of cycloheximide the TNF-resistant S-EL4 cells were lysed by both TNFs. PF-fixed macrophages was cytolytic after 1 hr activation but not after 3 or more hours of activation. Their activity was totally inhibited by anti-TNF antibodies and was a composite of transmembrane (integral) TNF and soluble TNF conjugated to macrophage membrane TNF receptors. Treatment of the macrophages with glycine pH 3.0 buffer dissociated the conjugated TNF without affecting the integral membrane TNF. When macrophages were activated with LPS +/- IFN-gamma in the presence of cycloheximide or activated just with IFN-gamma their activity after fixation with paraformaldehyde was no longer detected. Nonfixed macrophages under these conditions still remained cytotoxic. Tumor cell susceptibility to membrane-associated TNF activity, in contrast to recombinant (soluble) TNF, was greatly reduced in the presence of nicotinamide, an inhibitor of ADP-ribosyltransferase, suggesting that the mechanisms of lysis by these TNFs may be different. The lytic activity of both TNFs was found to be receptor-dependent in that tumor cells, whose TNF binding sites were "down-regulated" by TPA, were rendered resistant to lysis by both membrane-associated and soluble TNFs.
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PMID:Cytolytic activities of activated macrophages versus paraformaldehyde-fixed macrophages; soluble versus membrane-associated TNF. 183 87

The ability of normobaric oxygen and carbogen (95% O2 + 5% CO2) combined with nicotinamide to enhance the radiosensitivity of two rodent adenocarcinomas and of mouse skin and kidneys, using a 10 fraction radiation schedule, was compared with the effect of radiation in air with and without the drug. Tumour response was assayed using local control and regrowth delay, and compared with acute skin reactions, decreased renal 51Cr-EDTA clearance and reduction in haematocrit. Nicotinamide increased the radiation sensitivity of CaNT tumours under all three different oxygen concentrations tested (21, 95 and 100% oxygen). The effect was statistically significant for oxygen and carbogen but not for air; the combination of nicotinamide with carbogen gave the greatest increase in tumour radiosensitivity. Relative to treatments in air without the drug, the enhancement ratios (ER) at the TCD50 level were 1.17, 1.65 and 1.83 for CaNT tumours irradiated in air, oxygen or carbogen and injected with nicotinamide 1 h before each fraction. The ER in CaRH tumours irradiated in carbogen plus the drug was 1.83, which was greater, but statistically not significantly different, to that seen with carbogen alone (ER = 1.68). In skin, relative to air without the drug, the increase in radiosensitivity by nicotinamide was greater in oxygen and carbogen than in air (1.29, 1.36 and 1.08, respectively). The ERs for both assays of renal damage were similar and lower than those in skin: less than or equal to 1.07, less than or equal to 1.13 and less than or equal to 1.16 for irradiations done in air, oxygen and carbogen plus nicotinamide, relative to air alone. A comparison of these results in the tumours and normal tissues showed that a significant therapeutic benefit was obtained with normobaric oxygen and carbogen combined with nicotinamide. This benefit is greater than observed with other radiosensitizers tested so far. Toxic side effects of the treatment are unlikely in a clinical situation, since prolonged administration of nicotinamide is well tolerated in man. The combination of normobaric carbogen with nicotinamide could be an effective method of enhancing tumour radiosensitivity in clinical radiotherapy where hypoxia limits the outcome of treatment.
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PMID:A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated X-ray treatments. 183 42

Nicotinamide methyltransferase (Nmd CH3transferase) activity increased in the liver of mice after i.p. transplantation of Ehrlich ascites tumor (ascitic form), but not in the liver of mice with acute inflammation induced by the i.p. administration of D-galactosamine, and it rather showed a decrease together with necrosis after carbon tetrachloride administration. When Nmd CH3transferase activity of rat hepatocytes in primary culture was investigated with the addition of dexamethasone, epidermal growth factor, transforming growth factor-beta, tumor necrosis factor-alpha and N1-methylnicotinamide (1-CH3Nmd), changes in activity were not correlated with DNA synthesis, suggesting that the increase of this enzyme activity in the tumor host liver was not directly related to liver cell proliferation. Thus, in order to make use of the increase of this enzyme activity as a tumor burden marker, a procedure for its estimation by measuring the blood level of 1-CH3Nmd, a metabolite of Nmd produced by Nmd CH3transferase, was established. The 1-CH3Nmd level in the blood of mice bearing Ehrlich ascites tumor 4 h after s.c. loading of Nmd (500 mg/kg body weight) was closely correlated with this enzyme activity in the liver (r = 0.835, P less than 0.00001) from the early to the terminal stage of tumor development. Furthermore, similar correlations were seen in the animal groups bearing various other tumors, such as s.c. implanted Ehrlich ascites tumor (solid form) and i.p. implanted sarcoma S-180, hepatoma MH-134, Yoshida ascites sarcoma and leukemia L-1210, but not solid tumors such as Lewis lung carcinoma and melanoma B-16, although almost all of the animals bearing these tumors showed a higher enzyme activity than their control normal animals.
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PMID:N1-methylnicotinamide level in the blood after nicotinamide loading as further evidence for malignant tumor burden. 183 57

The coupling of p-aminophenyl 2-acetamido-2-deoxy-3-O-beta-D- galactopyranosyl-beta-D-galactopyranoside (gal-beta 1,3-galNAc) to bovine serum albumin (BSA) was achieved by using 1,2-diethoxycyclobutene-3,4-dione (squaric acid diester) as a new coupling reagent. Two selective consequential steps afforded the desired neoglycoprotein: reaction of the p-aminophenyl group of gal-beta 1,3-galNAc with squaric acid diester gave the corresponding squaric acid amide ester, which was transformed into the BSA conjugate by coupling with the lysyl epsilon-amino group of BSA through formation of a squaric acid 1,2-bisamide. The experimental conditions for the reactions and the optimization of average were performed by using p-anisidine as model substance, the methyl group substituting for the carbohydrate part of a p-aminophenylglycoside. Neoglycoproteins have proven to be valuable tools for lectin detection. To evaluate the properties of this type of probe, the obtained neoglycoprotein with the histochemically crucial T-antigen structure was used for glycocytological and glycohistochemical studies. Three cultured human tumor cell lines and tissue sections from human breast carcinomas were chosen. Its efficiency was similar in comparison to measurements with a probe, derived by diazotization with the p-aminophenyl glycosides of gal-beta 1,3-galNAc and already shown to be a reliable marker for lectin localization in tissue sections and cultured cells.
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PMID:Conjugation of p-aminophenyl glycosides with squaric acid diester to a carrier protein and the use of neoglycoprotein in the histochemical detection of lectins. 193 13

It is known that cells in a nutritionally deprived and acidic environment are sensitive to heat. In general these same cells are chronically hypoxic and therefore heat possesses the potential to eliminate (some) of this radioresistant population. A direct radiosensitization is observed when heat is given simultaneously with radiation. This effect occurs to the same extent in both aerobic and hypoxic cells, thus the oxygen enhancement ratio is unchanged. By giving heat several hours after radiation the direct radiosensitization is avoided and the specific heat killing of the acidic, chronically hypoxic, tumor cells may be utilized to improve the therapeutic gain. The current investigation clearly demonstrates this concept in a C3H mammary carcinoma using a local tumor control assay. This effect could be further enhanced by adding hypoxic radiosensitizers (nimorazole, misonidazole) or a blood flow modifier (nicotinamide) which can eliminate acutely hypoxic cells.
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PMID:The potential of using hyperthermia to eliminate radioresistant hypoxic cells. 202 Jul 61

A cDNA termed reg was recently isolated by differential screening of a library prepared from regenerating islets isolated from pancreatic remnants of rats subjected to 90% pancreatectomy and nicotinamide treatment. This led to speculation that this gene may be involved in expansion of beta-cell mass. In the current study we have measured reg expression after implantation and resection of a solid insulinoma tumor into rats, maneuvers known, respectively, to reduce and reexpand the volume of beta-cells in the islet. Animals with an implanted insulinoma tumor became profoundly hypoglycemic. Islet beta-cells declined from the normal 75% of total islet volume to less than 30%, in concert with a marked reduction in the reg mRNA level. Removal of the tumor resulted in a sharp increase in beta-cell replication, as measured by [3H]thymidine incorporation and a return to normal beta-cell volume within 4 days of tumor resection. This was associated with a transient induction in reg expression compared to that in tumor-bearing animals, effectively returning the amount of reg mRNA to the levels found in normal animals within 48 h; at later time points after tumor removal (3-7 days) reg expression declined, but then rose toward normal. In situ hybridization analysis localized the initial induction in reg mRNA expression to the exocrine pancreas. Continuous infusion of insulin into normal rats for 4 days, a maneuver that does not significantly reduce beta-cell mass, resulted in dramatically reduced insulin mRNA in islets, but no change in the levels of reg mRNA. We conclude that the diminution in pancreatic beta-cell mass caused by subcutaneous implantation of an insulinoma is associated with reduced reg gene expression and that the increase in beta-cell replication after resection of the tumor is preceded by return of reg gene expression toward normal.
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PMID:Expression of reg/PSP, a pancreatic exocrine gene: relationship to changes in islet beta-cell mass. 203 44

In vitro and in vivo studies with N,N',N''-triethylene-thiophosphoramide (thiotepa) alone and in combination with cyclophosphamide (CTX) were carried out using the MCF-7 human breast carcinoma cell line and the EMT6 mouse mammary carcinoma cell line. In vitro, survival curves were essentially linear. The cytotoxicity of thiotepa toward MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with a 3-log greater cell kill at 500 mumol with cells that were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate in the presence of a reduced nicotinamide adenine dinucleotide phosphate-regenerating system resulted in an eightfold increase in cytotoxicity toward the MCF-7 cells over a wide range of drug concentrations. The thiotepa metabolite N,N',N''-triethylenephosphoramide (TEPA) was significantly less cytotoxic toward the MCF-7 cells than was thiotepa. Simultaneous and immediately sequential treatments with thiotepa and CTX produced supra-additive cell killing of both cell lines, although the magnitude of the supra-additivity was greater in the MCF-7 cell line than in the EMT6 cell line. These drugs Vppeared to be equally effective as thiol-depleting agents. By DNA alkaline elution, there was a pattern of increasing DNA cross-linking similar to the increasing levels of cytotoxicity of this drug combination as the concentrations of thiotepa increased. In the EMT6 tumor in vivo, the maximally tolerated combination therapy (5 mg/kg x 6, thiotepa, and 100 mg/kg x 3, CTX) produced about 25 days of tumor growth delay, which was not significantly different than expected for additivity of the individual drugs. The survival of EMT6 tumor cells after treatment of the animals with the various single doses of thiotepa and CTX was assayed. Tumor cell killing by thiotepa produced a very steep, linear survival curve through 5 logs with increasing dose. The tumor cell survival cure for CTX to 500 mg/kg had linear tumor cell kill through almost 4 logs. In vivo modeling of quasicontinuous exposure (3 intraperitoneal over 9 hours) versus pulse (single-dose) administration of thiotepa and CTX compared EMT6 tumor cell survival with survival of bone marrow as a representative sensitive normal tissue. With CTX, there was a considerable increase in the therapeutic index (killing of tumor cells/killing of colony forming units-granulocyte macrophage) when the same total dose of drug was administered in multiple injections versus a single injection. For thiotepa, smaller increases in therapeutic index were also observed with the multiple-injection schedule.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Preclinical studies relating to the use of thiotepa in the high-dose setting alone and in combination. 210 64

Phorbol ester-induced promotion of initiated NMRI mouse skin keratinocytes to papillomas could be largely prevented when nicotinamide-like inhibitors of poly(ADP-ribose)polymerase (nicotinamide, benzamide, 3-aminobenzamide) were applied simultaneously with 12-O-tetradecanoylphorbol-13-acetate (TPA). A similar suppression of tumor promotion by nicotinamide analogues was demonstrated in clone 41 JB6 epidermal cells which are promotable by TPA to anchorage-independent growth. The antipromotion effect of nicotinamide analogues, however, does not appear to come about by an inhibition of poly(ADP-ribose)polymerase. Acid analogues of nicotinamide, such as benzoic acid or 3-aminobenzoic acid which do not inhibit the polymerase, showed antipromotion activity similar to that of their corresponding amides. It could also be ruled out that these antipromoters mediate their effect on keratinocytes by a cytostatic action, by scavenging the promoter TPA in a chemical reaction, or by inhibiting protein kinase C. In initiated mouse skin, nicotinamide analogues strongly suppressed TPA-induced accumulation of inflammatory cells and vascular permeability, while epidermal hyperplasia was not significantly affected.
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PMID:Nicotinamide and nicotinamide analogues as antitumor promoters in mouse skin. 213 6

Nicotinamide, an agent previously reported to reduce hypoxia and increase the irradiation response of experimental tumors, has been evaluated for its effect on the occurrence of acute hypoxia in the murine squamous cell tumor SCCVII. Treatment of C3H mice bearing 500-750-mg subcutaneous tumors with nicotinamide (1.0 mg/g intraperitoneally) 1 hour prior to irradiation resulted in an enhancement ratio of 1.3 (+/- 0.1). We assessed the effect of nicotinamide on the response of acutely hypoxic cells in vivo using a recently developed fluorescence-activated-cell sorting technique. This technique employs the in vivo pharmacokinetic and DNA binding properties of the bisbenzamide stain Hoechst 33342. The results clearly show that nicotinamide, at the doses used, reduces the amount of acute hypoxia in these SCCVII tumors. We confirmed these findings using a histological technique that facilitates the assessment of functional tumor vasculature at two instances in time. This method shows that nicotinamide reduces the number of vessels opening and closing over a 20-minute period from 10.3% to 2.0%. The identification of a compound that can modify the dynamic fluctuations in microregional oxygen delivery in tumors could have important implications for radiation therapy.
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PMID:Effect of nicotinamide on the microregional heterogeneity of oxygen delivery within a murine tumor. 213 79

A number of observations indicate an essential role of macrophage activity in the development of hyperglycemia in animal models of Type I diabetes. Administration of macrophage-toxic silica particles prevents spontaneous diabetes development in BB rats or NOD mice. The same result was noted in the low-dose streptozotocin-induced diabetes model in mice. Macrophages appear to be the first immune cells infiltrating islets during early insulitis. Macrophages in inflamed islets of BB rats bear the ED1 marker, whereas resident islet macrophages are ED2-positive. In vitro, ED1-positive macrophages were found to lyse pancreatic islet cells to a similar degree to various tumor cells but not normal thyrocytes. Macrophage-mediated lysis of islet cells was inhibited in the presence of 10-100 mM nicotinamide.
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PMID:Essential contribution of macrophages to islet cell destruction in vivo and in vitro. 214 Feb 61


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