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

The mechanism of human interleukin (IL)-1 beta-mediated cytolysis was studied in a human melanoma cell line, A375.6. Purified recombinant human IL-1 beta produced 50% cytocidal activity at 50 pg/ml. A variety of compounds were tested for their ability to interfere with A375.6 lysis. Compounds were added simultaneously with IL-1 beta (100 pg/ml), and tumor cytolysis was measured after 72 hr of culture by release of 125I from DNA of A375.6 cells labeled with [125I]-dUrd. A variety of anti-inflammatory/immunosuppressive agents (including auranofin, chloroquine, cyclosporin A, d-penicillamine) and several cyclooxygenase/lipoxygenase inhibitors (AA-861, BW755c, and indomethacin) lacked protective activity. Similarly, phospholipase inhibitors (mepacrine and 4-bromophenacyl bromide), putrescine, inhibitors of lysosomal activity (chloroquine and NH4Cl), calcium channel blockers (nifedipine and verapamil), calmodulin inhibitors (W-7 and calmidazolium), and inhibitors of ADP ribosylation (nicotinamide and 3-aminobenzamide) were inactive. In contrast, corticosteroids (dexamethasone, hydrocortisone, and paramethasone acetate), tilorone, and protein kinase C inhibitors (1-[5-isoquinolinyl-sulfonyl]-2-methylpiperazine and staurosporine) significantly inhibited IL-1 beta-mediated A375.6 cytolysis. These compounds also interfered with tumor necrosis factor-mediated lysis of A375.6, suggesting common mechanisms of tumor cytotoxicity by these monokines. This model may be useful for delineating intracellular biochemical events integral to IL-1 action.
 ...
PMID:Potent inhibition of interleukin 1 beta-mediated human melanoma (A375.6) lysis by corticosteroids, staurosporine, and tilorone. 262 25

The antitumor activity of the antineoplastic agent, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), has previously been shown to require intracellular anabolism of the drug to a nicotinamide adenine dinucleotide (NAD) analog (2-beta-D-ribofuranosylthiazole-4-carboxamide adenine dinucleotide or "tiazofurin adenine dinucleotide"), which then acts as a potent inhibitor of the target enzyme inosine monophosphate (IMP) dehydrogenase. Inhibition of the latter enzyme in turn brings about a profound depletion of intracellular guanosine nucleotides essential for tumor cell growth and replication. In the present study, the cytotoxicity and metabolism of tiazofurin have been examined in six human lung cancer cell lines. At the pharmacologically attainable drug concentration of 100 microM, colony survival was less than 1.5% in three cell lines ("sensitive"), while survival in the remaining three was greater than 50% ("resistant"). The metabolism of tritiated tiazofurin was examined at concentrations ranging from 0.5 to 100 microM following both brief (6 h) and protracted (14 d) exposures. The sensitive lines accumulated concentrations of tiazofurin adenine dinucleotide that were approximately 10 times those achieved by the resistant lines at both time points. We also observed tendencies for the sensitive cell lines to exhibit: (a) higher specific activities of NAD pyrophosphorylase, the enzyme required for the synthesis of tiazofurin adenine dinucleotide, (b) significantly lower levels of a phosphodiesterase which degrades the latter dinucleotide, (c) greater inhibition of the target enzyme IMP dehydrogenase, and (d) greater depressions of guanosine nucleotide pools after drug treatment. By contrast, the basal levels of IMP dehydrogenase and purine nucleotides in these six lines did not correlate in any obvious way with their responsiveness or resistance. The accumulation and monophosphorylation of parent drug were also not prognostic variables. These studies thus suggest that the extent of accumulation of tiazofurin adenine dinucleotide, as regulated by its synthetic and degradative enzyme activities, is the single most predictive determinant of the responsiveness of cultured human lung tumor cells to tiazofurin.
 ...
PMID:Relationships between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells. 285 24

Chronic exposure to ethionine (0.05%) combined with dietary choline deficiency was used to study changes in aldehyde dehydrogenase (ALDH) activity during hepatocarcinogenesis in male Sprague-Dawley rats. Over a period of 43 weeks, animals were sacrificed at intervals and the ALDH phenotype of normal liver and any lesions was characterized by histochemical analysis, total activity assays, and gel electrophoresis, using propionaldehyde and nicotinamide adenine dinucleotide (NAD+) to detect normal liver ALDH activity and benzaldehyde and nicotinamide adenine dinucleotide phosphate (NADP+) for tumor-associated ALDH. In animals receiving ethionine plus choline deficiency, significant changes in ALDH were observed histochemically by 9 weeks, when there was a distinct shift in activity from its normal centrilobular pattern to a periportal distribution. The first NAD+- and NADP+-dependent ALDH-positive enzyme-altered foci were also seen at 9 weeks. There was no correlation between the ALDH and gamma-glutamyl transpeptidase phenotypes of an individual focus. Areas of cholangiofibrosis, cystic degeneration, and bile duct proliferation were distinctly ALDH negative. No significant changes in benzaldehyde and NADP+ ALDH activity were detectable by total activity assays or gel electrophoresis prior to the appearance of overt neoplasms at 26 weeks. No significant changes in ALDH activity occurred in animals receiving either ethionine or choline deficient diet alone. By histochemistry, total activity assays and gel electrophoresis, only 7 of the 28 (25%) of the hepatic neoplasms examined expressed the tumor-associated ALDH phenotype. An additional five neoplasms had barely detectable levels of benzaldehyde and NADP+ ALDH activity. These results are in striking contrast to changes in ALDH activity occurring during hepatocarcinogenesis induced by other protocols we have tested previously in which from 50 to 96% of all neoplasms were ALDH positive.
 ...
PMID:Changes in aldehyde dehydrogenase occurring during rat hepatocarcinogenesis induced by ethionine combined with dietary choline deficiency. 287 26

Four hours after an i.p. injection of 500 mg/kg nicotinamide, there was a decrease in kidney ODC activity, followed by a substantial increase by 24 h. Exposing rats to 0, 0.67, 6.7 and 30 mM nicotinamide in their drinking water for 7 and 28 days also resulted in a statistically significant increase in kidney ODC activity, but the rates of DNA synthesis were unaffected, as measured by incorporation of [3H]thymidine into DNA and % labeled proximal tubule nuclei; the total amount of DNA/kidney was also unaffected. The results of this investigation demonstrate that nicotinamide, a known renal tumor promoter, was able to induce a significant increase in ODC activity in the rat kidney without a concomitant increase in DNA synthesis, suggesting that early stimulation of ODC is associated with tumor promotion even in the absence of effects on DNA replication.
 ...
PMID:Induction of rat kidney ornithine decarboxylase by nicotinamide without a concomitant increase in DNA synthesis. 293 21

Several sulfur containing 5- and 6-membered heterocyclic carboxylic acids (or esters) were shown to decrease the number of pulmonary metastases in C57BL/6 mice implanted with Lewis lung carcinoma. The numbers of such metastatic nodules were reduced more than 5-fold. In addition, these compounds, which could be viewed as analogs of nicotinamide, were shown to inhibit the growth rate of the primary implanted tumor by about 50%.
 ...
PMID:The antimetastatic and tumor growth retarding effects of sulfur containing analogs of nicotinamide. 293 26

H2O2, in concentrations achieved in the proximity of stimulated leukocytes, induces injury and lysis of target cells. This may be an important aspect of inflammatory injury of tissues. Cell lysis in two target cells, the murine macrophage-like tumor cell line P388D1 and human peripheral lymphocytes, was found to be associated with activation of poly(ADP-ribose) polymerase (EC 2.4.2.30), a nuclear enzyme. This enzyme is activated under various conditions of DNA damage. Poly(ADP-ribose) polymerase utilizes nicotinamide adenine dinucleotide (NAD) as substrate and has been previously shown to consume NAD during exposure of cells to oxidants that was associated with inhibition of glycolysis, a decrease in cellular ATP, and cell death. In the current studies, inhibition of poly(ADP-ribose) polymerase by 3-aminobenzamide, nicotinamide, or theophylline in cells exposed to lethal concentrations of H2O2 prevented the sequence of events that eventually led to cell lysis--i.e., the decrease in NAD, followed by depletion of ATP, influx of extracellular Ca2+, actin polymerization and, finally, cell death. DNA damage, the initial stimulus for poly(ADP-ribose) polymerase activation, occurred despite the inhibition of this enzyme. Cells exposed to oxidant in the presence of the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide failed to demonstrate repair of DNA strand breaks.
 ...
PMID:Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. 294 60

The effects of a range of different analogs of nicotinamide and benzamide on the X ray response of the EMT-6 tumor in vivo was investigated. Using an in vivo/in vitro survival assay, sensitization was seen at a dose of 2 mmole/kg for all but one of the analogs tested. The enhancement ratios (ER's) ranged from 1.0 to 1.5. Of particular interest were nicotinamide and SR-4350 which gave large ER's (1.5 and 1.4 respectively) at doses which were only about 12% of the LD50 values. In one normal tissue studied (skin reaction) a large single dose of nicotinamide (8 mmole/kg) only gave an ER of 1.1. These results will be discussed with reference to the mechanisms involved and the clinical implications.
 ...
PMID:Preferential tumor radiosensitization by analogs of nicotinamide and benzamide. 294 59

In this report we describe various aspects of tumor and normal tissue radiosensitization by nicotinamide. The LD50 for a single injection of nicotinamide in C3H mice was found to be 2050 mg/kg. When a large nonlethal dose (1000 mg/kg) was injected into tumor-bearing mice, peak plasma and tumor levels were reached 30-60 min after injection and decayed with a half-life of about 3 h. This dose of nicotinamide enhanced radiation-induced cell killing in three different tumor models (EMT6, Lewis Lung, and RIF-1) when injected at least 1 h before irradiation and produced enhancement ratios (ERs) of between 1.2 and 1.7. The ER in the EMT6 tumor was dependent on the dose of nicotinamide injected, but even at doses as low as 25% of the LD50 value an ER greater than 1.5 could still be observed. In two normal tissue assays (jejunum crypt cell survival and mean skin reaction) ERs of less than 1.2 were obtained. These results, and the fact that high levels can be tolerated in humans, suggest that nicotinamide, or a structurally related compound, could be a likely candidate for development in clinical trials.
 ...
PMID:Radiosensitization by nicotinamide in vivo: a greater enhancement of tumor damage compared to that of normal tissues. 295 65

Data concerning effects of the essential vitamin niacin and its active form nicotinamide were evaluated. Dietary deficiencies and excesses of these nutrients by themselves do not appear to exert any influence on in vivo carcinogenesis in animals. Varying results were produced when nicotinamide was administered at pharmacologic doses concurrently with or following carcinogen administration to mice or rats. Some investigators found significantly increased tumor formation, whereas others reported a decreased effect or no effect. Epidemiologic studies have not investigated the relationship between niacin deficiency or excess and carcinogenesis in humans.
 ...
PMID:The influence of niacin and nicotinamide on in vivo carcinogenesis. 295 38

Nicotinamide and arabinoside cytosine mixed with hydroxyurea were shown to influence the relative amount of double-stranded DNA in Ehrlich ascites tumor cells in vitro subjected to single irradiation (10-30-52 Gy) and in Guerin's carcinoma in rat lungs exposed to fractionated 6 MeV neutron-radiation (1.25 Gy X 4). The DMF values for Ehrlich ascites tumor were a function of a dose range and the duration of the drugs' effect. Guerin's carcinoma DNA was found to be affected more readily when treated with radiation and drugs than when exposed to neutron radiation alone.
 ...
PMID:[Inhibition of the repair of neutron-induced DNA single-strand breaks in experimental tumor cells]. 296 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>