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 interaction among nicotinamide, radiation, and heat was studied in vivo using a C3H mouse mammary carcinoma grown in the feet of CDF1 mice. Response following local tumor treatment was assessed by tumor control and regrowth delay. Nicotinamide (1000 mg/kg i.p.) produced maximal radiosensitization when injected 30 min to 2 h before irradiation [enhancement ratios (ERs), 1.2-1.5]. Radiation damage was also increased by heating tumors (43.5 degrees C for 60 min) 4 h after irradiation (ERs = 1.6-2.6). This combined radiation and heat treatment was enhanced by nicotinamide but the effect depended on the assay procedure, such that although a significant increase was observed with the tumor control assay, only a slight increase was seen using regrowth delay as the end point. The development of moist desquamation in normal feet was used to estimate skin damage after irradiation. Nicotinamide and heat both resulted in a small yet significant increase in skin damage (ERs less than 1.2 and 1.1, respectively). A combined treatment resulted in a greater ER of 1.7, but when compared to the tumor response it still gave a therapeutic gain. A histological fluorescent staining technique was used to assess functional tumor vasculature at two periods in time separated by 20 min. Under normal conditions 7.7% of the vessels in this tumor were functional at one time but not the other. This value was reduced to 2.8% after nicotinamide administration. Since these fluctuations in blood flow can result in acute hypoxia we conclude that while heat eliminates chronically hypoxic tumor cells, nicotinamide probably removes the presence of acute hypoxia.
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PMID:Combination of nicotinamide and hyperthermia to eliminate radioresistant chronically and acutely hypoxic tumor cells. 214 77

Neoplasms produce substances that induce blood vessel formation (angiogenesis). Fractions from ethanol extracts of the Walker 256 carcinoma were isolated by silica column chromatography and C18 reversed-phase high-performance liquid chromatography. Two of the isolated fractions induced neovascularization when tested in the rabbit corneal micropocket assay. One of the fractions was identified as nicotinamide by desorption-electron impact mass spectrometry, nuclear magnetic resonance spectroscopy, and gas chromatography-mass spectrometry. The second active fraction contained nicotinamide as part of a more complex, as yet unidentified, molecular arrangement. Microgram quantities of commercial nicotinamide induced neovascularization in the corneal micropocket assay and in the chick chorioallantoic membrane assay.
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PMID:Chemical identification of a tumor-derived angiogenic factor. 243 56

A series of poly (ADP-ribose) synthesis inhibitors was evaluated for their ability to potentiate the cytotoxicity of bleomycin compared with their inhibition of poly(ADP-ribose) synthesis in L1210 cultured cells. Theophylline, nicotinamide, 3-aminobenzamide and thymidine inhibited 70 to 80% of poly(ADP-ribose) synthesis in L1210 cells. The degree of inhibition of poly(ADP-ribose) synthesis by these inhibitors corresponded in general with their potentiating ability of bleomycin cytotoxicity. Among these inhibitors, 3-aminobenzamide significantly potentiated the cytotoxic activity of bleomycin (3.6 fold), but it could not potentiate the cytotoxic activity of other antitumor agents, including nitrosourea and Cis-DDP, in L1210 cells in vitro. Treatment of Ehrlich ascites tumor bearing mice with bleomycin and 3-aminobenzamide produced a synergistic effect. 6-Aminonicotinamide also potentiated the antitumor activity of bleomycin against Ehrlich ascites tumor.
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PMID:Enhancement of bleomycin activity by 3-aminobenzamide, a poly (ADP-ribose) synthesis inhibitor, in vitro and in vivo. 245

Tumor induction with chronic feeding of methyl-donor-deficient diets has been well established; however, the biochemical and molecular mechanisms which predipose to tumorigenesis in this model are still not well understood. The purpose of the present investigation was to assess DNA damage and altered nucleotide metabolism in lymphocytes from Fischer 344 rats fed one of four semi-purified diets: (i) deficient in methionine and choline; (ii) deficient in folic acid; (iii) deficient in methionine, choline and folic acid; or (iv) a supplemented control diet. The accumulation of DNA-strand breaks, as assessed by DNA unwinding in alkali, was increased in lymphocytes from both the methionine/choline-deficient and folate-deficient groups, but was most severe in the group deficient in all three methyl donors. Lymphocyte DNA damage was consistently associated with alterations in folate-dependent thymidylate synthesis, and a decrease in intracellular levels of the DNA-repair-associated pyridine nucleotide, nicotinamide adenine dinucleotide. In the liver, a synergistic lipotropic interaction between folate deficiency and methionine/choline deficiency was observed, confirming the metabolic inter-relationship between these nutrients. Taken together, the results suggest that folate deficiency interacts with methionine/choline deficiency to potentiate symptoms of methyl-donor deficiency and that alterations in folate-dependent thymidylate synthesis are related to DNA damage in lymphocytes. These metabolic aberrations may contribute to immune dysfunction with chronic feeding of methyl-donor-deficient diets.
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PMID:Diet-induced DNA damage and altered nucleotide metabolism in lymphocytes from methyl-donor-deficient rats. 247 30

Growth of a variety of human tumor cell lines is inhibited by interferon-gamma (IFN-gamma) in vitro. This mechanism is not well understood. The present experiments identify two separate mechanisms which account for the growth inhibitory activity of IFN-gamma. Cell lines most sensitive to IFN-gamma (inhibited by 10-30 U/ml IFN-gamma in 3 d) were stimulated by IFN-gamma to oxidize tryptophan in media to kynurenine and completely eliminated tryptophan from the culture media after 48-72 h. Addition of L-tryptophan, but not other aromatic amino acids, other essential amino acids, or D-tryptophan, prevented inhibition of cell growth by IFN-gamma. The amount of IFN-gamma required to yield 50% inhibition of cell growth was directly related to the concentration of L-tryptophan in culture media and increased from approximately 3 to 600 U/ml as the concentration of tryptophan in the media was increased from 25 to 1,000 microM. By contrast, inhibition of growth of the cell lines, BT20 and HT29, was not prevented by addition of tryptophan. Inhibition by IFN-gamma (100-300 U/ml after 5-6 d) was, however, completely prevented by addition of two inhibitors of adenosine diphosphate-ribosyl transferase (ADP-RT), 3-aminobenzamide or nicotinamide. Activity of ADP-RT was increased in these cell lines after addition of IFN-gamma. ADP-RT catalyzes the incorporation of the ADP moiety of nicotinamide adenine dinucleotide (NAD) into proteins and causes depletion of intracellular NAD. All tumor cell lines tested had reduced levels of intracellular NAD after treatment with IFN-gamma and loss of NAD preceded inhibition of cell growth by 12-24 h. Inhibitors of IFN-gamma-mediated inhibition of cell growth prevented loss of levels of intracellular NAD. Generation of reactive oxygen species lead to DNA strand breaks which result in activation of ADP-RT. Increased DNA strand breaks were induced in BT20 and HT29 cells but not ME180 and A549 cells after culture with IFN-gamma. The two enzymes known to catalyze the decyclization of tryptophan to kynurenine require superoxide anion for activity. Increased amounts of superoxide anion were released from ME180 and A549 cells after culture with IFN-gamma. Reduced oxygen concentration decreased the ability of IFN-gamma to inhibit tumor cell growth in vitro. Intracellular glutathione has been shown to protect cells against oxidative damage by various agents. Elevation or reduction of intracellular glutathione concentrations lowered or raised sensitivity of cell lines to IFN-gamma, respectively. These data indicate that at least two distinct mechanisms can account for IFN-gamma-madiated inhibition of tumor cell growth. Both mechanisms appear to be sensitive to oxygen tension and to changes in intracellular glutathione concentrations, and both mechanisms lead to loss of intracellular NAD.
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PMID:Inhibition of tumor cell growth by interferon-gamma is mediated by two distinct mechanisms dependent upon oxygen tension: induction of tryptophan degradation and depletion of intracellular nicotinamide adenine dinucleotide. 250 44

Nicotinamide has been shown to sensitize tumors to radiation in preference to normal tissues. We have extended our studies to examine the mechanism responsible for this radiosensitization, using the EMT6 tumor model. Our results confirm that nicotinamide (1000 mg/kg) significantly enhances the radiation damage in this tumor when given as a single intraperitoneal injection 90 min before irradiation. The data also show that nicotinamide does not directly sensitize hypoxic cells to radiation either in vitro or in vivo. Excising tumors immediately after irradiation and exposing them to nicotinamide (7 mM) for 24 h similarly failed to increase the radiation damage, implying that nicotinamide does not inhibit the repair of radiation-induced potentially lethal damage. Nicotinamide did, however, produce a decrease in the binding of [14C]-misonidazole in tumors, consistent with a reduction in the degree of tumor hypoxia. There was also an increase in mean tumor cell fluorescence of Hoechst 33342 in nicotinamide-treated mice compared to that of controls, suggesting that the increase in tumor oxygenation was probably a consequence of an increase in tumor blood perfusion.
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PMID:Tumor radiosensitization by nicotinamide: a result of improved perfusion and oxygenation. 252 79

Nicotinamide induced radiosensitization of tumors has been suggested to be a consequence of a reduction in tumor hypoxia. We have investigated the possibility that nicotinamide may produce significant radiosensitization in a normal tissue in which the radiation response is also influenced by hypoxia. The normal tissue studied was testis and radiation damage was assessed by measuring survival of spermatogonial stem cells. The radiosensitizing action of nicotinamide in testis was compared to that observed in a C3H mammary carcinoma when assayed by both regrowth delay and local tumor control. Our results show that nicotinamide (1000 mg/kg; i.p.) enhanced radiation damage in both tissue types when the radiation was given up to at least 3 hr after drug injection. Enhancement ratios obtained when the drug and radiation were separated by a 1 hr time interval were between 1.1 to 1.2 for the testis and 1.0 to 1.5 for the tumor. The results suggest that nicotinamide will produce radiosensitization in testis, but the effect is small and less than that observed in tumors.
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PMID:Radiosensitization by nicotinamide in tumors and normal tissues: the importance of tissue oxygenation status. 252 83

Because of evidence linking methyl group deficiency and increased tumor formation in experimental animals, we explored other possible methods of producing a methyl group deficiency. Rats fed a low methionine diet lacking choline (MCD) were injected intraperitoneally daily for 3 wk with large doses of nicotinamide. Hepatic levels of lipids were elevated, S-adenosylmethionine (SAM) levels and the SAM:S-adenosylhomocysteine (SAH) ratio were decreased, and SAH level was not consistently changed. In livers of rats fed the MCD diet without folate (MCFD), lipids were also elevated and SAM reduced as compared to MCD-fed rats. In rats fed the MCD diet plus a methionine (Met) supplement (MCD + Met), hepatic SAM levels and the SAM:SAH ratio were higher and lipid levels lower than in MCD-fed rats, indicating that the MCD diet is marginally deficient in methyl donor groups. The injection of nicotinamide or the removal of folate from the MCD diet increased the severity of methyl donor deficiency, as shown by lower hepatic SAM levels and higher hepatic lipid levels. Hepatic glutathione levels were similar in MCD- and MCFD-fed rats and were lower than in rats fed the methionine-supplemented MCD diet or injected with nicotinamide.
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PMID:Hepatic content of S-adenosylmethionine, S-adenosylhomocysteine and glutathione in rats receiving treatments modulating methyl donor availability. 253 Dec 21

Nicotinamide which is an inhibitor of poly (ADPR) synthetase and precursor of NAD has been observed to prevent diabetes in some experimental models possibly by protecting beta cells. To determine whether nicotinamide could cure or prevent type 1 diabetes, we administered large doses (0.5 g/Kg/d) to BB rats. When used in the 45 days following diagnosis nicotinamide failed to bring remission. As a preventive treatment, nicotinamide administered between the 40th and 90th day of age, alone or in association with desferrioxamine did not significantly lower the incidence of diabetes (23% and 30.8% respectively vs. 56.6%). When used earlier, immediately after weaning, nicotinamide did not affect the incidence of diabetes in this model (62.5%). The degree of protection was not comparable with that obtained with cyclosporin A (15% of diabetic animals). Histology study of the pancreas from the animals killed either immediately or 1 year after treatment revealed no endocrine tumor. These findings suggest that in BB rats nicotinamide has little or no effect on the course of autoimmune diabetes mellitus thus dampening the high hopes for this drug in the treatment of human diabetes.
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PMID:High dose nicotinamide fails to prevent diabetes in BB rats. 253 59

Rats injected with streptozotocin and nicotinamide developed grossly visible islet cell tumors of the pancreas. During i.v. glucose tolerance tests, two populations of tumor-bearing rats were identified: fast responders exhibited significantly lower plasma glucose and markedly elevated plasma immunoreactive insulin (IRI) levels relative to those of the controls. In slow responders, the plasma glucose level was significantly elevated up to 2 h after glucose injection, and the plasma IRI level was lower than that of the controls. During in vitro perfusions with glucose at 300 mg/dl (16.7 mM), tumor-bearing pancreata of fast responders released elevated levels of IRI and immunoreactive somatostatin (IRS); after tumor removal, glucose-stimulated release of these hormones returned to control levels. However, during similar perfusions of pancreata from slow responders, the IRI and IRS release did not decrease after tumor removal, suggesting that the nontumorous pancreatic islets rather than the gross tumors of the slow-responder group were the source of the glucose-stimulated hormone release. These studies demonstrate that gross tumors in the two responder subgroups differ in their glucose-stimulated hormone release.
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PMID:Glucose-stimulated hormone release in rats bearing streptozotocin/nicotinamide-induced islet adenomas: evidence for slow and fast responders. 254 77


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