Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotensin(8-13), the carboxyl-terminal portion of neurotensin, is 4-50 times more potent than native neurotensin in binding to intact neuroblastoma N1E-115 cells and human brain tissue and in stimulation of intracellular cyclic GMP production and inositol phospholipid hydrolysis in clone N1E-115 (Gilbert JA and Richelson E, Eur J Pharmacol 99: 245-246, 1984; Gilbert JA et al., Biochem Pharmacol 35: 391-397, 1986; Kanba KS et al., J Neurochem 46: 946-952, 1986; and Kanba KS and Richelson E, Biochem Pharmacol 36: 869-874, 1987). A series of novel analogs of neurotensin (8-13) was synthesized, and a structure-activity study was done comparing the abilities of these peptides to stimulate intracellular cyclic GMP production in intact neuroblastoma clone N1E-115 and to inhibit the binding of [3H]neurotensin to these cells and to membranal preparations from human brain. A direct correlation was found for each analog between its EC50 for biochemical activity and its KD for binding ability in studies with clone N1E-115. Furthermore, a strong correlation existed for each peptide between its KD for binding to neurotensin receptors on these cells and its KD for binding to neurotensin receptors in human brain tissue. In this study, the residues that were important to the biochemical and binding activities of neurotensin (8-13) proved to be identical to the amino acids that are necessary for the functional integrity of native neurotensin (Gilbert JA et al., Biochem Pharmacol 35: 391-397, 1986.
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PMID:Neurotensin(8-13): comparison of novel analogs for stimulation of cyclic GMP formation in neuroblastoma clone N1E-115 and receptor binding to human brain and intact N1E-115 cells. 255 23

Murine neuroblastoma clone N1E-115 possesses receptors that specifically bind the tridecapeptide neurotensin, mediate the formation of intracellular cyclic GMP, and stimulate inositol phospholipid hydrolysis. These cells also rapidly degrade neurotensin in a sequential fashion. We studied the effect of prolonged exposure of cells to neurotensin on subsequent neurotensin receptor-mediated intracellular cyclic GMP formation under conditions that prevented degradation of this peptide [J. A. Gilbert and E. Richelson, Soc. Neurosci. Abstr. 12, 762 (1986)]. Neurotensin receptor-mediated cyclic GMP formation in neuroblastoma clone N1E-115 was decreased following prolonged exposure of intact cells to nondegraded neurotensin. The time course of this desensitization was very rapid; the maximal effect on cyclic GMP production (reduction to 10-30% of control values) occurred within 5 min of exposure of intact cells to neurotensin. This desensitization was homologous, as cells desensitized by neurotensin demonstrated no decrease in their cyclic GMP response to angiotensin II (1 microM) or bradykinin (10 nM). Neurotensin preincubation with intact N1E-115 cells for increasing lengths of time caused time-dependent shifts to the right of the dose-response curve and reductions in the maximum cyclic GMP response. Desensitization was reversible, but resensitization was a slower process than desensitization: full recovery of cyclic GMP production required incubation of the desensitized cells for at least 10 min at 37 degrees. From binding studies with [3H]neurotensin, we found that both the apparent equilibrium dissociation constant, KD, and the maximum number of receptor sites, Bmax, for this radioligand were decreased significantly (P less than 0.05) for completely desensitized cells from those values for control cells. These data suggest that desensitization of the neurotensin receptor involved an uncoupling of the pathway of events connecting receptor activation to intracellular cyclic GMP formation; complete desensitization involved both the apparent loss of neurotensin receptors on the cellular surface and the increase in affinity of the remaining receptors for the agonist. This decrease in Bmax is more likely to be a result of intracellular sequestration of recyclable NT receptors than of true down-regulation due to the rapid resensitization seen for the NT-mediated biological response.
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PMID:Desensitization of neurotensin receptor-mediated cyclic GMP formation in neuroblastoma clone N1E-115. 284 79

The receptors which mediate neurotensin-stimulated intracellular cyclic GMP formation in murine neuroblastoma clone N1E-115 [J. A. Gilbert and E. Richelson, Eur. J. Pharmac. 99, 245 (1984)] were further characterized. The binding of [3H]neurotensin to intact N1E-115 cells at 0 degree displayed specificity, saturability, reversibility, and tissue linearity. A single class of neurotensin receptors was demonstrated with an apparent KD of 9-11 nM and a Bmax of 180-250 fmoles/10(6) cells, determined by the type of serum employed in the cellular culture medium. A number of neurotensin analogs and fragments were compared for their ability to inhibit [3H]neurotensin binding and stimulate intracellular cyclic GMP formation with intact N1E-115 cells. A direct correlation was found to exist between the KD and EC50 for each peptide. The carboxyl-terminal portion of neurotensin proved to be responsible for the binding and biochemical activities of this peptide with clone N1E-115. Neurotensin(8-13) was, in fact, fifty times more potent than native neurotensin in stimulating intracellular cyclic GMP formation and had an 18-fold higher affinity for the neurotensin receptor on this neuronal cell type.
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PMID:Neurotensin and its analogs--correlation of specific binding with stimulation of cyclic GMP formation in neuroblastoma clone N1E-115. 286 25

Neurotensin, some of its analogs, and neuromedin N were examined for comparison of their potencies at stimulating inositol phospholipid hydrolysis and cyclic GMP synthesis in intact murine neuroblastoma cells (clone N1E-115). Neurotensin(8-13) and acetylneurotensin(8-13) had the highest potencies for the stimulation of the hydrolysis of inositol phospholipid, which were about three times as potent as neurotensin (EC50 = 0.9 nM). On the other hand, fragments of the amino-terminal portion of neurotensin, such as neurotensin(1-6), neurotensin(1-8) and neurotensin(1-11), showed no ability to stimulate this hydrolysis. Neuromedin N, which is similar in structure to neurotensin(8-13) and which has been demonstrated to stimulate cyclic GMP formation [J.A. Gilbert and E. Richelson, Eur. J. Pharmac. 129, 379 (1986)], had EC50 values of 2.5 and 4.5 nM for release of [3H]inositol phosphates and stimulation of cyclic [3H]GMP respectively. A strong correlation was obtained between the EC50 values for neurotensin and several analogs in the stimulation of the release of inositol phosphates and the EC50 values for these peptides in the stimulation of cyclic GMP formation in neuroblastoma clone N1E-115 cells under similar experimental conditions. Thus, these two different biochemical effects of neurotensin and its analogs appear to be mediated by the same receptor site, which may also have been the site of action of neuromedin N in these cells.
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PMID:Comparison of the stimulation of inositol phospholipid hydrolysis and of cyclic GMP formation by neurotensin, some of its analogs, and neuromedin N in neuroblastoma clone N1E-115. 303 99

The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production. In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem. Pharmacol., 50: 845-850, 1995), we identified one significant difference: the Vmax of carcinoid AAAD was 50-fold higher than that in normal liver. Here, we report Western and Northern analyses detecting large quantities of AAAD polypeptide and mRNA in human carcinoid primary as well as metastatic tumors compared with normal surrounding tissues. To assess the feasibility of targeting these high AAAD levels for chemotherapy, AAAD inhibitors carbidopa (alpha-methyl-dopahydrazine), alpha-monofluoromethyldopa (MFMD), and 3-hydroxybenzylhydrazine (NSD-1015) were incubated (72 h) with NCI-H727 human lung carcinoid cells. Carbidopa and MFMD were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); NSD-1015 had no effect on proliferation. On exposure to other human tumor lines, carbidopa was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively). Carbidopa (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines. The rank order of lines by AAAD activity was NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145, MCF7, and NCI-H460 had no measurable activity. For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), AAAD activity was correlated with the potency of carbidopa-induced cytotoxicity. However, carcinoid cell death was not solely attributable to complete inhibition of either AAAD activity or the serotonin synthetic pathway. In further evaluating potential applications of these findings with carbidopa, we determined that sublethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan.
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PMID:The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells. 1110 55