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)

The biological significance of a major protein component in the fluid of gross cystic breast disease and a recognized marker of apocrine metaplasia, i.e. the 15-kDa glycoprotein (GCDFP-15), is presently unknown. We have added GCDFP-15 to cell culture medium and tested its effect on proliferation of 4 human breast-cancer cell lines (MCF7, BT474, MDA-MB231 and T47D) and a "normal" human immortal breast-cell line (MCF10A). These breast-cell lines showed a mitogenic response to GCDFP-15 (10 micrograms/ml). GCDFP-15 enhanced cell growth of the MCF10A, MCF7, BT474 and MDA-MB231 cell lines at both 48 and 96 hr of exposure. The glycoprotein exerted a mitogenic effect on the T47D cell line at 48 hr but not at 96 hr. This may be due to an auto-regulatory effect of endogenous GCDFP-15 synthesized by the T47D cells. GCDFP-15 was ineffective on 2 colon-cancer cell lines (HT29 and NIC-H716), on the IMR32 neuroblastoma cell line and on the NIC-H209 small-cell lung carcinoma cells. A separate major breast cystic disease fluid protein of 24 kDa (GCDFP-24) was tested, following the same experimental design, on the 5 breast-cell lines, and showed no mitogenic activity. The mitogenic effect of GCDFP-15 observed in this study in both "normal" and malignant breast epithelial cells suggests a possible relationship between apocrine metaplasia in breast cystic disease and the development of breast epithelial hyperplasia. In addition, a possible role of GCDFP-15 in breast-cancer progression should be considered.
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PMID:Mitogenic effect of the 15-kDa gross cystic disease fluid protein (GCDFP-15) on breast-cancer cell lines and on immortal mammary cells. 782 19

Target cells of cytotoxic T lymphocytes (CTL) directed to the individual structural proteins (except for the large polymerase (L) protein) of rabies virus were established by expressing only the respective protein in murine neuroblastoma (NA) and murine macrophage (J774-1) cell lines. Mice infected with the ERA strain of rabies virus developed CTL responses to all of these rabies virus proteins. The cytotoxic activity was abrogated by pretreatment of the effector cells with anti-CD8 monoclonal antibody (MAb) and complement but not with anti-CD4 MAb. Cell lysis by CTL was blocked in the presence of anti-major histocompatibility complex (MHC) class 1 antibodies in J774-1 cell lines. Rabies virus-infected cells express these proteins at the surface, which can be recognized and lysed by the respective CTL. Mice immunized with beta-propiolactone-inactivated virus induced a CTL response against glycoprotein but not against internal viral components. This assay system might be useful for further analysis of the possible contribution of these proteins in the cell-mediated immune protection against rabies.
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PMID:Target cells of cytotoxic T lymphocytes directed to the individual structural proteins of rabies virus. 785 13

The MRP gene (Cole et al., Science (Washington DC), 258: 1650-1654, 1992) encodes a membrane-bound glycoprotein the expression of which correlates with non-P-glycoprotein-mediated multidrug resistance in a variety of cultured human cell lines. Using an RNA-polymerase chain reaction assay, expression of this gene was examined in the highly chemoresistant pediatric malignancy, neuroblastoma. MRP expression was observed in 5 human neuroblastoma cell lines and in all 25 primary neuroblastoma tumors of stage I through IVS. Tumors with amplification of the N-myc oncogene were found to have significantly higher MRP expression that those with no amplification (P = 0.0016). Expression of the MRP gene in the tumor specimens was highly correlated with expression of the N-myc gene (P = 0.0009), while expression of the MDR1 gene, encoding P-glycoprotein, was not related to expression of either the N-myc or MRP genes. Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. Expression of the MRP gene is thus common in both primary neuroblastoma tumors and cultured cell lines, and correlates with amplification and overexpression of the N-myc oncogene, which is central to the malignant phenotype of this disease.
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PMID:Expression of the multidrug resistance-associated protein (MRP) gene correlates with amplification and overexpression of the N-myc oncogene in childhood neuroblastoma. 792 12

Several monoclonal antibodies (mAbs) were screened on different neuroblastoma cell lines to evaluate ricin A-chain immunotoxins for possible use against human neuroblastoma. Four mAbs were identified that exhibited high antitumor activity against neuroblastoma cell lines as measured in an indirect cytotoxicity assay. These mAbs, including 14G2a (antidisialoganglioside), ch14.18 (a humanized switch variant), BW704 (antidisialoganglioside), and chCE7 (anti-glycoprotein of M(r) 190,000), were subsequently linked via the bivalent linker N-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-piridyldithio++ +)toluene to deglycosylated ricin A chain. The most potent immunotoxin, 14G2a.dgA, inhibited the protein synthesis of neuroblastoma cell lines IMR5 and NMB by 50% at concentrations of 6 x 10(-12) M. To test the antitumor efficacy of these immunotoxins in vivo, we developed a disseminated human neuroblastoma model in severe combined immunodeficiency mice. Treatment of tumor-bearing mice with 14G2a.dgA 12 days after tumor challenge resulted in a significant prolongation of survival as compared with phosphate-buffered saline-treated controls (16.8 versus 6.5 weeks). We conclude that ricin A-chain immunotoxins might be of potential use in the treatment of human neuroblastoma.
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PMID:Antidisialoganglioside ricin A-chain immunotoxins show potent antitumor effects in vitro and in a disseminated human neuroblastoma severe combined immunodeficiency mouse model. 795 65

Previously we found that ethanol increases expression of the constitutive 70-kDa heat shock protein (Hsc70) in NG108-15 neuroblastoma x glioma cells. We suggested that known ethanol actions on cellular protein trafficking may relate to Hsc70 induction because Hsc70 functions as a molecular chaperone. Here we use a subtractive hybridization protocol to isolate ethanol-responsive genes (EtRGs). Northern blot hybridization verified ethanol-induced increases in mRNA abundance for five cDNA clones isolated from ethanol-treated NG108-15 neuroblastoma x glioma cells. DNA sequence analysis identified one EtRG as 94-kDa glucose-regulated protein (GRP94), a member of the "glucose-responsive" subgroup of stress proteins. Other identified EtRGs included an insulin-induced growth-response protein gene and an intracisternal A-type particle gene. Sequence analysis of the remaining two EtRGs showed no homology in DNA sequence databases. All EtRGs showed wide tissue expression, except SL64, which was not detected in Northern blot analyses of adult mouse or rat tissues. Ethanol also increased mRNA abundance for 78-kDa glucose-regulated protein (GRP78), a molecular chaperone known to function in glycoprotein trafficking and usually coordinately regulated with GRP94. However, ethanol induced GRP94 more than GRP78, a pattern distinct from those of other inducers of these genes. All EtRGs, including GRP94 and GRP78, showed similar ethanol concentration-dependent increases in mRNA abundance. In contrast, thapsigargin and other inducers of glucose-responsive proteins increased GRP94 and GRP78 mRNA levels without altering expression of other EtRGs. Our studies demonstrate that several molecular chaperones constitute a subset of EtRGs. Ethanol appears to regulate these EtRGs by a unique mechanism, rather than one shared by classical inducers of stress proteins.
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PMID:Ethanol-responsive genes in neural cells include the 78-kilodalton glucose-regulated protein (GRP78) and 94-kilodalton glucose-regulated protein (GRP94) molecular chaperones. 796 74

Our studies in the NG108-15 neuroblastoma x glioma cell line previously showed that the molecular chaperonin, Hsc70, is an ethanol-responsive gene (EtRG) regulated at the level of transcription by ethanol. We recently identified two related molecular chaperonins, GRP94 and GRP78, as EtRGs with GRP94 mRNA abundance being induced by ethanol more than three-fold vs. control. Stable transfection studies show that GRP78 transcription is also regulated by ethanol and that ethanol also potentiates GRP78 induction by classical inducing agents such as tunicamycin. Recently, we have found that ethanol induction of Hsc70 may require cis-acting promoter sequences recognized by the DNA-binding protein Sp1. Chronic ethanol exposure does not alter Sp1 DNA-binding activity, thus suggesting a possible ethanol-induced post-translational modification that activates Sp1 function. We predict that the molecular mechanisms underlying ethanol regulation of Hsc70, GRP94 and GRP78 may be similar since they have related functions. GRP94 and GRP78 (GRP94/78) are known to be induced by agents which inhibit glycoprotein processing or deplete endoplasmic reticulum stores of calcium. In turn, induction of GRP78 expression is known to selectively alter the transport of glycoproteins and produce "tolerance" to depletion of sequestered intracellular calcium. The regulation of these genes by ethanol could thus relate to the known effects of ethanol on calcium homeostasis and protein trafficking. The actions of ethanol on chaperonin gene expression may have important mechanistic implications for CNS adaptation to ethanol, particularly if other EtRGs share the same regulatory mechanisms.
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PMID:Effects of alcohol on gene expression in neural cells. 803 72

The DCC (deleted in colorectal cancer) gene was identified because it is affected by somatic mutations in colorectal tumors, including allelic losses in greater than 70% of cancers and localized mutations in a subset of cases. The DCC gene also may be inactivated in other tumor types, including cancers of the pancreas, stomach, breast, prostate, and brain, as well as some leukemias. We have characterized DCC complementary DNAs obtained from human fetal brain tissues and IMR32 human neuroblastoma cells. Based on the fetal brain complementary DNA sequence, the predicted transmembrane DCC protein product has 1447 amino acids. The extracellular domain of about 1100 amino acids has four immunoglobulin-like domains and six fibronectin type III-like domains; the 325-amino acid cytoplasmic domain does not show similarity to previously characterized proteins. Comparison of DCC complementary DNAs from IMR32 cells to those from fetal brain identified two potential alternative splice sites. Studies of adult mouse tissues revealed that DCC transcripts were present at very low levels in all tissues studied, and alternative splicing of DCC transcripts was seen in some tissues. Immunoblotting and immunoprecipitation studies with DCC-specific antisera identified protein species with molecular weights of approximately 175,000-190,000 in some rodent tissues and human tumor cell lines. DCC protein expression was highest in brain tissues and neural crest-derived cell lines and markedly reduced or absent in the majority of cancer cell lines studied. Treatment of DCC-expressing cells with tunicamycin decreased the apparent molecular weight of the immunoreactive proteins, establishing that DCC is a glycoprotein. The studies presented here demonstrate that the DCC gene encodes several related glycoprotein species that are likely to be expressed at very low levels in many normal adult tissues. Furthermore, the absence of DCC expression in some of the cancer cell lines studied may result from genetic inactivation of DCC.
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PMID:Expression and alternative splicing of the deleted in colorectal cancer (DCC) gene in normal and malignant tissues. 804 1

Etoposide has demonstrated highly significant clinical activity against a wide variety of neoplasms, including germ-cell malignancies, small-cell lung cancer, non-Hodgkin's lymphomas, leukemias, Kaposi's sarcoma, neuroblastoma, and soft-tissue sarcomas. It is also one of the important agents in the preparatory regimens given prior to bone marrow and peripheral stem-cell rescue. Despite its high degree of efficacy in a number of malignancies, the optimal dose, schedule, and dosing form remain to be defined. It is possible that continuous or prolonged inhibition of the substrate, i. e., topoisomerase II, may be the key factor for the cytotoxic effects of etoposide. Clinical studies have shown the activity of etoposide to be schedule-dependent, with prolonged dosing, best accomplished by the oral dosing form, offering a therapeutic advantage. This benefit awaits validation by prospective randomized studies, some of which are in progress. Recent clinical investigations have focused on the use of etoposide in combination with (a) cytokines to ameliorate myelosuppression, the dose-limiting toxicity of etoposide; (b) agents such as cyclosporin A and verapamil to alter the p-glycoprotein (mdr1) function; and (c) topoisomerase I inhibitors to modulate the substrate upon which it acts. There is continued interest in the development of etoposide to its maximal clinical dimensions and in the examination of alternative biochemical and mechanistic approaches to further our understanding of this highly active agent.
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PMID:Etoposide: current status and future perspectives in the management of malignant neoplasms. 807 20

We have previously developed a homoharringtonine (HHT) resistant murine C1300 neuroblastoma cell line with increased p-glycoprotein expression and cross resistance to Adriamycin. Drug resistance in this cell line was reversed using cyclosporin-A, dipyridamole and cremophor-EL (CRE). Because of the high CRE content of parenteral taxol, we examined the ability of this solvent to reverse taxol cross-resistance in this cell line. Comparative ID-50s using clonogenic assays in agar indicate a 214-fold resistance to HHT. CRE reverses taxol cross-resistance in a dose-dependent manner from 0.003 to 0.1%, and is maximally effective at a subtoxic concentration of 0.03%. High pressure liquid chromatography (HPLC) analysis of taxol treated C1300/HHT cells reveal that CRE causes changes in intracellular drug levels that are not related to drug efflux. Our work shows that clinical preparations of taxol, when diluted to effective doses, contain enough CRE to mitigate multi-drug resistance. Clinical successes of taxol in refractory tumors may be due in part to the ability of its CRE base to reverse multi-drug resistance.
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PMID:Cremophor-EL enhances taxol efficacy in a multi-drug resistant C1300 neuroblastoma cell line. 809 92

We have prepared a monoclonal antibody, Neuro-1, that recognizes the human homolog of the chicken contactin/F11 and mouse F3 cell adhesion molecules. The Neuro-1 antigen, structurally characterized as a 135 kDa glycosylphosphatidylinositol-linked glycoprotein, was immunoaffinity purified and partially sequenced. Comparison of an internal peptide sequence to that predicted from the chicken contactin/F11, mouse F3 and human contactin (reported herein) cDNA sequence identifies the Neuro-1 antigen as human contactin. Moreover, a polyclonal antisera generated against the purified Neuro-1 antigen was immunoreactive with a fragment of human contactin expressed in bacteria. The complete coding and deduced amino acid sequences of human contactin were determined and are 86% and 95% identical to the respective mouse F3 sequences. Structural features shared with contactin/F11/F3 include six immunoglobulin type C2 and four fibronectin type III-like domains, multiple sites for asn-linked glycosylation and a COOH-terminal signal peptide presumably removed during the generation of a phosphatidylinositol cell surface linkage. The potential for glycosylation and GPI-linkage is also consistent with protein chemical studies of human contactin. Contactin mRNA expression was characterized using Northern blot analyses of human tissues and cell lines. High level expression of a single contactin transcript in adult brain, and low level expression of multiple transcripts in lung, pancreas, kidney and skeletal muscle are observed. Highly expressed multiple transcripts, similar in pattern to that of pancreas, lung, kidney and skeletal muscle, are also observed in human neuroblastoma and retinoblastoma cell lines.
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PMID:Identification and characterization of the human cell adhesion molecule contactin. 816 10


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