Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beckwith-Wiedemann syndrome, familial atypical multiple mole melanoma syndrome, and hereditary tylosis are bona fide genodermatoses with malignant potential. Each of these conditions is associated with an increased incidence of certain tumors: Wilms' tumor, adrenocortical carcinomas, pancreatoblastomas, and hepatoblastomas in Beckwith-Wiedemann syndrome; intraocular malignant melanoma, pancreatic carcinoma, and noncolorectal gastrointestinal cancers in familial atypical multiple mole melanoma syndrome; and squamous cell carcinoma of the esophagus in hereditary tylosis. Other cancer-related genodermatoses are Birt-Hogg-Dube syndrome (associated with medullary carcinoma of the thyroid and renal cell carcinoma) and its variant, Hornstein-Knickenberg syndrome (associated with colon carcinoma). Kidney tumors (Wilms' tumor and malignant rhabdoid tumor), leukemias (acute myelogenous and acute myelomonocytic), retinoblastoma, and paratesticular rhabdomyosarcoma have been reported recently in children with another genodermatosis-incontinentia pigmenti. Supernumerary nipples (polythelia) may be sporadic or familial in occurrence; their presence has been associated with an increased incidence of renal adenocarcinoma, testicular cancer, prostate cancer, and urinary bladder carcinoma. The general characteristics, mucosal and skin manifestations, and noncutaneous features of all these conditions are reviewed. Also, the associated malignancies of these genodermatoses and other conditions that are characterized by dermatologic manifestations and may be either familial or secondary to an inherited gene defect are summarized.
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PMID:Miscellaneous genodermatoses: Beckwith-Wiedemann syndrome, Birt-Hogg-Dube syndrome, familial atypical multiple mole melanoma syndrome, hereditary tylosis, incontinentia pigmenti, and supernumerary nipples. 771 45

The laminin beta2 chain is a basement membrane component expressed in a tissue- and developmental stage-specific manner. In this report we have examined the transcriptional and post-transcriptional regulation of the human laminin beta2 chain in human tumor cell lines. Both the A204 rhabdomyosarcoma and clone A colon carcinoma cells express the laminin beta2 chain mRNA, but only the A204 cells secrete laminin heterotrimers containing the beta2 chain. Segments of the beta2 chain gene promoter region were cloned into luciferase reporter vectors, and their ability to stimulate transcription was tested by transient transfection. Sequences downstream of the transcription start site between nucleotides +91 and +120 were found to be essential for luciferase activity in the two cell lines. Additional positive regulatory regions were present further upstream, between nucleotides -164 to -667 and between nucleotides -667 to -1724. Genomic DNA at the 3' end of the gene also appeared to have enhancer activity, as a 1.1-kb fragment located downstream of the last exon stimulated the luciferase activity of the nucleotides -667/+297 promoter segment approximately threefold. Alternative splicing of the first intron of the human laminin beta2 chain gene generates two isoforms of the 5' untranslated region of the beta2 chain mRNA. The translational efficiencies of the two laminin beta2 chain leaders did not differ significantly, when assayed by polysome profile analysis of endogenous clone A cell beta2 chain mRNA, transient transfection of chimeric beta2 chain leader/luciferase expression plasmids in clone A cells, and translation of in vitro synthesized RNAs in rabbit reticulocyte lysates.
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PMID:Regulation of laminin beta2 chain gene expression in human cancer cell lines. 1143 48

To determine whether inhibition of either the ribosomal p70 S6 kinase or eukaryotic initiation factor (eIF) 4E pathways downstream of the mammalian target of rapamycin, mTOR, contributes to rapamycin-induced growth arrest, clones of Rh30 rhabdomyosarcoma cells were selected for rapamycin resistance. Expression of c-Myc and anchorage-independent growth were enhanced in resistant cells. Resistance was unstable in each of three clones characterized. In resistant cells, as compared with parental cells, approximately 10-fold less 4E-binding protein (4E-BP) was bound to eIF4E, and total cellular 4E-BP was markedly reduced. Levels of eIF4E were unchanged. Steady-state levels of 4E-BP transcript remained unaltered, but the rate of 4E-BP synthesis was reduced in resistant cells. In cells that reverted to rapamycin sensitivity, levels of total 4E-BP returned to those of parental cells. Compared with parental cells, resistant clones had either similar or lower levels and activity of ribosomal p70 S6 kinase, but c-Myc levels were elevated in both resistant and revertant clones. Several colon carcinoma cell lines with intrinsic rapamycin resistance were found to have low 4E-BP:eIF4E ratios. In stable clones of HCT8 carcinoma engineered to overexpress 4E-BP, rapamycin sensitivity increased markedly (>1000-fold) as 4E-BP expression increased. These results suggest that the 4E-BP:eIF4E ratio is an important determinant of rapamycin resistance and controls certain aspects of the malignant phenotype.
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PMID:4E-binding proteins, the suppressors of eukaryotic initiation factor 4E, are down-regulated in cells with acquired or intrinsic resistance to rapamycin. 1184 16

Mammalian target of rapamycin (mTOR) controls initiation of translation through regulation of ribosomal p70S6 kinase (S6K1) and eukaryotic translation initiation factor-4E (eIF4E) binding protein (4E-BP). mTOR is considered to be located predominantly in cytosolic or membrane fractions and may shuttle between the cytoplasm and nucleus. In most previous studies a single cell line, E1A-immortalized human embryonic kidney cells (HEK293), has been used. Here we show that in human malignant cell lines, human fibroblasts, and murine myoblasts mTOR is predominantly nuclear. In contrast, mTOR is largely excluded from the nucleus in HEK293 cells. Hybrids between HEK293 and Rh30 rhabdomyosarcoma cells generated cells co-expressing markers unique to HEK293 (E1A) and Rh30 (MyoD). mTOR distribution was mainly nuclear with detectable levels in the cytoplasm. mTOR isolated from Rh30 nuclei phosphorylated recombinant GST-4E-BP1 (Thr-46) in vitro and thus has kinase activity. We next investigated the cellular distribution of mTOR substrates 4E-BP, S6K1, and eIF4E. 4E-BP was exclusively detected in cytoplasmic fractions in all cell lines. S6K1 was localized in the cytoplasm in colon carcinoma, HEK293 cells, and IMR90 fibroblasts. S6K1 was readily detected in all cellular fractions derived from rhabdomyosarcoma cells. eIF4E was detected in all fractions derived from rhabdomyosarcoma cells but was not detectable in nuclear fractions from colon carcinoma HEK293 or IMR90 cells.
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PMID:Predominant nuclear localization of mammalian target of rapamycin in normal and malignant cells in culture. 1200 Jul 55

The development of O(6)-(3-[(125)I]iodobenzyl)-2'-deoxyguanosine ([(125)I]IBdG), the glycosylated analogue of the O(6)-3-iodobenzylguanine (IBG), as an agent for the in vivo mapping of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) is described. Synthesis of its tin precursor, O(6)-3-trimethylstannylbenzyl-2'-deoxyguanosine (TBdG) was achieved in four steps from deoxyguanosine. Radioiodination of TBdG in a single step gave [(125)I]IBdG in 70-85% isolated radiochemical yield. [(125)I]IBdG bound specifically to pure AGT with an IC(50) of 7.1 microM. From paired-label assays, [(125)I]IBdG showed a 2- to 3-fold higher cellular uptake than [(131)I]IBG in DAOY medulloblastoma, TE-671 rhabdomyosarcoma, SK-Mel-28 melanoma, and HT-29 colon carcinoma human cell lines. Uptake of both labeled compounds in these cell lines decreased with increasing concentrations of unlabeled O(6)-benzylguanine (BG) when BG was present in the medium during incubation with the labeled compounds. Compared to BG, unlabeled IBdG diminished the uptake of [(125)I]IBdG and [(131)I]IBG in DAOY cells more efficiently (IC(50)<1 microM vs >10 microM for BG). There was no significant change in cell-bound activity of [(125)I]IBdG and [(131)I]IBG when BG was removed from the incubation medium before incubating cells with the tracers, suggesting that only a very small portion of radioactivity taken up by the cells is AGT bound. This was corroborated by gel-electrophoresis performed on extracts from cells treated with varying amounts of BG and then incubated with [(125)I]IBdG in the presence of BG. No radiolabeled AGT band was discernable by phosphor-imaging, signifying low cellular AGT binding of the radiotracer. In contrast, when cell extracts were prepared from BG pre-treated cells and aliquots were incubated with [(125)I]IBdG subsequently, the intensity of radiolabeled AGT band decreased linearly as a function of BG concentration. This suggests that the low level of [(125)I]IBdG that binds to AGT does so in a concentration dependent manner. These data suggest that IBdG is transported across the cell membrane to a higher degree than IBG. However, to be a practical tracer for quantifying cellular AGT, considerable localization of such derivatives need to occur within the cell nucleus where AGT is present predominantly.
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PMID:O6-3-[125I]iodobenzyl-2'-deoxyguanosine ([125I]IBdG): synthesis and evaluation of its usefulness as an agent for quantification of alkylguanine-DNA alkyltransferase (AGT). 1591 5

Tumor growth depends on blood supply, requiring the development of new vessels, and vascular endothelial growth factor (VEGF) plays a central role in neoangiogenic processes. For this reason, VEGF represents a target for the development of new therapeutic antiangiogenic molecules. Clinical trials using anti-VEGF mAbs such as bevacizumab have validated the efficacy of this therapeutic approach but have also revealed adverse effects. Here we report that a VEGF-derived immunogen, consisting of a heterocomplex of a murine (m)VEGF and keyhole limpet hemocyanin, called "mVEGF kinoid," triggered a strong Ab immune response in mice. The anti-VEGF Abs inhibited both the proliferation of human umbilical vein endothelial cells cultured in the presence of mVEGF and the binding of mVEGF to its receptor-2 Flk-1. In mVEGF kinoid-immunized BALB/c mice challenged with syngeneic CT26 colorectal tumor cells, the number and size of lung metastases were significantly decreased. In human (h)VEGF kinoid-immunized BALB/c mice, high levels of serum Abs to hVEGF were present, and purified IgG from these mice decreased by > or =50% the tumor growth of human A673 rhabdomyosarcoma cells and HT29 colon carcinoma xenografted in Swiss nude and NOD/SCID mice, respectively. Tumor cell growth inhibition was similar to that observed in mice receiving therapeutic doses of bevacizumab. These experiments suggest that a therapeutic vaccine containing VEGF kinoid may represent a strategy for safely combating VEGF-dependent neovascularization and metastases occurring in malignant tumors.
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PMID:VEGF kinoid vaccine, a therapeutic approach against tumor angiogenesis and metastases. 1766 4

The effect of the potent and selective poly(ADP-ribose) (PAR) polymerase-1 [and PAR polymerase-2] inhibitor CEP-8983 on the ability to sensitize chemoresistant glioblastoma (RG2), rhabdomyosarcoma (RH18), neuroblastoma (NB1691), and colon carcinoma (HT29) tumor cells to temozolomide- and camptothecin-induced cytotoxicity, DNA damage, and G(2)-M arrest and on the potentiation of chemotherapy-induced myelotoxicity was evaluated using in vitro assays. In addition, the effect of the prodrug CEP-9722 in combination with temozolomide and/or irinotecan on PAR accumulation and tumor growth was also determined using glioblastoma and/or colon carcinoma xenografts relative to chemotherapy alone. CEP-8983 sensitized carcinoma cells to the growth-inhibitory effects of temozolomide and/or SN38 increased the fraction of and/or lengthened duration of time tumor cells accumulated in chemotherapy-induced G(2)-M arrest and sensitized tumor cells to chemotherapy-induced DNA damage and apoptosis. A granulocyte-macrophage colony-forming unit colony formation assay showed that coincubation of CEP-8983 with temozolomide or topotecan did not potentiate chemotherapy-associated myelotoxicity. CEP-9722 (136 mg/kg) administered with temozolomide (68 mg/kg for 5 days) or irinotecan (10 mg/kg for 5 days) inhibited significantly the growth of RG2 tumors (60%) or HT29 tumors (80%) compared with temozolomide or irinotecan monotherapy, respectively. In addition, CEP-9722 showed "stand alone" antitumor efficacy in these preclinical xenografts. In vivo biochemical efficacy studies showed that CEP-9722 attenuated PAR accumulation in glioma xenografts in a dose- and time-related manner. These data indicate that CEP-8983 and its prodrug are effective chemosensitizing agents when administered in combination with select chemotherapeutic agents against chemoresistant tumors.
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PMID:The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. 1769 24

Betulin is a pentacyclic triterpene found in many plant species, among others, in white birch bark. The aim of the study was in vitro characterization of the anticancer activity of betulin in a range of human tumour cell lines (neuroblastoma, rhabdomyosarcoma-medulloblastoma, glioma, thyroid, breast, lung and colon carcinoma, leukaemia and multiple myeloma), and in primary tumour cultures isolated from patients (ovarian carcinoma, cervical carcinoma and glioblastoma multiforme). In this study, we demonstrated a remarkable anti-proliferative effect of betulin in all tested tumour cell cultures. Neuroblastoma (SK-N-AS) and colon carcinoma (HT-29) were the most sensitive to the anti-proliferative effect of betulin. Furthermore, betulin altered tumour cells morphology, decreased their motility and induced apoptotic cell death. These findings demonstrate the anti-cancer potential of betulin and suggest that they may be applied as an adjunctive measure in cancer treatment.
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PMID:Betulin elicits anti-cancer effects in tumour primary cultures and cell lines in vitro. 1982 31

The 2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole set are well known compounds with interesting in vitro and in vivo anti-cancer profiles. The aim of this study was an in vitro evaluation of the anti-cancer activity of a new synthesized aminothiadiazole derivative 2-(3-chlorophenyloamino)-5-(2,4-dihydroxyphenyl)- -1,3,4-thiadiazole 4ClABT. The effect on tumor cell proliferation, motility and morphology, DNA synthesis as well as the influence on normal cells was assessed. The antiproliferative activity of 4ClABT in tumor cells derived from peripheral cancers including breast carcinoma (T47D), colon carcinoma (HT-29), thyroid carcinoma (FTC-238), teratoma (P19), and T-cell leukemia (Jurkat E6.1), as well as cancers of the nervous system including rhabdomyosarcoma/medulloblastoma (TE671), brain astrocytoma (MOGGCCM) and glioma (C6) was studied by means of MTT assay. DNA synthesis level was determined in BrdU ELISA test. Wound assay model was applied for tumor cell motility assessment. Morphological changes induced by 4ClABT in cancer and normal cells were analyzed in HE staining specimens. Moreover, the influence of 4ClABT on normal cells including skin fibroblasts (HSF), hepatocytes (Fao), astroglia and neurons was studied by means of LDH assay. The tested compound inhibited the proliferation of tumor cells in dose-dependent fashion. The anti-cancer effect was attributed to decreased DNA synthesis, prominent changes in tumor cell morphology as well as reduced cell motility. In antiproliferative concentrations, 4ClABT was not toxic to normal cells. Our study showed prominent anti-cancer effects of the tested aminothiadiazole derivative in the absence of toxicity in normal cells. The obtained results confirmed the promising anti-cancer profile of previously tested 2-(monohalogenphenylamino)- -5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole derivatives (ClABT - chlorophenyl derivative, FABT and 3FABT - fluorophenyl derivatives and 4BrABT - bromophenyl derivative). The molecular mechanisms and the in vivo activity of aminothiadiazole derivatives will be the subject of further studies.
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PMID:The activity of a new 2-amino-1,3,4-thiadiazole derivative 4ClABT in cancer and normal cells. 2203 23

Recent studies have suggested that pan inhibitors of dipeptidyl peptidase-4 activity and/or structure homologs (DASH), including ARI-4175, can mediate tumor regression by immune-mediated mechanisms. This study assessed the potential of combining ARI-4175 with cancer vaccines. We evaluated ARI-4175's effect on immunogenic modulation, ability to sensitize tumor cells to antigen-specific CTL killing, effect on immune-cell subsets and function, and antitumor activity in 2 tumor models, both as a monotherapy and in combination with a recombinant viral or dendritic cell (DC)-based tumor-cell vaccine. ARI-4175's effects on the growth, surface phenotype, and antigen-specific CTL-mediated lysis of murine and human carcinoma cell lines were assessed in vitro. In vivo, C57BL-6 mice were treated orally with ARI-4175, after which splenocytes were assessed by flow cytometry and functional assays. Antitumor studies were performed in murine models of colon carcinoma (MC38-CEA(+) in CEA-transgenic C57BL-6 mice) and rhabdomyosarcoma (M3-9-M in C57BL-6 mice). Mice received oral ARI-4175 alone or in combination with a vaccine consisting of recombinant vaccinia/fowlpox CEA-TRICOM (colon model) or a DC-based tumor-cell vaccine (rhabdomyosarcoma model). Exposure to ARI-4175 had no effect on the proliferation or viability of carcinoma cells in vitro; however, it did alter tumor phenotype, making murine and human tumor cells more sensitive to antigen-specific CTL killing. Assessment of immune-cell subsets and function indicated that ARI-4175 increased levels of natural killer cells and DCs. Detrimental immune effects, including reduced T effector cells and increased immunosuppressive cells (Tregs, MDSCs), were normalized when treatment stopped, suggesting that scheduling is critical when combining this agent with vaccine. As a monotherapy, ARI-4175 had potent antitumor activity in both tumor models, and had even greater effects when combined with a vaccine (either DC-based or poxviral vector based). These findings provide the rationale for the combined use of cancer immunotherapy with DASH enzyme inhibitors such as ARI-4175.
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PMID:A pan inhibitor of DASH family enzymes induces immunogenic modulation and sensitizes murine and human carcinoma cells to antigen-specific cytotoxic T lymphocyte killing: implications for combination therapy with cancer vaccines. 2473 9


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