Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the bcl-2 and the related bcl-xL protooncogene proteins enhance cell survival by inhibiting apoptosis induced by many agents including oxidants. Whether these proteins contribute to survival in oxidant-resistant cells is not known. The current study assessed the expression of bcl-2 and bcl-xL proteins in human glioblastoma U87MG cells and human lung adenocarcinoma A549 cells selected for resistance to 0, 50, 100, 200, and 400 microM H2O2 by exposure to this oxidant one time each passage for 9 months. When examined 7 to 32 days after cessation of peroxide exposure (times when peroxide resistance was maintained), bcl-2 protein levels were significantly increased in most peroxide-resistant U87MG cells. However, the increase was not dose dependent and was not accompanied by an increase in mRNA levels. A549 cells did not express significant levels of bcl-2 protein, although bcl-2 mRNA was detectable. A549 cells expressed large amounts of bcl-xL and immunohistochemistry demonstrated extensive localization of this protein around the nucleus. However, expression of this protein was not altered in peroxide-resistant lines nor was bcl-2 protein increased to a measurable level. U87MG cells also expressed bcl-xL but it was not altered in peroxide-resistant cells. Although the increased bcl-2 protein in peroxide-resistant U87MG cells may contribute to their oxidant tolerance, the lack of a dose-response relationship, the failure to induce bcl-xL protein, and the absence of any bcl-2 or bcl-xL protein induction in peroxide-resistant A549 cells suggest these genes are not primary factors in oxidant resistance.
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PMID:Bcl-2 and Bcl-xL in peroxide-resistant A549 and U87MG cells. 957 23

The fidelity of DNA synthesis associated with uracil-initiated base excision repair was measured in human whole cell extracts. An M13mp2 lacZalpha DNA-based reversion assay was developed to assess the error frequency of DNA repair synthesis at a site-specific uracil residue. All three possible base substitution errors were detected at the uracil target causing reversion of opal codon 14 in the Escherichia coli lacZalpha gene. Using human glioblastoma U251 whole cell extracts, approximately 50% of the heteroduplex uracil-containing DNA substrate was completely repaired, as determined by the insensitivity of form I DNA reaction products to cleavage by a combined treatment of E. coli uracil-DNA glycosylase and endonuclease IV. The majority of repair occurred by the uracil-initiated base excision repair pathway, since the addition of the bacteriophage PBS2 uracil-DNA glycosylase inhibitor protein to extracts significantly blocked this process. In addition, the formation of repaired form I DNA molecules occurred concurrently with limited DNA synthesis, which was largely restricted to the HinfI DNA fragment initially containing the uracil residue and specific to the uracil-containing DNA strand. Based on the reversion frequency of repaired M13mp2 DNA, the fidelity of DNA repair synthesis at the target was determined to be about one misincorporated nucleotide per 1900 repaired uracil residues. The major class of base substitutions propagated transversion mutations, which were distributed almost equally between T to G and T to A changes in the template. A similar mutation frequency was also observed using whole cell extracts from human colon adenocarcinoma LoVo cells, suggesting that mismatch repair did not interfere with the fidelity measurements.
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PMID:Fidelity and mutational specificity of uracil-initiated base excision DNA repair synthesis in human glioblastoma cell extracts. 973 86

Differences on 5'-nucleotidase activity in intact Rugli and BCS-TC2 cells (rat glioblastoma and human colon adenocarcinoma cell lines, respectively) are not due to differences in the characteristics of the ectoenzyme. A membrane-bound 5'-nucleotidase from BCS-TC2 cells has been purified to homogeneity with a high specific activity (130 U/mg), yielding a single 72-kDa band on SDS-PAGE. It is a metalloenzyme and, after inhibition by EDTA, its activity can be partially restored by divalent cations. The hydrolysis of the nucleosides 5'-monophosphate used as substrate follows Michaelis-Menten kinetics; ADP and concanavalin A are competitive and non-competitive inhibitors of the AMPase activity, respectively. This ecto-5'-nucleotidase is a high-mannose glycoprotein; deglycosylation converts the 72-kDa into a 59-kDa protein with a concomitant activity loss. The enzyme purified from BCS-TC2 cells shows similar characteristics from that previously isolated from Rugli cells; differences between them are mainly due to glycosylation. Polyclonal antibodies against 5'-nucleotidase from BCS-TC2 cells also show cross-reactivity with the enzyme from Rugli cells. When the ectoenzyme activity is measured in cells in culture, Rugli cells present a higher activity than BCS-TC2 cells however, they express very low amounts of ecto-5'-nucleotidase. Our results also show a reduction in protein level and enzyme activity associated with a decrease in the differentiation degree and an increase in tumorigenicity of human colon adenocarcinoma BCS-TC2 sublines.
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PMID:Ecto-5'-nucleotidase from a human colon adenocarcinoma cell line. Correlation between enzyme activity and levels in intact cells. 978 49

Pyrazoloacridine (PA), an acridine congener that has shown selective toxicity in solid tumor cells, full activity against noncycling and hypoxic cells, and promising activity in a recent Phase I trial, is currently undergoing Phase II testing as a solid tumor-selective agent. In the present study, clonogenic assays were used to examine the cytotoxic effects when PA was combined with other antineoplastic agents in A549 human non-small cell lung cancer cells in vitro. Data were analyzed by the median effect method. Combinations of PA with antimetabolites (5-fluorouracil, methotrexate, and cytarabine) or with antimicrotubule agents (paclitaxel and vincristine) failed to exhibit synergy. Likewise, combinations of PA with alkylating agents (melphalan, 4-hydroperoxycyclophosphamide) were less than additive. In contrast, the combination of PA and cisplatin exhibited cytotoxicity that was additive or synergistic over a broad range of clinically achievable concentrations. Moreover, studies involving sequential exposure to PA and cisplatin revealed a synergistic interaction when cells were exposed to the two agents in either sequence. Synergy was likewise observed with this combination in T98G human glioblastoma cells and HCT8 human intestinal adenocarcinoma cells as well as AuxB1 hamster ovary cells. Flow microfluorimetry revealed that PA caused arrest of A549 cells in G1 and G2 phases of the cell cycle, providing a potential explanation for the antagonism between PA and antimetabolites or antimicrotubule agents. Further studies revealed that PA inhibited removal of platinum-DNA adducts in A549 cells in a dose-dependent fashion, with almost complete inhibition occurring at 1 microM PA. These latter observations provide a mechanistic explanation for the synergy between PA and cisplatin and suggest that this combination warrants further preclinical and clinical investigation.
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PMID:Cytotoxic synergy between pyrazoloacridine (NSC 366140) and cisplatin in vitro: inhibition of platinum-DNA adduct removal. 981 47

We established a protocol for the non-isotopic in situ detection of adhesion molecule CD44 messenger RNA (mRNA) in archival formalin-fixed paraffin-embedded sections of human surgical materials. Four brain tumor samples with different histopathologies (a metastatic adenocarcinoma, a metastatic squamous carcinoma, a glioblastoma and a craniopharyngioma) were thus studied using a 157 nt digoxigenin-labeled RNA probe complementary to the common mRNA region to all the CD44 isoforms. The CD44 transcript was detected in the cytoplasm of glioma and such epithelial tumor cells as metastatic carcinoma and craniopharyngioma. A competitive hybridization study confirmed the specificity of the CD44 probe. The optimization of critical conditions are also discussed. This protocol should therefore be useful in making an accurate evaluation of mRNA localization and may also facilitate the successful completion of extensive retrospective studies on a large number of archival samples.
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PMID:Non-isotopic in situ hybridization of CD44 transcript in formalin-fixed paraffin-embedded sections. 1023 50

Although CTLs bear main immune responses in human tumors, stable CTL clones against human lung cancer have rarely been generated. Our previous study demonstrated efficient autologous CTL induction in human gastric cancer and glioblastoma by cytokine combination of interleukin (IL)-1beta (167 IU/ml), IL-2 (67 IU/ml), IL-4 (67 IU/ml), and IL-6 (134 IU/ml). In this study, we demonstrated successful induction of autologous stable CTLs in five of six patients with lung adenocarcinoma from mixed-lymphocyte tumor culture using this cytokine combination. All CTLs revealed potent and specific killing activity against autologous target cells (over 75% in CD8+ CTLs and over 50% in CD4+ CTLs at an E:T ratio of 10 for 24 h). Using a series of antibodies, CD8+ CTLs showed to recognize tumor-specific antigens of lung cancer cells through HLA class I. In the separate experiments, failure of CTL induction from monocyte-depleted peripheral blood mononuclear cells and appearance of cells with characteristics of dendritic cells from adherent peripheral blood mononuclear cells in the culture of the same concentration of IL-1beta, IL-4, and IL-6 indicated that CTLs can be efficiently generated by this cytokine combination via possible dendritic cell induction. This is the first study of an efficient and reproducible in vitro CTL induction against human lung cancer.
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PMID:Autologous high-killing cytotoxic T lymphocytes against human lung cancer are induced using interleukin (IL)-1beta, IL-2, IL-4, and IL-6: possible involvement of dendritic cells. 1035 58

We used differential display-PCR (DD-PCR) to identify glucocorticoid-inducible genes that regulate lung development in late gestation. DD-PCR, a method to screen for differentially expressed genes, is based on a comparison of mRNAs isolated from a subset of two or more cell populations by analysis of RT-PCR products on DNA-sequencing gels. We isolated cDNA probes representing mRNAs expressed in primary cultures of rat lung fibroblasts, but not in epithelial cells, on fetal day 20. A day 20 glucocorticoid-treated fibroblast cDNA library was screened with a single probe to isolate the 3.1-kb cDNA late-gestation lung 1 (LGL1; GenBank accession no. AF109674) encoding a deduced polypeptide of 188 amino acids. Northern analysis confirmed that LGL1 is expressed in human, rat, and mouse fetal lungs, induced by glucocorticoid, developmentally regulated in fibroblasts but not detectable in epithelium. In situ hybridization confirmed LGL1 expression in the mesenchyme, but not in the epithelium, of fetal rat lung, kidney, and gut. The predicted LGL1 gene product (lgl1) showed 81% homology to P25TI, a polypeptide trypsin inhibitor recently identified in human glioblastoma and neuroblastoma cells but not detected in normal human tissues. Both lgl1 and P25TI belong to the CRISP family of cysteine-rich extracellular proteins. Trypsin is produced by both normal bronchial epithelial and lung adenocarcinoma cells. Although additional studies will be necessary to clearly establish a functional role for lgl1, we propose that lgl1 has a role in normal lung development that is likely to be via regulation of extracellular matrix degradation.
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PMID:A novel developmentally regulated gene in lung mesenchyme: homology to a tumor-derived trypsin inhibitor. 1036 28

We report the distribution pattern of the target antigen of an IgG1 monoclonal antibody, Ki-OC III raised in BALB/C mice against solubilised ovarian adenocarcinoma, in normal tissue and in a collection of human tumour types. Special reference was made to benign and malignant ovarian tumours. The reactive antigen protein purified to homogeneity for a planned amino acid analysis showed three bands between 37-40 kDa. Immunohistochemical analysis revealed a specificity of 98% and a sensitivity of 77%. The tracer kinetics of the radiolabelled antibody were tested on a human ovarian carcinoma cell line in athymic mice. The results were compared to cell lines derived from breast and stomach carcinomas as well as to a human glioblastoma cell line. The results show the preferential uptake by ovarian cancer cells followed by breast cancer cell lines. In animal models, scintigraphic monitoring and direct measurement of the radio-labelled monoclonal antibody showed a preferential accumulation in tumours, in addition to high level signals in the liver, kidney, spleen and heart which were related to degradation, excretion and high circulation. The Ki-OC III reactive antigen could be a potential candidate for immunomonitoring of ovarian and possibly also of breast cancer, for in vivo tumour imaging as well as for histopathologic examinations.
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PMID:Characterization of a MAb to ovarian cancer and its possible diagnostic application. 1047 26

We investigated the ability of Fischer rat T9 glioblastoma cells transduced with cDNA genes for the secreted (s) or membrane-associated (m) isoform of M-CSF to elicit an antitumor response when implanted into syngeneic animals. Intracranial (i.c.) implantation of 1 x 10(5) T9 cells expressing mM-CSF (T9/mM-CSF) resulted in 80% tumor rejection. Electron microscopy of the T9/mM-CSF tumor site, 2-4 days postimplantation, showed marked infiltration by macrophages, many of which were in physical contact with the T9/mM-CSF cells. Animals that rejected T9/mM-CSF cells were resistant to i.c. rechallenge with T9 cells, but not syngeneic MadB106 breast adenocarcinoma cells, suggesting that T9-specific immunity can be generated within the brain via the endogenous APCs. Intracranial injection of parental T9, vector control (T9/LXSN), or T9 cells secreting M-CSF (T9/sM-CSF) was 100% fatal. Subcutaneous injection of 1 x 10(7) T9/sM-CSF, T9/LXSN, or parental T9 cells resulted in progressive tumors. In contrast, T9/mM-CSF cells injected s.c. were destroyed in 7-10 days and animals developed systemic immunity to parental T9 cells. Passive transfer of CD3+ T cells from the spleens of immune rats into naive recipients transferred T9 glioma-specific immunity. In vitro, splenocytes from T9/mM-CSF-immunized rats specifically proliferated in response to various syngeneic glioma stimulator cells. However, only marginal T cell-mediated cytotoxicity was observed by these splenocytes in a CTL assay against T9 target cells, regardless of restimulation with T9 cells. Subcutaneous immunization with viable T9/mM-CSF cells was effective in eradicating i.c. T9 tumors.
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PMID:Development of systemic immunity to glioblastoma multiforme using tumor cells genetically engineered to express the membrane-associated isoform of macrophage colony-stimulating factor. 1055 82

The aim of this study was to examine the cytotoxic effect of 10 newly synthesized diazenecarboxamides (diazenes). Using a modified colorimetric MTT assay, their cytotoxicity was determined on 10 human cell lines: cervical carcinoma parental and cisplatin-resistant cells, laryngeal carcinoma parental and cisplatin- and vincristine-resistant cells, glioblastoma parental and cisplatin-resistant cells, breast adenocarcinoma parental and doxorubicin-resistant cells, and mammary carcinoma cells. Results show that diazene JK-279 was most effective, reducing significantly the cell survival of all 10 cell lines examined, including five drug-resistant cell lines. A cytotoxic effect was observed also on nine from 10 cell lines for diazene JK-835. A small reduction in cell survival was obtained (mainly for highest drug concentrations) for diazenes LV-57 and MG-19 on two cell lines, and JK-429 and JK-913 on one cell line. Other diazenes did not demonstrate any cytotoxic activity. The results encourage further research on diazene JK-279 as a potential anticancer drug.
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PMID:Diazene JK-279: potential anticancer drug. 1058 96


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