Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown adenoviral transfer of the herpes simplex virus thymidine kinase (HSVtk) gene followed by the anti-viral drug ganciclovir (GCV) can be used to successfully treat established human mesothelioma tumors growing within the peritoneal cavities of severe combined immune deficient (SCID) mice. These findings raised a number of questions important to the applicability, efficiency, and safety of this treatment strategy. In this report, we have further characterized the use of recombinant adenovirus carrying the HSVtk gene to treat mesothelioma and other localized malignancies. Our results indicate that the Ad.RSVtk/GCV system is effective in causing tumor regression in animals inoculated with another mesothelioma cell line and a lung cancer cell line and that animals with bulky disease can be successfully treated. Effects are seen at a wide range of virus doses and significant anti-tumor activity is present at doses of ganciclovir that are clinically achievable. Finally, this treatment approach appears safe, with limited dissemination of virus using a sensitive RT-PCR detection system. These studies further characterize the use of adenoviral transfer of the HSVtk gene to treat experimental mesothelioma and suggest that clinical trials using this approach may be feasible.
Am J Respir Cell Mol Biol 1995 Jul
PMID:Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer. 759 39

We used a recombinant retrovirus as one of the potential vectors for human gene therapy to transfer a drug sensitivity gene into human lung cancer cells. The gene encoding the thymidine kinase (TK) of herpes simplex virus type 1 (HSV1) was used as the drug sensitivity gene. The antiherpes drugs acyclovir (ACV) and ganciclovir (GCV) were chosen to test the HSV1-TK activity transferred into the human lung cancer cell lines. The rationale for this approach was that ACV and GCV are nucleoside analogs specifically converted by HSV1-TK to a toxic form capable of inhibiting DNA synthesis or disrupting cellular DNA replication. The results obtained from our experiments demonstrate that the retroviral vector-mediated HSV1-TK gene transfer leads to ACV- and GCV-dependent cytotoxicity in human lung cancer cell lines, including both small-cell carcinoma and non-small-cell carcinoma. Although the gene transfer of HSV1-TK gene into tumor cells would be one model for gene therapy to control lung cancer, further investigations are necessary for the proper choice of the therapeutic gene and vector targeting such as tumor cell specific delivery of the gene or tumor cell specific expression of the transduced gene.
J Mol Med (Berl) 1995 Mar
PMID:Retroviral transfer of HSV1-TK gene into human lung cancer cell line. 763 46

The purpose of this study was to investigate the expression of tumor necrosis factor (TNF) receptors for the control of the biologic action of TNF-alpha in lung cancer cells and normal lung tissues. Lung cancer specimens and normal lung tissues were freshly obtained in pairs from 15 patients who underwent surgery for lung cancer. Thirteen lung cancer specimens expressed the 55 kDa TNF receptor messenger RNA (mRNA), whereas only six lung cancer specimens expressed the 75 kDa TNF receptor mRNA by Northern blot analysis. The 55 kDa and 75 kDa TNF receptors mRNA were detected in all and 11 normal lung tissues, respectively. All four lung carcinoma cell lines examined expressed the 55 kDa TNF receptor mRNA, but only RERF-LC-MS (MS) expressed both the 55 kDa and 75 kDa TNF receptors mRNA. Immunohistochemical examination revealed that lung cancer cells expressed the 55 kDa TNF receptor, but not the 75 kDa TNF receptor at the protein level. In normal lung tissues, the 55 kDa TNF receptor was detected in alveolar macrophages, bronchioles, and some small vessels. The 75 kDa TNF receptor was detected in alveolar macrophages. All four lung carcinoma cell lines examined exhibited the only 55 kDa TNF receptor. TNF-mediated tumor cell lysis was observed in all lung carcinoma cell lines that exhibited the 55 kDa TNF receptor except A549, which is a TNF-insensitive cell line. In surface binding assays, specific surface binding of TNF-alpha to TNF-insensitive cell line A549 was observed to be about half that of TNF-sensitive cell lines. We demonstrated the expression of two distinct TNF receptors in human lung cancer and normal lung tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Sep
PMID:Expression of tumor necrosis factor receptors in human lung cancer cells and normal lung tissues. 765 83

An abnormality in autonomic neural control in lung cancer has not yet been investigated. In the present work the role of histamine H1-receptors in the modulation of neurotransmitter receptors activity in human lung parenchyma in cancer is reported. It appeared that the activation of histamine H1-receptors may lead to the reduction of beta-adrenoceptors and the enhancement of muscarinic cholinergic receptors in cancer lung parenchyma. The above findings suggest the possibility of the interaction between neural and inflammatory systems in human lung cancer.
Biochem Mol Biol Int 1995 Jun
PMID:The role of histamine H1-receptors in the modulation of neurotransmitter receptors activity in human lung cancer. 766 47

Corticosteroids used orally and intravenously lead to lung diseases and vascular disorder. To investigate whether enolase levels are also changed by treatment with synthetic steroid dexamethasone (as alteration in the enolase levels have been correlated with lung cancer) we performed the following studies. A cDNA library was prepared from poly(A) mRNA extracted from human lung fibroblast cells. cDNA clone HLE1 containing 1.7 kb insert coding for enolase was isolated. Its identity was confirmed by (a) translation of the hybrid selected mRNA and (b) nucleotide sequence analysis of the insert and comparison with known enolase sequences from other species. The lung enolase is coded by a polypeptide of 458 amino acid residues (mr = 49.5 kD). Nucleotide sequencing and derived amino acid sequence data suggest that the cloned enolase is non-neuronal isoform of enolase (NNE). In lung fibroblast cells, dexamethasone caused remarkable increase in the abundance of the enolase mRNA, which was concentration and time dependent. The induction by dexamethasone required de novo RNA synthesis but not de novo protein synthesis.
Biochem Mol Biol Int 1993 Jun
PMID:Human lung enolase: cloning and sequencing of cDNA and its inducibility with dexamethasone. 768 84

Transcriptional regulation of the human parathyroid hormone-related protein (PTHrP) gene by calcitonin was examined in a lung cancer line (BEN cells). Northern analysis demonstrated that calcitonin caused a rapid 4.5-fold elevation in PTHrP mRNA. Transient transfection of a construct containing 1119 base pairs of the human PTHrP gene 5' to the ATG start site of translation, fused to the CAT reporter sequence, was used to demonstrate a five-fold increase in transcription by calcitonin. Similar increases were also observed when transfected cells were exposed to a number of cAMP agonists including forskolin, as well as isobutyl-methylxanthine. A putative cAMP responsive element (5'-TGACTTCA-3') present within exon 4 was placed upstream of the heterologous SV40 promoter. Expression of this construct was elevated 4.5-fold in response to calcitonin and 7-fold in response to forskolin. Similar responses to calcitonin occurred with a smaller construct (pZMR30) containing 530 bp of sequence upstream of the ATG start site. Thus we postulate that calcitonin acts at least partially via cAMP through this element in exon 4 of the human PTHrP gene.
Mol Cell Endocrinol 1993 Jul
PMID:Calcitonin increases transcription of parathyroid hormone-related protein via cAMP. 769 Jul 20

Retinoic acid (RA) is required for normal airway epithelial cell growth and differentiation both in vivo and in vitro. One of the earliest events following the exposure of bronchial epithelial cells to RA is the strong induction of RA receptor beta (RAR beta) mRNA. Previous work established that many lung cancer cell lines and primary tumors display abnormal RAR beta mRNA expression, most often absence or weak expression of the RAR beta 2 isoform, even after RA treatment. Restoration of RAR beta 2 into RAR beta-negative lung cancer cell lines has been reported to inhibit tumorigenicity. Since RAR beta 2 inactivation may contribute to lung cancer, we have investigated the molecular mechanism of defective RAR beta 2 expression. Nuclear run-on assays and transient transfections with RAR beta 2 promoter constructs indicate the presence of trans-acting transcriptional defects in most lung cancer cell lines, which map to the RA response element (RARE). These defects cannot be complemented by RAR-retinoid X receptor cotransfection and can be separated into two types: (i) one affecting transcription from direct repeat RAREs, but not palindromic RAREs, and (ii) another affecting transcription from both types of RARE. Studies using chimeras between RAR alpha, TR alpha, and other transcription factors suggest the existence of novel RAR-thyroid hormone receptor AF-2-specific cofactors, which are necessary for high levels of transcription. Furthermore, these factors may be frequently inactivated in human lung cancer.
Mol Cell Biol 1995 Jul
PMID:Evidence for impaired retinoic acid receptor-thyroid hormone receptor AF-2 cofactor activity in human lung cancer. 779

P-glycoprotein gene amplification has been described in several drug-resistant parasitic protozoa. The first P-glycoprotein related gene described in Leishmania was ltpgpA, a gene frequently amplified in arsenite resistant Leishmania. Hybridization experiments indicated that ltpgpA was part of a gene family. In addition to ltpgpA, four novel genes were cloned that are present in two loci: ltpgpB and ltpgpC tandemly linked to ltpgpA on a 800-kb chromosome; and ltpgpD and ltpgpE closely linked on a chromosome ranging from 950 kb to 1400 kb, depending on the Leishmania species. Another P-glycoprotein gene, homologous to the more recently described ldmdr1, was linked to ltpgpD and ltpgpE. Nucleotide sequencing of ltpgpB and ltpgpE revealed that the Leishmania P-glycoprotein-related genes have diverged considerably from the main branch of P-glycoproteins and are more homologous to the recently described multidrug resistance-associated protein found in multidrug-resistant human lung cancer cell lines. Cross-resistance studies and gene transfection experiments indicated that under the conditions tested only ltpgpA and ldmdr1 are involved in resistance to arsenite and antimonials or hydrophobic drugs such as vinblastine respectively.
Mol Biochem Parasitol 1994 Nov
PMID:The P-glycoprotein-related gene family in Leishmania. 789 50

Normal human bronchial epithelial (NHBE) cells are the putative progenitor cells of all types of lung cancer. NHBE cells immortalized by SV40 T-antigen retain many characteristics of the primary cells and are a useful model for investigating the role of oncogenes, tumor suppressor genes, and certain chemical carcinogens in the molecular pathogenesis of lung cancer. In this study, SV40 T-antigen-positive cells (BEAS-2B) were characterized for their metabolic functions and were shown to continue to express epoxide hydrolase, glutathione S-transferase pi, glutathione peroxidase, and catalase. To increase their metabolic activity towards human procarcinogens, human cytochrome P450 1A2 (CYP1A2) was stably expressed by introducing CYP1A2 cDNA into BEAS-2B cells either by infection with a high-titer recombinant retrovirus (pXT-1A2) or by transfection with a CYP1A2 expression vector (pCMV1A2), which produced the cell lines B-1A2 and B-CMV1A2, respectively. Cell lines established with either expression system expressed enzymatically active CYP1A2 protein and were 50- to 400-fold more sensitive to the cytotoxic effect of the carcinogen aflatoxin B1 (AFB1) than the corresponding control cell lines. The cytotoxic effects of AFB1 were paralleled by increased metabolism of AFB1 and enhanced formation of the AFB1-N7 guanine adduct in B-CMV1A2 cells. Cytotoxicity and adduct formation correlated with a significantly higher protein expression of CYP1A2 by the cytomegalovirus promoter-driven plasmid. Since this human epithelial cell line is the precursor cell type of lung cancer, has normal phase II enzymes, and exhibits highly reproducible expression of phase I enzymes, this in vitro model should aid in the evaluation of putative human carcinogens and anticarcinogens.
Mol Carcinog 1994 Oct
PMID:Activation of promutagens in a human bronchial epithelial cell line stably expressing human cytochrome P450 1A2. 791 94

The human CYP2D6 gene codes for the enzyme, debrisoquine 4-hydroxylase, which metabolizes over 25 therapeutically important drugs. The inability to metabolize these drugs, which results in a 'poor metabolizer' (PM) phenotype, can be attributed, in some cases, to the presence of any of three previously described mutations in the CYP2D6 gene. To identify new alleles responsible for the PM phenotype, we have examined the CYP2D6 gene from individuals whose phenotypes were not consistent with their apparent genotypes. DNA sequencing revealed a single base deletion in exon 3, T1795, resulting in a frame shift and generating a stop codon one codon after the deletion. A PCR-based test was designed for this new allele (designated CYP2D6(T)) and 236 unrelated individuals from a lung cancer case control study were tested for the presence of the CYP2D6(T) mutation. Eight unrelated individuals were found to carry the D6(T) allele. Four subjects also carry the non-functional D6(B) allele and the drug metabolism phenotypes of these four D6(B)/D6(T) individuals are consistent with the D6(T) allele being responsible for reduced debrisoquine 4-hydroxylase activity. The frequency of the D6(T) allele among Caucasian controls of the case-control study was 1.8% (4/220 chromosomes).
Hum Mol Genet 1994 Jun
PMID:Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype. 795 Dec 38


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