Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the relationship between transformation and multidrug resistance by employing the v-H-ras or v-raf oncogenes to transform rat liver epithelial (RLE) cells in vitro. The data indicate that transformation of RLE cells with v-H-ras or v-raf results in increased resistance to the cytotoxins adriamycin, vinblastine and 2-acetylaminofluorene. This multidrug resistance is accompanied by increasing expression of P-glycoprotein (MDR-1) and glutathione-S-transferase P (GST-P). Thus, neoplastic transformation of RLE cells with v-raf or v-H-ras, independently of chemical exposure, results in multidrug resistance.
Carcinogenesis 1988 Dec
PMID:Transformation of rat liver epithelial cells with v-H-ras or v-raf causes expression of MDR-1, glutathione-S-transferase-P and increased resistance to cytotoxic chemicals. 290 2

The aim of this study is to present our preliminary experience in treating BPH-related urine retention, resistant to other medical treatment, with transurethral brachytherapy. We also deal with dosimetric analysis so as to eliminate ethical concerns about the exposure of patients not suffering from cancer to a certain level of body irradiation. Patients suffering from BPH-related urethral obstruction were treated with two transurethral applications (three weeks apart) of Cs137 MDR, which delivered a total of 16 Gy, at 0.5 cm from the urethral walls (dose rate 5-7 Gy/h). The application was done under ultrasonographic observation. Dosimetric calculation of the radiation exposure of the human body during transurethral radiotherapy (TURT) was performed for patients suffering from prostate cancer and treated with external beam radiotherapy and a boost dose through transurethral brachytherapy. For this purpose we used TLDs on skin surface and dosimetric analysis of X-ray films. Five patients treated for BPH urethral obstruction presented no sign of acute toxicity. All of them were weaned of their indwelling catheter immediately after the end of the first application. Obstruction did not recur within 12-18 months of follow-up. The dose delivered outside the prostate ranges from 1-7 cG, depending upon location. Proximal rectal and bladder walls received 1-2 Gy, a dose that is far from inducing acute or late toxicity. The estimated risk for carcinogenesis is negligible, and the expected benefit for the quality of life transcends the risks. No ethical concern is justified for testing transurethral radiotherapy for BPH-related urethral obstruction. TURT seems to be effective and provides durable results. Further investigation is required.
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PMID:Transurethral radiotherapy for benign prostatic hypertrophy-related urethral obstruction. Dosimetry, ethics, and preliminary results. 752 61

The P-glycoproteins are integral membrane proteins that function as ATP-dependent transporters. The multidrug resistance genes which encode P-gp comprise a small gene family, with 2 members in humans and 3 in rodents. The P-gp encoded by the mdr1 gene functions as a drug efflux pump to remove drugs from cells and may serve as a barrier to protect cells from cytotoxic agents. In normal tissues, P-gp is localized on the luminal surface of transporting epithelia in the liver, kidney, small intestine, testes, and blood-brain barrier. Transient exposure to drugs transcriptionally increases the level of expression of the mdr1 genes, however, the cellular pathways critical to this regulation are yet unknown. This observation may have some implications on the level of expression in tumors and response to chemotherapy. Examination of the basal level of MDR expression in tumors may not be a reliable predictor of the effect of P-gp on chemotherapy. Induction of MDR transcription by drugs may further impede the effectiveness of anti-cancer agents. This is most obvious for drugs which are substrates for P-gp transport, however, it also applies significantly to compounds which are not themselves substrates but affect the response to other drugs simultaneously or subsequently administered. A clear understanding of the mechanisms that regulate basal and drug-induced mdr transcription will facilitate development of novel agents which circumvent this obstacle or permit targeted modification of mdr expression. Expressed on the bile canalicular surface of the liver, P-gps represent the first ATP-dependent biliary transporters to be characterized. The P-gp encoded by mdr2 is the major form of P-gp expressed in normal liver and transports phospholipids into bile. A defect in this protein leads to severe liver disease caused by chronic inflammation of the biliary system that results from high concentrations of free bile salts. The cellular origin and molecular basis of the ensuing liver tumors in these mice are unclear. It is possible that the chronic damage to the biliary ductules causes an increased growth rate of the surrounding cells, including putative stem cells in the liver. Thus, these mice may serve as a model for carcinogenesis in which the liver is under constant promotion placing the proliferating cells at increased risk to further genetic alterations or expansion of preexisting, but normally quiescent, mutations. Mdr2-deficient animals may also provide a model for human chronic inflammatory liver disease. Clearly, these exciting results indicate that further characterization of the P-gps as normal physiologic canalicular membrane transporters is necessary.
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PMID:Regulation and function of the multidrug resistance genes in liver. 922 99

Gene expression of human ovarian carcinoma cell lines and epithelial ovarian tumors was examined by oligonucleotide microarray for about 6000 human cDNAs. (1) Comparison of gene expression between CDDP-sensitive human ovarian serous adenocarcinoma cell lines and CDDP-resistant cell lines revealed that gamma-glutamylcysteine synthetase, glutathione peroxidase-like protein, dehydrogenase (UGDH), NAD(P)H: quinoneoxireductase, glucose-6-phosphatase, ornithine decarboxylase and dihydrodiol dehydrogenase were associated with a mechanism of CDDP-resistance. Comparison of gene expression between taxol-sensitive human ovarian cell lines and taxol-resistant cell lines showed that up-regulation of 30 kinds of gene expression including MDR and semaphorin E in taxol-resistant cell lines. (2) Comparison of gene expression among serous adenocarcinomas, clear cell adenocarcinomas and non-cancerous ovarian tissues by hierarchical clustering demonstrated that clear difference between carcinomas and non-cancerous ovarian tissues but not obvious difference between serous and clear adenocarcinomas. Genes that were up- and down-regulated specifically in these two types of ovarian carcinomas were further selected by the criteria that difference in the mRNA level by more than 4-fold between tumors and non-cancerous tissues. Tissue type specific alterations of gene expression are likely to play important roles in the carcinogenesis of epithelial ovarian tumors. cDNA microarray is a powerful and high-throughput tool to analyze gene expression of cancer development.
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PMID:[Gene expression profiling of human ovarian epithelial tumors by digo nucleotide microarray]. 1192 26

Array-based comparative genomic hybridization (aCGH) allows the identification of DNA sequence copy number changes at high resolution by co-hybridizing differentially labelled test and control DNAs to a micro-array of genomic clones. The present study has analysed a series of 23 formalin-fixed, paraffin wax-embedded tissue samples of Barrett's adenocarcinoma (BCA, n = 18) and non-neoplastic squamous oesophageal (n = 2) and gastric cardia mucosa (n = 3) by aCGH. The micro-arrays used contained 287 genomic targets covering oncogenes, tumour suppressor genes, and DNA sequences localized within chromosomal regions previously reported to be altered in BCA. DNA sequence copy number changes for a panel of approximately 50 genes were identified, most of which have not been previously described in BCA. DNA sequence copy number gains (mean 41 +/- 25/BCA) were more frequent than DNA sequence copy number losses (mean 20 +/- 15/BCA). The highest frequencies for DNA sequence copy number gains were detected for SNRPN (61%); GNLY (44%); NME1 (44%); DDX15, ABCB1 (MDR), ATM, LAMA3, MYBL2, ZNF217, and TNFRSF6B (39% each); and MSH2, TERC, SERPINE1, AFM137XA11, IGF1R, and PTPN1 (33% each). DNA sequence copy number losses were identified for PDGFB (44%); D17S125 (39%); AKT3 (28%); and RASSFI, FHIT, CDKN2A (p16), and SAS (CDK4) (28% each). In all non-neoplastic tissue samples of squamous oesophageal and gastric cardia mucosa, the measured mean ratios were 1.00 (squamous oesophageal mucosa) or 1.01 (gastric mucosa), indicating that no DNA sequence copy number chances were present. For validation, the DNA sequence copy number changes of selected clones (SNRPN, CMYC, HER2, ZNF217) detected by aCGH were confirmed by fluorescence in situ hybridization (FISH). These data show the sensitivity of aCGH for the identification of DNA sequence copy number changes at high resolution in BCA. The newly identified genes may include so far unknown biomarkers in BCA and are therefore a starting point for further studies elucidating their possible role in Barrett's carcinogenesis.
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PMID:Array-based comparative genomic hybridization for the detection of DNA sequence copy number changes in Barrett's adenocarcinoma. 1522 37

In cancer chemotherapy, it is necessary to design an agent that suppresses or inhibits the targets that influence cell growth and apoptosis. We focus on the apoptotic pathway via mitochondria in this article. In this pathway, c-Jun N-terminal kinase (JNK), one of the stress activated protein kinases, is predominantly activated by apoptotic stimuli. JNK activity is inhibited by the binding of glutathione S-transferase P1-1 (GST P1-1) through protein-protein interactions. It has been noted that GST P1-1 overexpression plays an important role in carcinogenesis and in part in the MDR phenotype. We show several useful modifications of an anticancer agent that suppress the enzyme activity and expression of GST P1-1. The release of cytochrome c from mitochondria to the cytosol during apoptosis is mediated by the mitochondrial permeability transition pore, which is a protein complex formed by the voltage-dependent anion channel, members of the pro- and anti- apoptotic Bax-Bcl-2 protein family, cyclophilin D, and adenine nucleotide (ADP/ATP) translocators. We propose some drugs, including a proteasome inhibitor that can triger the permeability transition.
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PMID:Chemotherapeutic agents that induce mitochondrial apoptosis. 1557 15

NADP(H)-dependent retinol dehydrogenase/reductase (NRDR) plays an important role in maintaining the homeostasis of retinoid. Aberrations in retinoid metabolism are considered as early events in carcinogenesis. We identified a novel alternatively spliced variant, NRDRB1, in HeLa cell and human cervical squamous carcinoma tissues, which is characterized by a complete deletion of exon 3. The latter resulted in changes in subcellular localization of NRDRB1 when compared with the peroxisomal localization of NRDR. To clarify the clinical significance of NRDRB1, we investigated its mRNA and protein expressions in normal cervical and cervical squamous carcinoma tissues, using RT-PCR, quantitative real-time PCR, Gateway expressing system, immunoprecipitation, immunoblotting, MALDI-TOF mass spectrometry and immunohistochemistry. We detected NRDRB1 mRNA in 14 of 26 (53.9%) cervical cancer tissues, but in none of the 12 normal cervical tissues. NRDRB1 protein was expressed in NRDRB1 mRNA-positive cases. While the full-length NRDR mRNA was observed in both normal and neoplastic cervical tissues, its protein was only expressed in normal cervical epithelium. The results presented here provide evidence that metabolic disturbances of retinal and retinoic acid, due to abnormal splicing and functional disorder of NRDR, may be involved in cervical tumorigenesis.
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PMID:Expression of a novel alternatively spliced variant of NADP(H)-dependent retinol dehydrogenase/reductase with deletion of exon 3 in cervical squamous carcinoma. 1723 May 27

The incidence of lung cancer has been increasing over recent decades. Previous studies show that polymorphisms of the genes involved in carcinogen-detoxication, DNA repair and cell cycle control compose of the risk factors for lung cancer. Recent observations reveal that the components of CAK: Cdk7, MAT1 and cyclin H, may play important roles in cell cycle control, transcriptional control, and DNA repairing process, all of which are important in carcinogenesis. To test whether the genetic variants of CAK genes modify the risk of lung cancer, we compared the manifestation of 25 single nucleotide polymorphisms (SNPs) and the haplotypes of Cdk7, MAT1 and cyclin H between 500 patients with lung cancer and 517 healthy controls. Our results indicated that the genotype frequency of MAT1 79023A/G (p = 0.042) and MAT1 85693C/T (p = 0.005) of cases significantly differed from those of the controls. Further analyses revealed that cyclin H 11817C/T, MAT1 12199A/G, MAT1 70650A/G, MAT1 79023A/G and MAT1 85693C/T significantly influenced the susceptibility of lung cancer in a dominant genetic model while cyclin H 12128A/T and MAT1 42172A/G did in a recessive model. Strongest association between cyclin H alleles and lung cancer patients was found in the non-smoke subpopulation. The haplotype 'TAC' (p = 0.007) increased and the haplotype 'TTC' (p = 0.043) decreased the risk of lung cancer. The potential gene-gene and gene-environmental interactions on lung cancer risk was evaluated using MDR software. A significant interaction between the three CAK component genes was identified and the combination of smoking status and genetic factors barely increased the accuracy. Our results suggested that genetic variants in CAK genes, Cdk7, cyclin H, MAT1, might modulate the risk of lung cancer in a gene-gene interaction mode, which consist to the biochemical interaction of corresponding proteins.
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PMID:Polymorphisms of CAK genes and risk for lung cancer: a case-control study in Chinese population. 1770 48

The incidence of lung cancer has been increasing over recent decades. Previous studies showed that polymorphisms of the genes involved in carcinogen-detoxication, DNA repair and cell cycle control comprise risk factors for lung cancer. Recent observations revealed that the growth hormone receptor (GHR) might play important roles in carcinogenesis and Rudd et al. found that the Thr495Pro polymorphism of GHR was strongly associated with lung cancer risk in Caucasians living in the UK (OR = 12.98, P = 0.0019, 95% CI: 1.77-infinity). To test whether this variant of GHR would modify the risk of lung cancer in Chinese population, we compared the polymorphism between 778 lung cancer patients and 781 healthy control subjects. Our results indicate that the frequency of 495Thr (2.8%) allele in cases was significantly higher than in controls (OR = 2.04, P = 0.006, 95% CI: 1.21-3.42) which indicated this allele might be a risk factor for lung cancer. Further analyses revealed Thr495Pro variant was associated with lung cancer in the subpopulation with higher risk for lung cancer: male subpopulation, still-smokers subpopulation and the subpopulation with familial history of cancer. In different histological types of lung cancer, Thr495Pro SNP was significantly associated with small cell and squamous cell lung cancer, but not with adenocarcinoma, which suggested a potential interaction between this polymorphism and metabolic pathways related to smoking. The potential gene-environment interaction on lung cancer risk was evaluated using MDR software. A significant redundant interaction between Thr495Pro polymorphism and smoking dose and familial history of cancer was identified and the combination of genetic factors and smoking status or familial history of cancer barely increased the cancer risk prediction accuracy. In conclusion, our results suggested that the Thr495Pro polymorphism of GHR was associated with the risk of lung cancer in a redundant interaction with smoking and familial history of cancer.
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PMID:Lung cancer risk associated with Thr495Pro polymorphism of GHR in Chinese population. 1829 12

AKR1B10 has been identified as a potential biomarker for human nonsmall cell lung carcinoma and as a tobacco exposure and response gene. AKR1B10 functions as an efficient retinal reductase in vitro and may regulate retinoic acid homeostasis. However, the possibility that this enzyme is able to activate polycyclic aromatic hydrocarbon (PAH) trans-dihydrodiols to form reactive and redox-active o-quinones has not been investigated to date. AKR1B10 was found to oxidize a wide range of PAH trans-dihydrodiol substrates in vitro to yield PAH o-quinones. Reactions of AKR1B10 proceeded with improper stereochemistry, since it was specific for the minor (+)-benzo[a]pyrene-7S,8S-dihydrodiol diastereomer formed in vivo. However, AKR1B10 displayed reasonable activity in the oxidation of both the (-)-R,R and (+)-S,S stereoisomers of benzo[g]chrysene-11,12-dihydrodiol and oxidized the potentially relevant, albeit minor, (+)-benz[a]anthracene-3S,4S-dihydrodiol metabolite. We find that AKR1B10 is therefore likely to play a contributing role in the activation of PAH trans-dihydrodiols in human lung. AKR1B10 retinal reductase activity was confirmed in vitro and found to be 5- to 150-fold greater than the oxidation of PAH trans-dihydrodiols examined. AKR1B10 was highly expressed at the mRNA and protein levels in human lung adenocarcinoma A549 cells, and robust retinal reductase activity was measured in lysates of these cells. The much greater catalytic efficiency of retinal reduction compared to PAH trans-dihydrodiol metabolism suggests AKR1B10 may play a greater role in lung carcinogenesis through dysregulation of retinoic acid homeostasis than through oxidation of PAH trans-dihydrodiols.
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PMID:Oxidation of PAH trans-dihydrodiols by human aldo-keto reductase AKR1B10. 1878 56


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