Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A human colon cancer cell line with acquired multidrug resistance (MDR) was assayed for the intracellular GSH level and the activity of GSH-S-transferase (GST), which catalyzes the conjugation reaction of electrophilic drugs with GSH. The GSH level and GST activity (as measured with 1-chloro-2,4-dinitrobenzene) were elevated in the resistant cells by 1.7-fold and 2-fold, respectively. This elevated catalytic activity of the resistant cells was reflected in a 2-fold increase in GST-pi mRNA, which was not the result of gene amplification. In addition, buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly increased Adriamycin sensitivity in both the MDR and the parental cells, affecting the former more than the latter. The effects seen with buthionine sulfoximine were not seen with puromycin and actinomycin D. A dramatic overexpression of mdr1, a P-glycoprotein gene responsible for the MDR phenotype, was also observed in the MDR cells. In contrast, none of these products (i.e., mdr P-glycoprotein, GSH level, total GST activity, GST-pi gene copy, and GST-pi mRNA level) was elevated in HeLa cells resistant to cisplatin and some alkylating agents, supporting the notion that the acquisition of cisplatin resistance differs from the mechanism of MDR. These results indicate that the intrinsic GSH level and GST-pi activity affect anthracycline resistance per se and not MDR in the human colon cancer cells.
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PMID:Overexpression of glutathione S-transferase and elevation of thiol pools in a multidrug-resistant human colon cancer cell line. 134 33

Feasibility of immunohistochemical staining of P-glycoprotein for the prediction of doxorubicin resistance in gastrointestinal cancers was examined. Among 10 cancer cell lines which consist of two gastric cancer cell lines and eight colon cancer cell lines, seven cell lines were stained positively by the monoclonal antibody to P-glycoprotein, C219. In consequence of the evaluation on the effect of doxorubicin on these tumour cells by means of succinic dehydrogenase inhibition test (SDI test), zero out of seven cell lines stained positively by C219 was sensitive to doxorubicin, but two out of three cell lines stained negatively were sensitive. Among 23 fresh surgical specimens of gastrointestinal cancers which consisted of 15 gastric cancers and eight colon cancers, seven tumour tissues were stained positively by C219. All P-glycoprotein positive tumours were resistant to doxorubicin. On the other hand, four of 16 P-glycoprotein tumours were sensitive to doxorubicin. These data indicate that positively stained cancer cells by C219 are resistant to doxorubicin.
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PMID:Prediction of doxorubicin resistance in gastrointestinal cancer by P-glycoprotein staining. 135 49

The human P-glycoprotein gene family contains the mdr1 and the mdr3 gene. The mdr1 P-glycoprotein is over-expressed in multidrug resistant (MDR) tumor cells and is believed to play a role in the elimination of certain cytotoxic drugs used in the chemotherapy of cancer. The mdr3 gene has not been found to be amplified or over-expressed in MDR cells. In this study, gene-specific mdr gene probes were developed for the detection of the gene and the total mRNA level. Southern and Northern hybridization analyses showed that the mdr genes and the mRNA levels were increased 30--40-fold in a MDR human colon cancer cell line. In addition, this MDR cell line had an altered growth rate and morphology and detectable double minute chromosomes.
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PMID:Co-amplification and over-expression of two mdr genes in a multidrug-resistant human colon carcinoma cell line. 168 62

The relationship was analyzed between drug resistance and MDR1 (with MDR signifying multiple drug resistance) and glutathione S transferase-pi (GST-pi) gene expression in four stomach and four colon cancer cell lines. Northern blot analysis by pmdr1 probe showed that stomach cancer cell lines had no detectable level of MDR1 mRNA expression. By contrast, some levels of MDR1 mRNA expression were found in two colon cancer cell lines, indicating doxorubicin resistance. To examine the MDR1 mRNA in each cell level, in situ hybridization was used. It was found that all colon cell lines and two stomach cell lines had more silver grains per cell than KB cells (a human KB kidney epidermoid carcinoma cell line). However, the number of silver grains in each cell was heterogeneous in the colon and stomach cell lines. Low-level MDR1 mRNA expression could be detected even in cell lines without MDR1 mRNA expression by northern blot hybridization. These results suggest the possibility that all gastrointestinal cell lines can acquire multiple drug resistance. In addition, all examined gastrointestinal cell lines had high GST-pi mRNA expression. This GST-pi gene expression shows cisplatin resistance in the examined cell lines. Heterogeneity of GST-pi mRNA expression also was shown at the cellular level.
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PMID:Expression of MDR1 and glutathione S transferase-pi genes and chemosensitivities in human gastrointestinal cancer. 173 85

DNA is a very stable molecule and fixation as well as routine histological processing does not destroy its molecular structure. Hence the possibility exists to use this material for molecular genetic analyses. The polymerase chain reaction (PCR) opens the chance to amplify DNA to huge amounts from pathological paraffin and plastic blocks and to use this DNA for further examinations, such as detection of mutations or translocations in malignant tumors, e.g. t(14;18) in follicular lymphomas, bcr/abl in chronic myeloic leukemia, t(11;22) in Ewing sarcomas or of the ras-gene in colon cancer, overexpression of tumor related mRNA, e.g. mdr1-mRNA of the multidrug associated P-Glycoprotein, or detection of foreign DNA from viruses or bacteriae, as well as analysis of hereditary diseases. PCR in its various forms (conventional PCR, PCR with direct sequencing, reverse transcriptase (RT)-PCR, nested primer PCR, quantitative RT-PCR, inverse PCR, degenerated primer (DOP) PCR, in situ PCR, in situ RT-PCR etc.) has proven to supplement routine diagnostic work in many occasions, however, it has to be emphasized that up to now there exists no example for a complete replacement of histological or immunhistological examination by PCR. As consequence, histology remains the first and most important step towards a relevant diagnosis supplemented e.g. by PCR and other techniques of molecular biology.
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PMID:[Polymerase chain reaction in diagnostic pathology]. 753 75

Correlation between expression of the mdr-1 genes (a and b) at the mRNA and protein level and volume-activation of chloride-channels was studied in rat colon cancer CC531 cells by means of RT-PCR, Western blotting and patch clamp, respectively. Three different kinds of cell lines were used: CC531-PAR, CC531-COL and CC531-REV. At the mRNA level, the parental cell line CC531-PAR showed significantly less mdr-1a expression in comparison with CC531-COL, a drug-resistant cell line induced from the parental CC531 cells by growth in the presence of colchicin. The third cell line, CC531-REV, was a spontaneous revertant of the drug-resistant cell line to a drug-sensitive one, but with a maintained level of mdr-1a mRNA. In none of the three cell lines, mdr-1b mRNA could be detected. At the protein level, a clear difference in mdr1 expression between CC531-PAR/REV and CC531-COL was observed. Although the amount of mdr-1a mRNA detected in CC531-REV was comparable to that found in CC531-COL, the amount of mdr-1 encoded protein in CC531-REV was remarkably reduced. In all three cell types, cell swelling activated chloride-currents which could be blocked by NPPB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of correlation between mdr-1 expression and volume-activation of cloride-currents in rat colon cancer cells. 767 40

Colorectal adenocarcinomas are inherently resistant to anthracyclines and other topoisomerase-II inhibitors. Resistance to doxorubicin of colon cancer cells (Caco2) depends on 2 main mechanisms. The first is typical multi-drug resistance, characterized by the mdr1 gene and its product the P170 membrane glycoprotein. P170 effluxes anthracyclines out of cancer cells and is antagonized in vitro by verapamil. The second mechanism, which develops when cell-culture density increases, we have designated confluence-dependent resistance. Confluence-dependent resistance depends on the reduced topoisomerase II content of the G0/G1-phase cells which accumulate in the confluent population. We show here that short treatments of confluent Caco2 cells with slightly toxic concentrations of DNA-damaging agents (cisplatin, melphalan or mitomycin C) produced a transient accumulation of cells in S- and G2/M-phases of the cell cycle. Concomitantly with the increase in the S-phase population, the topoisomerase II cellular level and the sensitivity of cells to doxorubicin were greatly enhanced. Overcoming confluence-dependent resistance through S-phase accumulation and inhibition of multi-drug resistance by verapamil were fully additive, and a nearly complete reversal of confluent Caco2 cells' resistance to doxorubicin was obtained when both strategies were combined.
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PMID:Circumvention of confluence-dependent resistance in a human multi-drug-resistant colon-cancer cell line. 779 Jan 24

We investigated the mechanism of sodium butyrate (NaB)-mediated induction of mdr1 mRNA in parental (wild type) and multidrug-resistant (Ad1000) SW620 colon cancer cell lines. NaB treatment resulted in reversible, time-dependent increases in nuclear run-on transcription of endogenous mdr1 in these cell lines that paralleled the reversible increases of mdr1 mRNA in both timing and magnitude. In contrast, NaB treatment had no effect on mdr1 mRNA stability. Thus, the effects of NaB on mdr1 mRNA levels are fully attributable to altered mdr1 transcription. Furthermore, NaB induces the expression of transiently transfected chloramphenicol acetyltransferase reporter plasmids that are under the transcriptional control of the mdr1 promoter (mdrCAT vectors). Transfections using mdrCAT vectors modified by deletion and site-directed mutagenesis of the mdr1 promoter indicate that NaB-mediated induction of these vectors is at least partially dependent upon sequences present in the basal mdr1 promoter between -89 and +11 relative to the start site of transcription. The Y-box motif located between -82 and -73 contributes to NaB inducibility of mdrCAT vector expression in Ad1000 SW620 cells.
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PMID:Reversible transcriptional activation of mdr1 by sodium butyrate treatment of human colon cancer cells. 790 96

We describe the development of a rapid colorimetric in situ hybridization technique utilizing oligonucleotide probes labeled with six biotin molecules at the 3' end to detect mdr1 in mouse colon cancer cells growing in culture and in vivo. mRNA integrity was verified by the use of a multibiotinylated poly d(T) oligonucleotide, and the specificity of the reaction was confirmed by use of labeled sense and anti-sense probes in serial cryostat sections and cultured cells. The multiple biotin label produced a strong signal after a short hybridization time. Avidin-alkaline phosphatase detection and the capillary technology used in the Microprobe Accelerated System allowed completion of the procedure in less than 5 hr. Excellent correlations with the MDR phenotype of the cells, Northern blot analysis, and immunohistochemistry recommend this procedure for identifying cells that express the MDR phenotype in culture and in vivo.
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PMID:A rapid colorimetric in situ mRNA hybridization technique using hyperbiotinylated oligonucleotide probes for analysis of mdr1 in mouse colon carcinoma cells. 809 9

The anthracycline doxorubicin has little activity against colorectal cancers. It is hypothesized that this is attributable to a multifactorial resistance mechanism in which the glutathione S-transferases (GST) may play a role. We studied the relationship between GST expression and doxorubicin resistance in four human colon adenocarcinoma cell lines (HT-29, LoVo, SW620, and Caco-2), with the goal of modulating GST activity to overcome resistance. Caco-2 cells were the most resistant to doxorubicin, showing an IC50 value approximately 80- to 90-fold higher than HT-29 or LoVo and 600-fold higher than SW620. Total GST catalytic activity was significantly higher in Caco-2 cells compared with the other lines. All four cell lines expressed GST-pi at the catalytic activity, protein, and mRNA levels; however, no significant differences were observed among the cell lines. GST-mu expression was not detectable at the protein and mRNA levels, and the four cell lines displayed very low catalytic activity toward a GST-mu-selective substrate. Caco-2 cells showed a unique, highly expressed GST-alpha-immunoreactive band that was not detected in the other lines; however, the glutathione peroxidase activity of Caco-2 cells was the lowest among the four cell lines. Neither ethacrynic acid nor glutathione analogues that function as GST class-selective inhibitors were able to potentiate the cytotoxic effects of doxorubicin in these colon cancer cell lines, as demonstrated in both microplate colorimetric and clonogenic assays. The multidrug resistance-associated protein and P-glycoprotein were either not detectable or expressed at such low levels that they are not likely to contribute to the differences in doxorubicin sensitivity observed among these cell lines.
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PMID:Role of glutathione S-transferases in the resistance of human colon cancer cell lines to doxorubicin. 950 Apr 55


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