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)

In many cell systems, resistance to cytotoxic drugs is acquired by the amplification and/or overexpression of the multidrug resistance (mdr) gene, which codes for the glycoprotein, p170 (P-glycoprotein). Moreover, in a variety of malignant tumours there is increasing evidence of the relationship between the DNA ploidy pattern of patients and their prognosis. In this study we aimed to evaluate these two potential indicators of constitutive drug resistance in human colorectal tumours. We employed a method to quantify simultaneously, on a per cell basis, mdr gene expression (using the C219 monoclonal antibody for P-glycoprotein) and nuclear DNA content with high-resolution bivariate flow cytometry. The study was performed on a human colon-carcinoma-derived cell line (LoVo) and its doxorubicin-resistant variant (LoVo/Dx) and on tumour samples and adjacent normal mucosa from 35 untreated patients with colon cancer. The P-glycoprotein was found in both LoVo and LoVo/Dx cells with levels slightly lower in the parental than in the resistant subline (P, NS). A multi-drug-resistant specific probe for mRNA expression and Western blot assay confirmed the specificity of p170 expression. All of the colon cancer with unimodal diploid DNA distribution and all the normal colonic mucosa samples showed P-glycoprotein expression, without a statistically significant difference in median values between tumours and normal samples. Tumours with bimodal DNA distribution showed median values of P-glycoprotein expression of their hyperdiploid cell clones significantly higher than those of their diploid clones and of the tumours with unimodal DNA distribution (P less than 0.005). Our results show the feasibility of bivariate flow-cytometric analysis of P-glycoprotein expression and DNA content on clinical material and support the hypothesis that the MDR phenotype and DNA ploidy together may influence the biological behaviour of colon cancer in vivo.
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PMID:Flow cytometric analysis of multidrug-resistance-associated antigen (P-glycoprotein) and DNA ploidy in human colon cancer. 135 83

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

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

Cell suspensions of normal human bone marrow were mixed with human acute lymphoblastic or myelogenous leukemic cells of the CCRF-SB or K-562 lines. After incubating the cell mixtures in vitro with different dose levels of Ambamustine (PTT-119), a quantity of 10(4) treated cells were dispensed into microculture plates, and graded cell numbers of the lines used to contaminate the normal marrow were added. Limiting dilution analysis (LDA) was used to estimate the frequency of leukemic cells persisting after treatment. Incubation with 50 micrograms/mL of PTT-119 produced a total elimination of K-562 acute myelogenous blasts, whereas nearly 0.17 and 0.27 leukemic cells were still present in the cell mixtures after treatment with 5 and 25 micrograms/mL, respectively. When normal bone marrow was contaminated with CCRF-SB lymphoblastic cells, incubation with either 50 or 25 micrograms/mL of PTT-119 produced a complete clearing of leukemic cells, whereas with 5 micrograms/mL the leukemic cells in each well were 0.18. When PTT-119 was incubated with LoVo-DX, a colon cancer cell line which expresses the pleiotropic drug resistance MDR phenotype, virtually complete inhibition of clonogenic colonies was observed with as little as 5 micrograms/mL. This suggests that PTT-119 could be used in clinical trials as a non-cross-resistant agent in multidrug protocol.
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PMID:Limiting dilution analysis of a novel tripeptide anticancer agent Ambamustine (PTT-119): effect on K-562, CCRF-SB and multidrug resistant LoVo-Dk cell lines. 818 48

Colorectal cancer affects around 5% of the population in Westernised countries and is associated with a high level of morbidity and mortality. Overall, around 50% of patients can expect to be fully cured by surgery, along with recent improvements in survival due to the use of adjuvant therapy. However, in patients who develop metastatic disease, the prognosis is poor, and the appropriateness of anticancer chemotherapy in such patients has been controversial. Nevertheless, there is increasing evidence that chemotherapy can extend life expectancy in colorectal cancer and that in metastatic disease patients achieve a significant benefit from early rather than late chemotherapy. For first-line treatment of metastatic colorectal cancer, the best available regimens have been those which include 5-fluorouracil (5-FU) and folinic acid; a meta-analysis of nine randomised clinical studies of such regimens produced a mean response rate of 23%. However, in those who fail or relapse, there has been no established second-line alternative. The development of CPT-11 (Campto, irinotecan), a specific inhibitor of topoisomerase I, represents a significant advance in the management of colorectal cancer. Following encouraging observations of sustained activity in colon cancer cell lines, including those having the MDR phenotype, clinical studies of CPT-11 monotherapy in both chemotherapy-naive and pretreated patients with advanced colorectal cancer demonstrated response rates at least equivalent to those achieved with first-line 5-FU/folinic acid combination therapy. This indicates that CPT-11 does not exhibit cross-resistance with 5-FU, making it the first effective second-line agent in this setting. Further studies are ongoing to define the optimum dosage schedule for CPT-11 and to assess the utility of CPT-11 as a single agent in second-line therapy, or combined with 5-FU and other anticancer agents as first-line therapy. In conclusion, CPT-11 offers a different cytotoxic approach that may complement the use of 5-FU/folinic acid in colorectal cancer in the future.
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PMID:Current status of colorectal cancer: CPT-11 (irinotecan), a therapeutic innovation. 894 58

P-glycoprotein plays an important role in highly drug resistant cells. But its high expression cannot be achieved by chemotherapy. In order to study the effect of P-glycoprotein on clinical tumors, we established a low ADM resistant colon cancer cell line HR/ADM and determined the amplification and expression of mdr-1 gene. The GLC/ADM showed a resistant pattern similar to classical MDR and the transcription of mdr-1 gene determined by RT-PCR increased. The immunocytochemical analysis showed strong positive staining with monoclonal antibody. The gene amplification of mdr-1 was clearly demonstrated by southern blot. Our results suggested that moderate expression of P-glycoprotein might be enough for a high resistant pattern.
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PMID:The amplification and expression of MDR1 gene in adriamycine resistant cell line of colon cancer cell HR8348. 920 12

CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m2. The maximum tolerated dose was 14.4 mg/m2. Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level 8 (intended dose was 19.2 mg/m2; actual dose was 15.6 mg/m2) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T1/2 = 5.52 hours, plasma clearance 1163 mL/min/m2, and Vdss 376 L/m2.
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PMID:A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors. 938 46

The transcription factor YB-1 is expressed in a wide range of cell types and has been implicated in the regulation of various genes involved in cell proliferation. Nuclear expression of YB-1 is correlated with MDR-1 gene expression in breast cancer and osteosarcoma. In this study, we asked whether YB-1 expression is enhanced in human colorectral carcinoma and if it is associated with the expression of target genes such as MDR-1, DNA topoisomerase II alpha and PCNA. YB-1, DNA topoisomerase II alpha, PCNA and MDR-1 expression were assessed by Western blotting, Northern blotting and immunohistochemistry in 26 human colorectal carcinomas. The involvement of YB-1 in DNA topoisomerase II alpha gene expression was examined by transient DNA transfection assays. YB-1 was overexpressed in almost all cancerous lesions in comparison with normal mucosa in surgically resected colorectal carcinomas of 26 patients. YB-1 expression correlated well with both DNA topoisomerase II alpha and PCNA expression. In contrast, no correlation was observed between YB-1 and MDR-1 expression. We also found that a transient co-transfection with a DNA topoisomerase II alpha promoter-luciferase plasmid and an antisense YB-1 expression construct resulted in a significant reduction of the promoter activity in KM12C human colon cancer cells. YB-1 may be an excellent proliferation-associated marker and may be a transcription factor regulating DNA topoisomerase II alpha gene expression in human colorectal carcinoma.
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PMID:Enhanced coexpression of YB-1 and DNA topoisomerase II alpha genes in human colorectal carcinomas. 1059 87

Genotoxic stress leads to nuclear translocation of the Y-box transcription factor YB-1 and enhanced expression of the multidrug resistance gene MDR1. Because hyperthermia is used for the treatment of colon cancer in combination with chemoradiotherapy, we investigated the influence of hyperthermia on YB-1 activity and the expression of multidrug resistance-related genes. Here we report that hyperthermia causes YB-1 translocation from the cytoplasm into the nucleus of human colon carcinoma cells HCT15 and HCT116. Nuclear translocation of YB-1 was associated with increased MDR1 and MRP1 gene activity, which is reflected in strong efflux pump activity. However, a combination of hyperthermia and drug treatment effectively reduced cell survival of the HCT15 and HCT116 cells. These results demonstrate that activation of MDR1 and MRP1 gene expression and increased efflux pump activity after hyperthermia were insufficient to cause an increase in drug resistance in colon cancer cell lines. The ability of hyperthermia to abrogate drug resistance in the presence of an increase in functional MDR proteins may provide an explanation for the efficacious results seen in the clinic in colon cancer patients treated with a combination of hyperthermia and chemotherapy.
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PMID:Hyperthermia-induced nuclear translocation of transcription factor YB-1 leads to enhanced expression of multidrug resistance-related ABC transporters. 1136 62

gamma-Glutamylcysteine synthetase (gamma-GCS) is a key enzyme in glutathione (GSH) synthesis, and is thought to play a significant role in intracellular detoxification, especially of anticancer drugs. Increased levels of GSH are commonly found in the drug-resistant human cancer cells. We designed a hammerhead ribozyme against gamma-GCS mRNA (anti-gamma-GCS Rz), which specifically down-regulated gamma-GCS gene expression in the HCT-8 human colon cancer cell line. The aim of this study was to reverse the cisplatin and multidrug resistance for anticancer drugs. The cisplatin-resistant HCT-8 cells (HCT-8DDP cells) overexpressed MRP and MDR1 genes, and showed resistance to not only cisplatin (CDDP), but also doxorubicin (DOX) and etoposide (VP-16). We transfected a vector expressing anti-gamma-GCS Rz into the HCT-8DDP cells (HCT-8DDP/Rz). The anti-gamma-GCS Rz significantly suppressed MRP and MDR, and altered anticancer drug resistance. The HCT-8DDP/Rz cells were more sensitive to CDDP, DOX and VP-16 by 1.8-, 4.9-, and 1.5-fold, respectively, compared to HCT-8DDP cells. The anti-gamma-GCS Rz significantly down-regulated gamma-GCS gene expression as well as MRP/MDR1 expression, and reversed resistance to CDDP, DOX and VP-16. These results suggested that gamma-GCS plays an important role in both cisplatin and multidrug resistance in human cancer cells.
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PMID:Reversal of cisplatin and multidrug resistance by ribozyme-mediated glutathione suppression. 1150 53


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