Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this review, recent advances in the clinical therapy of osteosarcoma, including results from the European Osteosarcoma Intergroup trial demonstrating the efficacy of a short intensive two drug protocol are discussed as well the evolving role of ifosfamide. Biologically, the area of interest on chromosome 3q, which may contain an osteosarcoma tumor suppressor gene, is being narrowed, and several promising new therapeutic approaches including tumor vaccine have been explored. In chondrosarcoma research, abnormalities in hereditary multiple exostoses genes, which encode protein products essential for normal cartilage development, and a potential mechanism for the characteristic chemotherapy resistance of cartilaginous tumors (overexpression of P-glycoprotein) have been described. Surgical advances include testing of total en bloc spondylectomy for vertebral tumors as well as a noninvasively extendable long bone endoprosthesis. Finally, new insights in diagnostic imaging, including the evolving role of 201Tl, 99mTc-MIBI (methoxyisobutylisonitrile), and newer variations on magnetic resonance imaging are reviewed.
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PMID:Osteosarcoma and other bone cancers. 970

The expression of the drug resistance (DR) mediators P-glycoprotein (P-gp) and the metallothioneins (MT) was assessed immunohistochemically in biopsy material from patients with high-grade malignant osteosarcoma (OS). No significant difference was found in survival rate between expressors of both P-gp and MT and non-expressors. Thus, it was concluded that lack of expression of these two drug resistance-related proteins does not appear to confer any advantage in terms of patient survival in osteosarcoma.
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PMID:P-glycoprotein and metallothionein expression and resistance to chemotherapy in osteosarcoma. 974 95

The Y-box-binding protein, YB-1, is a member of the DNA-binding protein family. It binds to the Y-box, an inverted CCAAT box, in the promoter region of the human multidrug resistance 1 gene, which encodes P-glycoprotein (P-gp). Nuclear localization of YB-1 protein has been reported to be associated with the intrinsic expression of P-gp in human breast cancer. We studied the immunohistochemical expression of YB-1 protein in 69 untreated biopsy specimens of conventional osteosarcomas and compared it with the expression of P-gp. Furthermore, cell proliferation, as determined by the MIB-1-labeling index (MIB-1-LI), was measured by immunohistochemistry. In all 69 untreated osteosarcomas, YB-1 protein was expressed in the cytoplasm. In 32 of 69 (46%) cases, YB-1 was also localized in the nucleus. The expression of P-gp was evident in 23 of these 32 cases, and there was a significant correlation between the nuclear expression of YB-1 and P-gp expression (P < 0.0001). Chondroblastic osteosarcoma expressed YB-1 in the nucleus more frequently (eight of nine cases) than did other types of osteosarcoma, whereas P-gp was also frequently expressed in chondroblastic subtype. There was no correlation between the nuclear expression of YB-1 and histological grade. The MIB-1-LI was significantly higher in cases showing the nuclear expression of YB-1 (MIB-1-LI averaged 22.56 in cases with only cytoplasmic expression of YB-1 but averaged 28.20 in cases with cytoplasmic and nuclear expression of YB-1; P = 0.0477). In human osteosarcoma, nuclear localization of YB-1 protein was associated with the expression of P-gp, suggesting that YB-1 could be a prognostic marker for multidrug resistance in osteosarcoma.
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PMID:Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human osteosarcoma. 974 49

The transcription of MDR1 gene may be increased by mutation or loss of function of p53 gene. In this study, we investigated whether in osteosarcoma, the p53 status is correlated with overexpression of the MDR1 gene product P-glycoprotein. The relationship between P-glycoprotein expression and p53 status was analyzed by immunohistochemistry in 64 primary and 11 metastatic high-grade osteosarcomas. In the same series, we also assessed the nuclear accumulation of MDM2 protein, whose binding to p53 protein provides an alternative mechanism of p53 inactivation. No association was found between mutant-p53 and MDM2 nuclear accumulation either with P-glycoprotein expression or with clinical course. Only increased expression of P-glycoprotein in tumor cells was significantly associated with a poor outcome, further supporting the adverse prognostic value of this marker in osteosarcoma.
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PMID:Relationship between P-glycoprotein expression and p53 status in high-grade osteosarcoma. 991 6

The relationship between P-glycoprotein expression and malignancy is controversial. We have recently found that, in osteosarcoma, multidrug resistance (MDR) is associated with a less aggressive behavior, both in vitro and in clinical settings. In this study, we evaluated whether P-glycoprotein overexpression has a cause-effect relationship with the reduced metastatic potential of MDR cells, or rather reflects a more complex phenotype. MDR1 gene-transfected osteosarcoma cell clones, showing different levels of P-glycoprotein expression, were analysed for their in vitro characteristics and their tumorigenic and metastatic ability in athymic mice. Apart from the different levels of P-glycoprotein, no significant change in the expression of surface antigens or in the differentiative features were observed in the MDR1 gene transfectants compared to the parental cell lines or control clones, obtained by transfection with neo gene alone. In contrast to controls, however, MDR1 transfectants showed a significantly lower ability to grow in semi-solid medium and were completely unable to grow and give lung metastases in athymic mice. These findings indicate that P-glycoprotein overexpression is causally associated with a low malignant potential of osteosarcoma cells, and open new insights on the role and functions of P-glycoprotein activity.
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PMID:The expression of P-glycoprotein is causally related to a less aggressive phenotype in human osteosarcoma cells. 998 24

Efflux of chemotherapy agents by P-glycoprotein at the plasma membrane is thought to be a major cause of cancer multidrug-resistance (MDR). However, the mechanism underlying the cellular accumulation and distribution of cytotoxic drugs is still poorly defined. We have recently found that P-glycoprotein is expressed also in the nucleus of MDR cell lines selected in doxorubicin (DXR), suggesting the possible involvement of this protein in the direct extrusion of the drug from the nucleus of resistant cells. In this study, we analyzed the subcellular localization of P-glycoprotein, in a series of U-2 OS osteosarcoma cell clones transfected with MDR1 gene in order to verify whether the nucleus is a constant site for the localization and functional activity of P-glycoprotein, and in which way some aspects of cell morphology related to MDR depend on the subcellular P-glycoprotein localization rather than on the exposure to the selective drug. Our results indicate that to achieve a subcellular drug distribution prevailing in the cytoplasm but not in the nucleus, a significant increase in the expression of P-glycoprotein at the different cellular compartments, including the plasma membrane, the cytoplasm, and the nucleus, is needed, although the in vitro drug resistance appears to be mainly dependent on the expression of P-glycoprotein at the cell surface. With regard to the morphological characteristics of MDR cells involving the cell surface and the chromatin arrangement, the influence of DXR appears to be prevalent, although P-glycoprotein overexpression cannot be excluded.
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PMID:P-glycoprotein subcellular localization and cell morphotype in MDR1 gene-transfected human osteosarcoma cells. 1032 Oct 19

We previously reported that the doxorubicin binding ability detected by the doxorubicin (adriamycin) binding assay was closely correlated with the chemosensitivity of human osteosarcomas. In this study, we undertook to clarify the relationship between P-glycoprotein positivity (%PPG) and doxorubicin binding ability (%DB) in human osteosarcomas in order to determine which is a more sensitive index of histologic response to chemotherapy. Ten primary osteosarcomas were analyzed by the doxorubicin binding assay and by immunofluorescence to detect cellular P-glycoprotein positivity. Three good responders to chemotherapy containing doxorubicin showed a %DB greater than 90% (average: 96.43%), whereas the seven poor responders had values less than 80% (average: 35.31%). The difference between the two groups was statistically significant (P = 0.0167). However, the average %PPG of the three good responders was 6.73%, whereas the %PPG of the seven poor responders was 14.27%. There was no significant difference in %PPG between the two groups (P = 0.3051). No negative correlation between the %DB and the %PPG of all osteosarcomas (r = 0.536, P = 0.1104) was found, although there was a trend that those tumors with a high %PPG showed a low %DB. These results suggest that osteosarcomas showing a low %DB and %PPG with poor response to chemotherapy, may have multidrug resistance mechanisms other than P-glycoprotein. Therefore, we conclude that doxorubicin binding ability, which reflects all of the doxorubicin-resistant mechanisms, was more sensitive than P-glycoprotein positivity in predicting the chemosensitivity of human osteosarcoma.
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PMID:Relationship between P-glycoprotein positivity, doxorubicin binding ability and histologic response to chemotherapy in osteosarcomas. 1037 94

Previous reports on osteosarcomas treated with multi-agent chemotherapy have shown that P-glycoprotein expression is a reliable prognostic indicator. The current thinking is that, of the several agents used for the treatment of osteosarcoma, only doxorubicin is involved in drug resistance mediated by P-glycoprotein. This study examines the relationship of P-glycoprotein expression to clinical outcome in osteosarcomas, treated only with doxorubicin in addition to surgery, to determine if the prognostic significance of P-glycoprotein expression reflects the ability of osteosarcoma to respond to this drug. The expression of P-glycoprotein in tumor specimens was assessed by immunohistochemistry in 37 nonmetastatic, operable osteosarcomas treated at a single institution with doxorubicin as a single adjuvant drug. The P-glycoprotein status was analysed in relation to the length of event-free survival. A widespread pattern of P-glycoprotein expression in tumor cells at diagnosis was significantly associated with a higher rate of systemic relapse (p < 0.001). On comparison of this group of patients with a similar series of 92 patients, all treated with multi-agent chemotherapy plus surgery of the primary lesion and previously analysed for P-glycoprotein status, only P-glycoprotein-positive, doxorubicin-resistant tumors consistently benefited from the addition of drugs other than doxorubicin (p < 0.001). Osteosarcomas with different abilities to respond to adjuvant chemotherapy can be identified by the expression of P-glycoprotein in tumor cells at the clinical onset. P-glycoprotein status may serve as a basis for risk-adapted, individualized therapeutic regimens. Standard programs are sufficient for P-glycoprotein-negative osteosarcomas, whereas P-glycoprotein-positive tumors may benefit from the use of more intensive therapeutic approaches.
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PMID:P-glycoprotein expression in osteosarcoma: a basis for risk-adapted adjuvant chemotherapy. 1056 69

After pulsed exposure of Dunn osteosarcoma cells (nonresistant cells) to Adriamycin (ADR) at increasing concentrations and single-cell cloning of surviving cells, ADR-resistant cells were obtained. These resistant cells expressed P-glycoprotein and had resistance more than 10 times that of their nonresistant parent cells. Compared to the nonresistant cells not exposed to pulsing electromagnetic fields (PEMF) in ADR-free medium, their growth rates at ADR concentrations of 0.01 and 0.02 micrograms/ml, which were below IC50, were 83.0% and 61.8%, respectively. On the other hand, in the nonresistant cells exposed to PEMF (repetition frequency, 10 Hz; rise time, 25 microsec, peak magnetic field intensity, 0.4-0.8 mT), the growth rate was 111.9% in ADR-free medium, 95.5% at an ADR concentration of 0.01 micrograms/ml, and 92.2% at an ADR concentration of 0.02 micrograms/ml. This promotion of growth by PEMF is considered to be a result of mobilization of cells in the non-proliferative period of the cell cycle due to exposure to PEMF. However, at ADR concentrations above the IC50, the growth rate tended to decrease in the cells not exposed to PEMF. This may be caused by an increase in cells sensitive to ADR resulting from mobilization of cells in the non-proliferative period to the cell cycle. The growth rate in the resistant cells exposed to PEMF was significantly lower than that in the non-exposed resistant cells at all ADR concentrations, including ADR-free culture (P</=0.0114). Therefore, this study suggests that PEMF promotes the growth of undifferentiated cells but progressively suppresses the growth of more differentiated cells, i.e., PEMF controls cell growth depending on the degree of cell differentiation. This study also shows the potentiality of PEMF as an adjunctive treatment method for malignant tumors.
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PMID:Effects of PEMF on a murine osteosarcoma cell line: drug-resistant (P-glycoprotein-positive) and non-resistant cells. 1065 22

To study the influence of cellular DNA content on the accumulation and efficacy of doxorubicin (DOX), we characterized P-glycoprotein (Pgp)-positive and -negative murine osteosarcoma cell clones that had a different DNA index. Statistical analysis demonstrated that the cytotoxic effects of DOX correlated significantly with the ratio of intracellular DOX accumulation divided by the cellular DNA content (DOX/DNA ratio) (P = 0.001), but not with the intracellular DOX accumulation (P = 0.16). We also tested this relationship for Pgp-negative human osteosarcoma cell lines with a different DNA ploidy, and found that these Pgp-negative cell lines all had similar DOX/DNA ratios. These results indicate that the DOX/DNA ratio is a determinant for the effects of DOX in osteosarcoma cells, regardless of their Pgp status and DNA ploidy. Thus, consideration of the cellular DNA content as well as the intracellular DOX accumulation is important to accurately detect DOX resistance.
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PMID:Improving the cytometric detection of doxorubicin resistance in osteosarcoma cells by determining cellular doxorubicin/DNA ratio. 1069 41


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