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

We evaluated 28 patients with advanced renal cell carcinoma for the initial expression of P-glycoprotein (MDR1 gene product) employing immunocytochemistry. Tumor specimens were obtained upon primary tumor nephrectomy. In all patients, progression-free survival time following nephrectomy was evaluated and correlated statistically with the staining results. Progression-free survival of patients with no or very few (< 1%) P-glycoprotein-positive tumor cells (n = 8, median survival 27.0 months) was significantly extended (p < 0.04) as compared to patients with 1% or more P-glycoprotein-positive tumor cells (n = 20, median survival 4.0 months). Correlations with histopathological tumor characteristics were insignificant. These results suggest a potential role for P-glycoprotein as a biologic parameter predictive of tumor progression in renal cell carcinoma patients.
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PMID:Immunocytochemical detection of P-glycoprotein: initial expression correlates with survival in renal cell carcinoma patients. 791 63

The expression of several resistance markers (P-glycoprotein, glutathione S-transferase-pi, thymidylate synthase, dihydrofolate reductase) was analyzed in matched primary tumors and lymph node metastases from 21 patients with lung cancer using immunohistochemistry. The analysis showed that expression of these resistance proteins is generally congruent in primary lung cancer and simultaneously resected lymph node metastases. This suggests that in general the resistance of a primary tumor predicts for the resistance of the metastases and vice versa.
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PMID:Detection of resistance proteins in matched primary lung tumors and lymph node metastases. 791 93

P-glycoprotein (P-gp) is a plasma membrane efflux transporter that maintains the intracellular concentration of chemotherapeutic agents at low levels. Since the clinical outcome of ovarian adenocarcinoma depends largely on its response to chemotherapy, an objective assessment of P-gp expression could serve as a prognostic indicator. Eighty-five patients were studied. Available tissue sections from the primary tumor (n = 75) and persistent or recurrent lesions (n = 19) were tested with anti-P-gp (JSB-1) monoclonal IgG. Multivariate survival analysis using Cox regression was performed controlling for fixed covariates (age, surgical stage, and presence of residual tumor) and included occurrence of postchemotherapy tumors and P-gp positivity in postchemotherapy neoplasms as time-dependent variables. P-gp was expressed in 49 prechemotherapy (65.3%) and 14 postchemotherapy (73.7%) tumors. After controlling for potentially confounding factors, patients with P-gp-positive postchemotherapy neoplasms were at three times greater risk of dying within 2 years than their counterparts with P-gp-negative tumors (hazard ratio = 3.1: 95% confidence interval = 1.2, 9.1; p < 0.05). Detection of P-gp-expressive subclones can serve as an independent poor prognostic indicator for patients with postchemotherapy tumors.
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PMID:P-glycoprotein as a prognostic indicator in pre- and postchemotherapy ovarian adenocarcinoma. 898 35

Two human cancer cell lines (MA 2 and MA 3) were established from pleural effusions of infiltrating ductal carcinomas of the breast. The lines were maintained in continuous monolayer culture with doubling times of 70 (MA 2) and 78 (MA 3) hr for more than two years and possessed extensively rearranged abnormal karyo-types with modal chromosome number of 83 (MA 2) and 81 (MA 3) and DNA index values of 1.65 and 1.77, respectively. No amplifications or rearrangements were evident in the c-myc, int-2, c-erb B2, c-Ha-ras, or hst 1 genes in MA 2 and MA 3 cell lines. The clinical histories of the patients from whom the cell lines were derived are reported and compared with the results observed in the cell lines in vitro. The presence of CEA, CA 15-3, and MCA tumor markers observed in the primary tumor tissues was retained by the established cell lines. While the primary tumor tissues were ER+/PgR borderline+ (MA 2) and ER-/PgR+ (MA 3), the MA 2 line was ER+/PgR- and the MA 3 line remained ER-/PgR+. The MDR P-glycoprotein was not expressed either in primary tumor tissues or in the respective cell lines. High expression of cytokeratins 7, 18, and 19 was evident by immunohistochemical analysis in each cell line. whereas cytokeratins 8 and 17 were poorly or not at all expressed. The treatment history of the patients from whom the cell lines were derived involved CMF followed six months later by novantrone and cisplatin plus VP 16 (MA 2) and FEC followed four years later by CMF (MA 3). The chemosensitivity pattern assay of the cell lines indicated that the MA 2 line was sensitive to doxorubicin, cisplatin, and vinblastine, whereas the MA 3 line was sensitive to doxorubicin and cisplatin. The characteristics of these cell lines indicate them to be a good experimental model to investigate breast cancer biology and anticancer drug response.
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PMID:Establishment and characterization of two new cell lines derived from human metastatic breast carcinomas. 913 Dec 70

Chondrosarcomas are alleged to be resistant to chemotherapy. A retrospective review of our experience primarily with dedifferentiated chondrosarcomas treated with chemotherapy was performed to reevaluate the efficacy of chemotherapy for this tumor. There were 18 patients: 14 stage IIB and four stage III. Seventeen patients had dedifferentiated chondrosarcoma. The median age at diagnosis was 57 years. Fourteen of the patients underwent wide excision of the tumor, two underwent amputation, and two had no surgery. The femur and the pelvis were the most common locations of the primary tumor. Chemotherapy for 11 of the patients consisted of cisplatin and doxorubicin. Survival was analyzed with the Kaplan-Meier method; the median survival was 12 months. The hypothesis that chondrosarcomas express P-glycoprotein was tested. Expression of P-glycoprotein was evaluated by immunostaining with use of the C494 and C219 antibodies on 41 benign and malignant cartilage tumors, six of which were from the patients in the chemotherapy group. Immunostaining revealed that 37 of 41 cartilage tumors expressed P-glycoprotein. The rate of survival of patients with high-grade chondrosarcoma treated with chemotherapy is poor. P-glycoprotein expression is common in benign and malignant cartilage lesions. The lack of response to chemotherapy may be related to the expression of P-glycoprotein.
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PMID:Chemotherapy and P-glycoprotein expression in chondrosarcoma. 982 Feb 82

Much remains to be learned about drug resistance in the biology of RCC and its metastases. We measured MDR-1/P-glycoprotein expression in 19 tumor samples from patients with metastatic RCC by RNase protection and quantitative PCR assays. The median level of the 16 tumor metastases was 4.9 (range: 0.10 to 156.2) relative to the level of 10 assigned to a reference cell line, SW620, which has been characterized as expressing a minimum level of MDR-1. Since these levels were lower than expected for RCC, we asked whether the metastases possessed a phenotype different from primary RCC and examined MDR-1 expression in 5 paired cell lines derived from primary and metastatic RCC. In 8/10 lines, MDR-1 expression was >10. Relative to the level in the primary line, MDR-1 expression was decreased (3 to 50-fold) in 3 metastatic lines, was increased in 1, and unchanged in 1. MRP mRNA expression was lower in the metastatic lines while EGFR expression was variable. IC50 values for 6 compounds (including 4 standard agents and one new Phase 1 agent) were determined for the paired lines. Rhodamine and calcein efflux assays were performed as measures of P-glycoprotein and MRP function. Rhodamine efflux correlated with MDR-1 mRNA expression (r = 0.87) and with the IC50s (r = 0.60) for paclitaxel in the paired cell lines. In contrast, calcein efflux did not correlate with MRP expression. Lastly, MDR-1 expression correlated with cytokeratin 8 (CK8) protein levels, a measure of cellular differentiation. In sum, these data suggest renal cell carcinoma (RCC) metastases have altered MDR-1 expression potentially due to altered differentiation relative to the primary tumor. Thus, the drug resistance phenotype of primary RCC tumors may not reflect that of their metastases.
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PMID:Intrinsic drug resistance in primary and metastatic renal cell carcinoma. 1037 90

In addition to its possible role in drug resistance, expression of the multidrug resistance-1 gene may also be associated with a more malignant phenotype and tumor progression. This study evaluated its expression during tumor progression in the MGH-OGS transplantable murine osteosarcoma tumor model. Three variables of tumor progression were analyzed: tumor size, local recurrence, and metastasis. With a highly sensitive reverse transcription-polymerase chain reaction method, mRNA levels of multidrug resistance-1 were compared in primary tumors of different sizes. In addition, the levels were compared in primary, locally recurrent, and metastatic tumors isolated from individual mice. No significant difference was found in the levels of expression with increasing primary tumor size. In addition, the levels in primary, locally recurrent, and metastatic tumors were not significantly different. Our results indicate that--at least in the MGH-OGS tumor model, which is analogous to the majority of spontaneously occurring human osteosarcomas in that it has low levels of multidrug resistance-1/P-glycoprotein and is sensitive to doxorubicin--there is no evidence of upregulation of multidrug resistance-1 expression during tumor progression.
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PMID:Multidrug resistance-1 gene expression does not increase during tumor progression in the MGH-OGS murine osteosarcoma tumor model. 1093 33

The expression of multidrug resistant proteins in bladder cancer and clinical implication was studied. Expression of multidrug-associated protein (MRP), P-glycoprotein (P-gp), P53 and Bcl-2 proteins were detected by using immunohistochemical method in 40 specimens of bladder transitional cell carcinoma. The results showed that the positive rate of MRP, P-gp, P53 and Bcl-2 was 52.5%, 57.5%, 47.5% and 62.5% respectively. The positive rate of MRP, P-gp, P53 and Bcl-2 in the grade I, II and III of tumors was 46.3%, 38.5%, 38.5%, 23.1%; 52.9%, 39.8%, 47.1%, 76.4%; 60.0%, 80.0%, 60.0%, 90.0% respectively. The positive rate of MRP, P-gp, P53 and Bcl-2 in 24 primary tumor specimens was 37.5%, 41.7%, 33.3%, 45.8% and that in 16 cases in recurrent specimens receiving chemotherapy 75.0%, 81.3%, 68.8%, 87.5% respectively. It was suggested the positive rate of MRP, P-gp, P53 and Bcl-2 was increased with the advance of tumor grade. The positive rate of four proteins in all recurrent cases was significantly increased (P < 0.05). The expression of MRP, P-gp, P53 and Bcl-2 proteins might be the important factors for chemotherapy failure.
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PMID:Expression of multidrug-associated protein, P-glycoprotein, P53 and Bcl-2 proteins in bladder cancer and clinical implication. 1152 49

From an undifferentiated soft tissue sarcoma (STS) a cell line designated US8-93 has been established. At subcloning the cell line US8-93 three different lines (US8-93A, B and C) could be set up. In a subsequent study characteristics for ultrastructure, growth, cell cycle distribution, karyotype, protein overexpression detected by immunohistochemistry (IHC) and p53 mutational status were determined. The cell line US8-93 as well as subclones contain mainly bipolar spindle-shaped cells and additionally some polygonal and multinucleated cells. Cells possess the characteristics of primitive mesenchymal cells based on their positive reactions with anti-vimentin and negative reactions for desmin, cytokeratin, myoglobin, S100, and NSE, implying a classification as an undifferentiated STS. Cytogenetic analysis revealed nearly diploid cells with several structural and numerical aberrations for chromosomes 1, 3, 4, 6, 9, 10, 12, 13, 15 and 18. IHC positivity was found for the tumor suppressor proteins p53 and Rb, the oncogene products Bcl-2, K-ras, N-ras, P-glycoprotein Mdr-1 and MDM-2. In the p53 gene a nonsense mutation in exon 4 was detected, that was confirmed in the original primary tumor and in three derivative clonal lines. The described STS cell line represents a valuable supplementation to the relatively small number of human STS cell lines currently available and may also provide a good in vitro model for studies of STS tumorigenesis in respect to a mutated p53 gene.
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PMID:Morphological and molecular characterization of an undifferentiated soft tissue sarcoma cell line and derivative clones. 2152 41

Increased expression of P-glycoprotein, encoded by the MDR1 gene, is considered to be responsible for chemotherapy failure in a number of human cancers. Although it is clear that mutations in the MDR1 gene affect substrate specificity of the transporter in multidrug-resistant cell lines, scant interest has been directed at whether mutations have a unique clinical presentation. To address this question, we studied exon 2 of the MDR1 gene in 9 patients with primary breast carcinoma and 9 healthy controls using PCR and DNA sequence analysis. In order to reduce the possibility of nucleotide misincorporations introduced by Tag polymerase, sequencing of six subclones of each DNA specimen was performed. A mutation was seen as a substitution from G to A at position -1 in two patients and one control. An A to G nucleotide substitution giving rise to an amino acid substitution (Asn-->Asp) in codon 21 at the first potential N-glycosylation site of the P-glycoprotein was seen in primary tumors from four patients and in an axillar lymph node metastases from one of these patients. This mutation was also seen in two healthy individuals, which similar to the patients, both seem to be heterozygous for this MDR1 exon 2 allele. Three other mutations were also found in the patients; a substitution of A to G at position 23 and A to G at position 52 in the same patient and in another patient, G at position 42 was changed to A. However, the last three mutations were not confirmed by repeating analysis of the original genomic sample. The results revealed different distribution of a point mutation between various parts of the same primary tumor and between a lymph node metastasis and the primary tumor tissue. Thus, demonstrating both intra-and inter-tumor heterogeneity. The results also emphasized constitutional allelic variation in the MDR1 gene. Whether this might affect sensitivity to chemotherapy has to be further evaluated.
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PMID:Intra-and inter-individual heterogeneity in exon 2 of the MDR1 gene in primary breast carcinoma and healthy individuals. 2152 63


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