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)

Human cancers, including hepatocellular carcinoma (HCC), are characterized by a high degree of drug resistance. The multidrug resistance (MDR) transporters MDR1-P-glycoprotein and MRP2 (multidrug-associated protein 2) are expressed in almost 50% of human cancers, including HCCs. In this study, we analyzed the effect of anti-MDR1 ribozymes, especially AFP promoter-driven anti-MDR1 ribozymes, to specifically chemosensitize HCC cells. Epirubicin-selected HB8065/R cells were used as MDR1-P-glycoprotein-overexpressing cells. Adenoviral vectors were constructed to allow an efficient gene transfer of anti-MDR1 ribozyme constructs. AFP promoter-driven anti-MDR1 ribozymes reduced the IC(50) 30-fold for epirubicin in HCC cells, whereas human colorectal cancer cells were unaffected. Target sequences were either the translational start site or codon 196 of the human MDR1 gene. Adenoviral delivery of CMV promoter-driven anti-MDR1 ribozymes resulted in a reduced IC(50) for epirubicin and doxorubicin (60- and 20-fold, respectively). They completely restored chemosensitivity in stably transfected anti-MDR1 ribozyme-expressing HCC cells as well as in HCC cells transduced with adenoviruses expressing wild-type anti-MDR1 ribozymes. Adenoviral delivery of ribozymes was so efficient that chemosensitization of HCC cells could be demonstrated in cell cultures without further selection of transduced cells for single anti-MDR1 ribozyme-expressing HCC cell clones. Northern blots showed a decreased MDR1 mRNA expression, and fluorescence-activated cell sorting (FACS) analysis revealed a significantly reduced expression of MDR1-P-glycoprotein on the cell surface of HB8065/R cells after transduction with the anti-MDR1 ribozymes. In conclusion, our data demonstrate that adenoviral delivery of ribozymes can chemosensitize HCC cells and that chemosensitization can be specifically achieved by ribozymes driven by an AFP promoter directed against human MDR1.
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PMID:Reversal of drug resistance of hepatocellular carcinoma cells by adenoviral delivery of anti-MDR1 ribozymes. 1229 34

This study was undertaken to investigate the expression and predictive value for outcome of multidrug resistance-associated (MDR) proteins P-glycoprotein (Pgp), MRP1, BCRP, and LRP, in advanced testicular germ-cell tumours (TGCT). Paraffin-embedded sections from 56 previously untreated patients with metastatic TGCT were immunostained for Pgp, MRP1, BCRP, and LRP. All patients received platinum-based chemotherapy after orchidectomy. Immunostaining was related to clinicopathological parameters, response to chemotherapy, and outcome. Strong and intermediate expressions of the different MDR-related proteins were: 27 and 41% (Pgp), 54 and 37% (MRP1), 86 and 7% (BCRP), and 14 and 29% (LRP). P-glycoprotein and MRP1 associated, respectively, to low AFP (P=0.026) and high LDH levels (P=0.014), whereas LRP expression associated with high beta-hCG levels (P=0.003) and stage IV tumours (P=0.029). No correlation was found between Pgp, MRP1, and BCRP expression and response to chemotherapy and survival. In contrast, patients with LRP-positive tumours (strong or intermediate expression) had shorter progression-free (P=0.0006) and overall survival (P=0.0116) than LRP-negative patients, even after individual log-rank adjustments by statistically associated variables. Our data suggest that a positive LRP immunostaining at the time of diagnosis in metastatic TGCT is associated with an adverse clinical outcome.
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PMID:Lung resistance-related protein as a predictor of clinical outcome in advanced testicular germ-cell tumours. 1264 25

The effects of hyperthermia (HT) on multidrug-resistant human hepatocellular carcinoma (HCC) were evaluated experimentally. This tumor, an AFP-producing human HCC, in which MDR1 mRNA and P-glycoprotein were overexpressed, was transplanted subsequently on nude mice. Ten days after the inoculation of the tumor into the rear section of the nude mice, either or both an intra-peritoneal injection of 8 mg/kg of adriamycin (ADR) was administered or hyperthermia (HT) was induced. HT was performed immediately by immersing the mice into a water bath at a temperature of 42-degrees-C for a period of 30 minutes. Hyperthermic therapy combined with ADR significantly inhibited the tumor growth compared with ADR or HT alone. Using ADR in combination with HT, the ADR concentration in the tumor remained at a significantly higher level for a prolonged period compared with ADR alone. The results indicate that HT enhanced the anti-tumor effect of chemotherapy even for multidrug-resistant HCC.
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PMID:Effects of hyperthermia on multidrug-resistant human hepatocellular-carcinoma. 2157 62