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)

Multidrug resistance for many types of cancer outside the central nervous system (CNS) has been found to be due to the overexpression of the multidrug resistance gene MDR1, of which the gene-product P-glycoprotein acts as a membrane-bound efflux pump for many anticancer drugs. To examine whether brain tumors overexpress the MDR1 gene, 25 brain-tumor specimens were subjected to Northern blot analysis: 10 gliomas, eight meningiomas, three schwannomas, one malignant lymphoma, and three tumors metastatic to the brain. Ten fresh-frozen autopsy specimens of various parts of normal brain were also analyzed. Blots were hybridized with 32P-labeled Chinese hamster complementary deoxyribonucleic acid (cDNA) and 32P-labeled human MDR1 cDNA. The MDR1 gene messenger ribonucleic acid (mRNA) was detected in two tumors using the Chinese hamster probe (one sphenoid wing meningioma and one metastatic prostate tumor) and in one CNS lymphoma using the human probe. Intact mRNA could not be extracted from the fresh-frozen autopsy specimens of normal brain. Seventeen tumors were examined for P-glycoprotein by immunohistochemical staining using murine monoclonal antibody C219: eight gliomas, eight meningiomas, and one craniopharyngioma. The neoplastic cells from two gliomas and three meningiomas and the blood vessels within six gliomas and two meningiomas stained positively for P-glycoprotein. Seven of 10 normal brain specimens stained positively for P-glycoprotein in blood vessels but no specimen demonstrated staining of parenchymal cells. This study demonstrates that the MDR1 gene can be detected in normal brain, and in malignant, benign, and metastatic lesions. P-glycoprotein can be present in tumor blood vessels even when it is not seen in neoplastic cells. Although the role of P-glycoprotein in tumor blood vessels needs to be further examined and more clearly defined, drug resistance in malignant primary brain tumors may result from characteristics not solely of neoplastic cells but also tumor vasculature.
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PMID:Multidrug resistance gene (MDR1) expression in human brain tumors. 168 28

Two weeks after the inoculation of 1.5 x 10(5) 9L glioma cells into the rat brain, the uptake of radiolabelled drugs into the brain and the experimental 9L glioma during the first cerebral circulation was measured with a liquid scintillation counter and analyzed by the method of Oldendorf (1970). The expression of P-glycoprotein, which is known to be associated with the efflux of drugs, was also studied, using anti-P-glycoprotein monoclonal antibody, C-219. Furthermore, the ultrastructure of brain capillaries, tumor vessels, and glioma cells was studied by conventional and immunoelectron microscopy. Sucrose (control), the transport of which through the blood-brain barrier is known to be negligible, accumulated to fivefold higher levels in the tumor than in normal brain. Ranimustine (MCNU), 5-fluorouracil (5-FU), and doxorubicin showed little accumulation in the normal brain, whereas nimustine (ACNU) showed an increased accumulation. MCNU and doxorubicin showed negligible accumulation in the glioma cells despite diffusion into the tumor interstitial space. In contrast, ACNU and 5-FU showed an increased accumulation in tumor cells. The accumulation of 5-FU in the cultured 9L glioma cells was decreased by ATP inhibitors or by low temperature. Although both brain capillary endothelial cells and glioma cell membrane were immunohistochemically positive for P-glycoprotein, the tumor vasculature showed low expression of P-glycoprotein. The endothelial cells of tumor vessels ultrastructurally showed increased fenestrations, swelling, and disrupted junctions. Accordingly, it is suggested that hydrophobic drugs such as doxorubicin, being pumped out by P-glycoprotein, do not accumulate in 9L glioma cells as do other lipophilic drugs such as ACNU, or drugs such as 5-FU, which accumulate by a carrier-mediated mechanism.
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PMID:Uptake of drugs and expression of P-glycoprotein in the rat 9L glioma. 810 17

The glioblastoma is the highest dedifferentiated form of astrocytic brain tumors, which is refractory to chemotherapy in most cases. The lack of chemotherapeutic success is correlated with overexpression of the product P-glycoprotein (PGP) coded by the multidrug resistance 1 (MDR1) gene and a subsequent release of drugs from the tumor cells. For the chemotherapeutical treatment of glioblastomas, the endothel cell is of special importance since due to its manifold metabolic and protective tasks within the blood-brain barrier, it already has a relatively high PGP expression under physiological conditions. The aim of the present study was to analyze the uptake of the antimitotic drug Doxorubicin (DOX) and the expression of PGP in human and rat glioblastoma cell lines and in a human endothelial cell line at different time points. In the following in vivo approach DOX enriched glioblastoma cells were transplanted into rats and the developed tumor was investigated histologically. The results showed an increased uptake and an enhanced expression of PGP at certain time points in every cell line. In the tissue a DOX release was mainly observed in perivascular surroundings. It was concluded that DOX enhanced the constitutive PGP expression which led to a subsequent exclusion of DOX in tumor cells but also in the endothelial cells of the tumor vasculature. Since the vascularization is a prerequisite for tumor growth, the inhibition of the PGP expression in tumor endothelial cells might be a clinical approach to make the DOX treatment more effective.
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PMID:Repetitive doxorubicin treatment of glioblastoma enhances the PGP expression--a special role for endothelial cells. 1294 Jun 27

Malignant brain tumor is a lethal disease with currently available treatment options having a limited impact on outcome. Nevertheless, novel therapeutic approaches combined with genetic prediction of chemosensitivity have, in the last decade, significantly improved clinical benefit for the treated patients. The fine characterization of the MDR1 gene encoding for P-glycoprotein (MDR1-Pgp) in brain tumors may be a crucial determinant for evaluating the long-term efficiency of specific anti-cancer compounds. By using a very high specific monoclonal antibody, the MDR1-Pgp was immunodetected in 34 out of 43 grade IV, 6 out of 10 grade III, 4 out of 7 grade II, and 1 out 3 grade I brain tumors. MDR1-Pgp resulted hyper-expressed, both in vessels and in neoplastic cells from the majority of tumors examined, compared to normal parenchyma. This study demonstrates that the MDR1 gene can be detected in all grade tumor brain malignancies and in endothelial cells of newly formed capillaries, thus, impairing drug access at the tumor cell level. Although the role of MDR1-Pgp in tumor blood vessels needs to be further examined and more clearly defined, drug resistance in malignant brain tumors may result from characteristics not only of tumor vasculature but also of neoplastic cells.
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PMID:Human brain tumors: multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells. 1759 88

Resistance to chemotherapeutic drugs is one of the main obstacles to effective cancer treatment. Multidrug resistance (MDR) is defined as resistance to structurally and/or functionally unrelated drugs, and has been extensively investigated for the last three decades. There are two types of MDR: intrinsic and acquired. Tumor microenvironment selection pressure leads to the development of intrinsic MDR, while acquired resistance is a consequence of the administered chemotherapy. A central issue in chemotherapy failure is the existence of heterogeneous populations of cancer cells within one patient and patient-to-patient variability within each type of cancer. Numerous genes and pathways contribute to the development of MDR in cancer. Point mutations, gene amplification or other genetic or epigenetic changes all affect biological functions and may lead to the occurrence of MDR phenotype. Similar to the characteristics of cancerogenesis, the main features of MDR include abnormal tumor vasculature, regions of hypoxia, aerobic glycolysis, and a lower susceptibility to apoptosis. In order to achieve a lethal effect on cancer cells, drugs need to reach their intracellular target molecules. The overexpression of the efflux transporter P-glycoprotein (P-gp) in MDR cancer cells leads to decreased uptake of the drug and intracellular drug accumulation, minimising drug-target interactions. New agents being or inspired by natural products that successfully target these mechanisms are the main subject of this review. Two key approaches in combating MDR in cancer are discussed (i) finding agents that preserve cytotoxicity toward MDR cancer cells; (ii) developing compounds that restore the cytotoxic activity of classic anticancer drugs.
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PMID:New Approaches With Natural Product Drugs for Overcoming Multidrug Resistance in Cancer. 2642 11