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European Journal of Cancer (Oxford,... 1995Drug resistance, be it intrinsic or acquired, is a major problem in cancer chemotherapy. In vitro, one well characterised form of resistance against many different... (Review)
Review
Drug resistance, be it intrinsic or acquired, is a major problem in cancer chemotherapy. In vitro, one well characterised form of resistance against many different cytotoxic drugs is caused by the MDR1 P-glycoprotein, a large plasma membrane protein that protects the cell by actively pumping substrate drugs out. Available evidence suggests that this protein may cause drug resistance in at least some clinical tumours. Drugs inhibiting the MDR1 P-glycoprotein activity are, therefore, co-administered during chemotherapy of these tumours. To predict the biological and pharmacological effects of the blocking of this protein, we have generated mice with a genetic disruption of the drug-transporting mdr1a P-glycoprotein. These mice are overall healthy, but they accumulate much higher levels of substrate drugs in the brain, and have markedly slower elimination of these drugs from the circulation. For some drugs, this leads to dramatically increased toxicity, indicating that P-glycoprotein inhibitors should be used with caution in patients.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Mice; Mice, Knockout; Phenotype
PubMed: 7577039
DOI: 10.1016/0959-8049(95)00130-b -
European Journal of Pharmaceutical... Feb 2009Oral administration is the most common route for drug administration. However, after oral administration, the absorption may be erratic and incomplete. P-glycoprotein,... (Review)
Review
Oral administration is the most common route for drug administration. However, after oral administration, the absorption may be erratic and incomplete. P-glycoprotein, an efflux transporter localized in the enterocyte, limits the absorption of transported drugs extruding them back to the intestinal tract. The interaction between new drug candidates and P-glycoprotein is investigated in vitro during early stages of drug development. However, it is uncertain how well the in vitro studies actually predict the in vivo P-glycoprotein effect on the extent of oral absorption, since the in vitro and in vivo correlation has not been achieved. In the present review, the recent approaches to compare the in vitro and in vivo data are described and parameters are proposed that could be adequate for a reliable in vitro and in vivo correlation of P-glycoprotein contribution on intestinal absorption. The present article identifies an evident lack of suitable in vivo data. A significant in vitro and in vivo correlation would increase the value of in vitro studies and could reduce costs during the process of drug development.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Animals; Biological Availability; Humans; Intestinal Absorption; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 19063964
DOI: 10.1016/j.ejps.2008.11.005 -
Biomedicine & Pharmacotherapy =... Apr 2005Multidrug resistance (MDR) is a major obstacle in the chemotherapeutic treatment of many human cancers. In this study, the reversal of P-glycoprotein (P-gp) mediated... (Review)
Review
Multidrug resistance (MDR) is a major obstacle in the chemotherapeutic treatment of many human cancers. In this study, the reversal of P-glycoprotein (P-gp) mediated multidrug resistance by (-)-epigallocatechin gallate (EGCG) and its molecular mechanism were investigated. A three-dimensional model of carboxyl-terminal nucleotide binding domain (NBD2) from P-gp was built by homology modeling. The structural model of the complex indicates that EGCG was tightly bound to the ATP-binding site of NBD2. EGCG modulated the function of P-gp and increased the intracellular accumulation of chemotherapeutic agent doxorubicin (DOX) in drug-resistant KB-A1 cells. When KB-A1 cells were exposed to 10 microg/ml DOX combined with 10, 30, 50 microM EGCG for 4 h, the intracellular concentrations of DOX were increased 1.5, 1.9, 2.3 times, respectively compared with DOX alone treatment. In vitro EGCG potentiated the cytotoxicity of DOX to drug-resistant KB-A1 cells. In KB-A1 cell xenograft model, EGCG could also enhance the efficacy of DOX and increased the DOX concentration in the resistant tumors. Thus, these results suggest that EGCG modulated the function of P-gp and reversed P-gp mediated multidrug resistance in human cancer cells.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Catechin; Cell Survival; Drug Resistance, Neoplasm; Humans; Tumor Cells, Cultured
PubMed: 15795098
DOI: 10.1016/j.biopha.2005.01.002 -
FEBS Letters Feb 2006Multidrug transporters are involved in mediating the failure of chemotherapy in treating several serious diseases. The archetypal multidrug transporter P-glycoprotein... (Review)
Review
Multidrug transporters are involved in mediating the failure of chemotherapy in treating several serious diseases. The archetypal multidrug transporter P-glycoprotein (P-gp) confers resistance to a large number of chemically and functionally unrelated anti-cancer drugs by mediating efflux from cancer cells. The ability to efflux such a large number of drugs remains a biological enigma and the lack of mechanistic understanding of the translocation pathway used by P-gp prevents rational design of compounds to inhibit its function. The translocation pathway is critically dependent on ATP hydrolysis and drug interaction with P-gp is possible at one of a multitude of allosterically linked binding sites. However, aspects such as coupling stoichiometry, molecular properties of binding sites and the nature of conformational changes remain unresolved or the centre of considerable controversy. The present review attempts to utilise the available data to generate a detailed sequence of events in the translocation pathway for this dexterous protein.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphate; Hydrolysis; Pharmaceutical Preparations; Phosphates; Protein Binding; Protein Transport
PubMed: 16380120
DOI: 10.1016/j.febslet.2005.11.083 -
Mini Reviews in Medicinal Chemistry Feb 2005The membrane bound drug efflux pump P-glycoprotein (P-gp) transports a wide variety of functionally and structurally diverse cytotoxic drugs out of tumour cells.... (Review)
Review
The membrane bound drug efflux pump P-glycoprotein (P-gp) transports a wide variety of functionally and structurally diverse cytotoxic drugs out of tumour cells. Overexpression of P-glycoprotein is one of the predominant mechanisms responsible for development of multiple drug resistance in tumour therapy. Thus, inhibition of P-gp represents a promising approach for treatment of multidrug resistant tumours. This review highlights concepts for identification and optimization of new inhibitors of P-glycoprotein.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Models, Chemical; Quantitative Structure-Activity Relationship
PubMed: 15720285
DOI: 10.2174/1389557053402729 -
Kidney International. Supplement Apr 1998There is a renewed attention on the multidrug resistance genes and their products, P-glycoproteins, since recent molecular and functional studies revealed unexpected... (Review)
Review
There is a renewed attention on the multidrug resistance genes and their products, P-glycoproteins, since recent molecular and functional studies revealed unexpected functions in normal tissues. There are two types of human P-glycoprotein: Type I, encoded by the MDR1 gene, present in excretory organs and in non-polarized cells; and Type II, encoded by MDR2, present in the canalicular membrane of hepatocytes. MDR1 Pgp transports xenobiotics, peptides, steroids, and phospholipids, and is also a regulator of swelling-activated chloride channels. MDR2 Pgp is exclusively a phosphatidylcholine translocase. In the kidney, the MDR1 gene and protein are expressed in mesangial, proximal tubule, thick loop of Henle, and collecting duct cells. In mesangial and proximal tubule cells Pgp transports xenobiotics. Concomitant exposure of kidney cells to two Pgp substrates results in increased cell toxicity. Extracts from supernatants of mesangial cell cultures inhibit Pgp-mediated transport, suggesting that a mesangial-cell metabolite could be a substrate of Pgp. Active vitamin D3 and platelet activating factor inhibit Pgp transport and are possible endogenous substrates in proximal tubule and mesangial cells, respectively. Pgp could be also a regulator of swelling-activated chloride channels present in the kidney.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Transport; Humans; Interleukin-2; Kidney; Steroids; Xenobiotics
PubMed: 9551426
DOI: No ID Found -
International Journal of Clinical... Jan 1998P-glycoprotein actively transports a wide variety of chemically diverse compounds out of the cell. Based on a comparison of 100 compounds previously tested as... (Review)
Review
P-glycoprotein actively transports a wide variety of chemically diverse compounds out of the cell. Based on a comparison of 100 compounds previously tested as P-glycoprotein substrates we suggest that a set of well-defined structural elements is required for an interaction with P-glycoprotein. The recognition elements are formed by 2 (type I unit) or 3 electron donor groups (type II unit) with a fixed spatial separation. Type I units consist of 2 electron donor groups with a spatial separation of 2.5 +/- 0.3 A. Type II units contain either 2 electron donor groups with a spatial separation of 4.6 +/- 0.6 A or 3 electron donor groups with a spatial separation of the outer 2 groups of 4.6 +/- 0.6 A. All molecules which contain at least 1 type I or 1 type II unit are predicted to be P-glycoprotein substrates. The binding to P-glycoprotein increases with the strength and the number of electron donor or hydrogen-bonding acceptor groups forming the type I and type II units. Correspondingly a high percentage of amino acids with hydrogen bonding donor side chains is found in the transmembrane sequences of P-glycoprotein relevant for substrate interaction. Molecules which minimally contain 1 type II unit are predicted to be inducers of P-glycoprotein overexpression.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Chemical Phenomena; Chemistry, Physical; Humans; Hydrogen Bonding; Protein Binding; Protein Conformation
PubMed: 9476149
DOI: No ID Found -
Biochimica Et Biophysica Acta Feb 2008P-glycoprotein (P-gp) is the most intensively studied eukaryotic ATP binding cassette (ABC) transporter, due to its involvement in the multidrug resistance phenotype of... (Review)
Review
P-glycoprotein (P-gp) is the most intensively studied eukaryotic ATP binding cassette (ABC) transporter, due to its involvement in the multidrug resistance phenotype of a number of cancers. In common with most ABC transporters, P-gp is comprised of two transmembrane domains (TMDs) and two nucleotide binding domains (NBD), the latter coupling ATP hydrolysis with substrate transport (efflux in the case of P-gp). Biochemical investigations over the past twenty years have attempted to unlock mechanistic aspects of P-glycoprotein through scanning and site-directed mutagenesis of both the TMDs and the NBDs. Contemporaneously, crystallographers have elucidated the atomic structure of numerous ABC transporter NBDs, as well as the intact structure (i.e. NBDs and TMDs) of a distantly related ABC-exporter Sav1866. Significantly, the structure of P-gp remains unknown, and only low resolution electron microscopy data exists. Within the current manuscript we employ crystallographic data for homologous proteins, and a molecular model for P-gp, to perform a structural interpretation of the existing "mutagenesis database" for P-gp NBDs. Consequently, this will enable testable predictions to be made that will result in further in-roads into our understanding of this clinically important drug pump.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphate; Amino Acid Sequence; Animals; Databases, Genetic; Humans; Mice; Models, Molecular; Molecular Sequence Data; Mutagenesis; Protein Conformation; Sequence Homology, Amino Acid
PubMed: 18035039
DOI: 10.1016/j.bbamem.2007.10.021 -
Novartis Foundation Symposium 2002P glycoprotein (Pgp) is expressed on cell membranes of various organs in the body, such as the capillary endothelial cells of the brain. Furthermore, Pgp can also be... (Review)
Review
P glycoprotein (Pgp) is expressed on cell membranes of various organs in the body, such as the capillary endothelial cells of the brain. Furthermore, Pgp can also be expressed on the cell membrane of tumour cells. Because of Pgp-mediated efflux, tissue levels of several Pgp substrates are lower than in Pgp-negative tissues. Drug levels in Pgp-expressing organs may be increased by modulation of this Pgp-facilitated transport with several compounds, such as cyclosporin A. Up to now, the presence of drug efflux pumps in tissues could only be examined at the mRNA and protein level. However, this gives no insight into the important question of the functionality of these drug efflux pumps. Information about the transport function of Pgp and the effect of modulating this function may improve the therapeutic treatment of these patients. Positron emission tomography (PET) gives us a unique opportunity to study non-invasively (patho)physiological dynamic processes in vivo. We have therefore developed and validated a method for studying Pgp-mediated transport and its modulation in vivo with PET.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Transport, Active; Blood-Brain Barrier; Colchicine; Daunorubicin; Drug Resistance, Multiple; Electrons; Humans; Mice; Neoplasm Proteins; Tomography, Emission-Computed; Verapamil
PubMed: 11990773
DOI: 10.1002/0470846356.ch10 -
Annual Review of Pharmacology and... 1996Multidrug resistance represents a major obstacle in the successful therapy of neoplastic diseases. Studies have demonstrated that this form of drug resistance occurs... (Review)
Review
Multidrug resistance represents a major obstacle in the successful therapy of neoplastic diseases. Studies have demonstrated that this form of drug resistance occurs both in cultured tumor cell lines as well as in human cancers. P-glycoprotein appears to play an important role in such cells by acting as an energy-dependent efflux pump to remove various natural product drugs from the cell before they have a chance to exert their cytotoxic effects. Expression of the MDR1 gene product has been associated with a poor prognosis in clinical studies. It has been demonstrated in the laboratory that resistance mediated by the P-glycoprotein may be modulated by a wide variety of compounds. These compounds, which include verapamil and cyclosporin, generally have little or no effect by themselves on the tumor cells, but when used in conjunction with antineoplastic agents, they decrease, and in some instances eliminate, drug resistance. Clinical trials to modulate P-glycoprotein activity are underway at the present time to determine if such strategies will be feasible. Although the P-glycoprotein is expressed in many cell lines and occurs in patient tumors, its expression is not a universal feature of multidrug resistance, suggesting that other mechanisms are operating.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Binding Sites; Clinical Trials as Topic; Drug Resistance, Multiple; Gene Expression Regulation, Neoplastic; Humans; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 8725386
DOI: 10.1146/annurev.pa.36.040196.001113