Murad Advances in Pharmacology

1. Auflage 1999
ISBN: 978-0-08-058138-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 46, 344 Seiten

Reihe: Advances in Pharmacology

Each volume of Advances in Pharmacology provides a rich collection of reviews on timely topics. Emphasis is placed on the molecular bases of drug action, both applied and experimental. - This volume includes reviews on some of the hottest topics in pharmacology, including: - Multidrug resistance and the MDR1 gene in gene therapy - Regulation of calcium channels in epithelial cells - Gene therapy and vascular disease - Potential therapeutic applications for Heparin - Calcium channel blockers - Antithrombotic agents - Regulation of potassium channels in epithelial cells

Autoren/Hrsg.

Murad, Ferid

Inhaltsverzeichnis

1;Front Cover;1
2;Advances in Pharmacology, Volume 46;4
3;Copyright Page;5
4;Contents;6
5;Contributors ;12
6;Chapter 1. Therapeutic Strategies Involving the Multidrug Resistance Phenotype: The MDRl Gene as Target, Chemoprotectant, and Selectable Marker in Gene Therapy;14
6.1;I. Introduction;14
6.2;II. Multidrug Resistance Mediated by P-Glycoprotein;16
6.3;III. The MDRI Gene as a Target for Therapeutic Intervention in Multidrug Resistance Cancer ;21
6.4;IV. Therapeutic Applications of the MDRI Gene;24
6.5;V. Future Prospects;37
6.6;VI. Conclusions;42
6.7;References;42
7;Chapter 2. The Diversity of Calcium Channels and Their Regulation in Epithelial Cells;56
7.1;I. Introduction;56
7.2;II. Brief History of Early Calcium Channel Discovery;58
7.3;III. Epithelial Calcium Channels;63
7.4;IV. Calcium Channel Regulation;79
7.5;V. Concluding Remarks;85
7.6;References;86
8;Chapter 3. Gene Therapy and Vascular Disease;98
8.1;I. Introduction;98
8.2;II. History of Gene Therapy;99
8.3;III. Requirements for Gene Transfer;101
8.4;IV. Vectors;101
8.5;V. Vascular Gene Delivery Techniques;121
8.6;VI. The Vascular Injury Response;127
8.7;VII. Vascular Gene Therapy to Prevent Neointimal Thickening Following Injury;129
8.8;VIII. Arterial Thrombosis;144
8.9;IX. Therapeutic Angiogenesis;145
8.10;X. Transplant Vasculopathy;146
8.11;XI. Limitations of Vascular Gene Therapy;147
8.12;References;150
9;Chapter 4. Heparin in Inflammation: Potential Therapeutic Applications beyond Anticoagulation;164
9.1;I. Introduction;164
9.2;II. Inflammation: Setting the Stage;171
9.3;III. Preclinical and Clinical Effectiveness of Heparin Therapy for Inflammatory Diseases;183
9.4;IV. Summary;202
9.5;References;202
10;Chapter 5. The Regulation of Epithelial Cell cAMP- and Calcium-Dependent Chloride Channels;222
10.1;I. Introduction;222
10.2;II. The Secretagogue-Activated cAMP-Regulated Chloride Conductance ;228
10.3;III. The Secretagogue-Activated Calcium-Regulated Chloride Conductance;241
10.4;IV. Summary;252
10.5;References;253
11;Chapter 6. Calcium Channel Blockers: Current Controversies and Basic Mechanisms of Action;266
11.1;I. Introduction;266
11.2;II. Classification;267
11.3;III. L-Type Calcium Ion Channels;267
11.4;IV. Physiology and Pharmacology of L-Type Calcium Ion Channels;273
11.5;V. Drug Binding Sites by Class;279
11.6;VI. Second Messenger and Intracellular Calcium Ion Regulation ;283
11.7;VII. Calcium Channel Blockers as Therapy for Cardiac Ischemia ;286
11.8;VIII. Calcium Channel Blockers for Prevention of Myocardial Infarction and Sudden Death ;289
11.9;IX. Calcium Channel Blockers in Hypertension–Survival Outcome ;294
11.10;X. Calcium Channel Blockers as Therapy for Congestive Heart Failure ;296
11.11;XI. Calcium Channel Blockers in Cardiac Transplant;297
11.12;XII. Calcium Channel Blockers for Supraventricular Arrhythmias;297
11.13;XIII. Calcium Channel Blockers for Hypertrophic Cardiomyopathy;298
11.14;References;299
12;Chapter 7. Mechanisms of Antithrombotic Drugs;310
12.1;I. Introduction;310
12.2;II. Hemostatic and Thrombotic Processes;311
12.3;III. Principles of Antithrombotic Therapy;315
12.4;IV. Anticoagulants;315
12.5;V. Antiplatelet Agents;323
12.6;VI. New Antithrombotic Strategy;329
12.7;VII. Conclusion and Perspectives;330
12.8;References;330
13;Index;338
14;Contents of Previous Volumes;344

Leseproben

Therapeutic Strategies Involving the Multidrug Resistance Phenotype: The MDRI Gene as Target, Chemoprotectant, and Selectable Marker in Gene Therapy
Josep M. Aran*; Ira Pastan*; Michael M. Gottesman†    * Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255
† Laboratory of Cell Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255 I Introduction
Since the late 1980s, considerable effort has been devoted to understanding the molecular mechanisms by which tumor cells become simultaneously resistant to a variety of chemotherapeutic drugs with no obvious structural homology or common cellular targets. This pleiotropic drug resistance, termed multidrug resistance (MDR), has proved a serious obstacle to cancer eradication by limiting the efficacy of systemic chemotherapy, the most widely used form of antitumor treatment. In addition to altered cell cycle, cell checkpoints, and altered sensitivity to induction of apoptosis, several cellular modifications have been shown to influence the development of the MDR phenotype including: (1) modifications in detoxification and DNA repair pathways, (2) increases in cellular drug sequestration, (3) decreases in drug–target affinity, (4) synthesis of drug inhibitors within cells, (5) inappropriate targeting of proteins, and (6) accelerated removal or secretion of drugs (reviewed in Simon and Schindler, 1994). Although multidrug resistance may be multifunctional, the most common MDR phenomenon detected in cancer cells is the expression of an energy-dependent efflux pump (P-glycoprotein, Pgp) encoded by the MDR1 gene, with the capacity to interact with many cytotoxic drugs. The existence of this single cause of MDR makes an attractive target for therapeutic intervention (Gottesman et al., 1995). In addition to MDR1, several genes have been described to induce a specific pattern of drug resistance when overexpressed in different cells and tissues, including those encoding dihydrofolate reductase (resistance to antifolates) (Williams et al., 1987; Corey et al., 1990; Li et al., 1994; Flass-hove et al., 1995), alkyltransferases (resistance to nitrosoureas) (Allay et al., 1995; Moritz et al., 1995; Harris et al., 1995), aldehyde dehydrogenase 1 (resistance to oxazaphosphorines) (Friedman et al., 1992; Webb and Sorrentino, 1994; Bunting et al., 1994), and glutathione S-transferase (resistance to alkylating agents) (Greenbaum et al., 1994; Chen and Waxman, 1995). Reduced expression of topoisomerase II results in resistance to anthracy-clines and epipodophyllotoxins (Beck et al., 1993; Hofmann and Mattern, 1993). There may be many more proteins, as yet to be identified, that play an active role in MDR. In this chapter we discuss the phenomenon of multidrug resistance to chemotherapy mediated by the MDR1 gene, among the most flexible of all known drug resistance genes in terms of multiple drug interaction. Thorough information about the biochemistry and molecular biology of the multidrug transporter has been discussed in several reviews to which the reader is referred (Endicott and Ling, 1989; Roninson, 1991; Schinkel and Borst, 1991; Gottesman and Pastan, 1993; Germann, 1993; Gottesman et al., 1995). We focus on recent genetic approaches to circumvent multidrug resistance due to Pgp overexpression in tumor cells. Moreover, we summarize current work on the potential application of the MDR1 gene for two main therapeutic purposes: (1) bone marrow chemoprotection in the gene therapy of cancer and (2) utility as a dominant selectable marker when coexpressed with a nonselectable gene for the gene therapy of genetic and acquired diseases. Recently, a 190-kDa membrane glycoprotein termed MRP (MDR- related protein) has also been associated with a phenotype of extended cross-resistance which overlaps to some extent with that of Pgp (Zaman et al., 1994). The complementary DNA encoding MRP has been cloned from non-Pgp-expressing multidrug-resistant small-cell lung cancer cells (H69/AR) (Cole et al., 1992). Only Pgp and MRP have been transfected into cells and demonstrated to affect drug sensitivity. Thus, although MRP has not yet been extensively characterized, it is possible that in the future the therapeutic applications developed for the MDR1 gene may be extended to the gene encoding MRP (Eijdems et al., 1992). II Multidrug Resistance Mediated by P-Glycoprotein
One of the distinguishing features of tumor cells is their high proliferation rate when compared to normal cells. Thus, the primary targets of chemotherapy with anticancer drugs are DNA replication, cell cycle regulation, and the mitotic apparatus of the cell. The observation that some malignantly transformed cell lines such as P388 murine leukemia cells, Chinese hamster ovary cells, and human KB cells (a subclone of the HeLa cervical carcinoma cell line) became simultaneously resistant to the cytotoxic effects of many anticancer drugs (Dano, 1973; Juliano and Ling, 1976; Akiyama et al., 1985; Shen et al., 1986a) led to the detection of two changes in these MDR cells: reduced drug accumulation and increased expression of a 170-kDa membrane glycoprotein termed “permeability” glycoprotein (P-glycoprotein). The expression of this protein correlated directly with the level of drug resistance in the MDR cell lines. These early studies also defined the pattern of cellular multidrug resistance to many natural product drugs, including colchicine, doxorubicin, and vinblastine. Stepwise selection of KB cells with increased amounts of these cytotoxic drugs resulted in a series of established multidrug-resistant cells, which were used to isolate and characterize the amplified MDR1 gene (Shen et al., 1986b; Fojo et al., 1985). A Biochemistry of the Multidrug Transporter P-Glycoprotein
Cloning and sequencing of the human MDR1 cDNA identified its 1280 amino-acid-encoded product as the multidrug transporter or Pgp (Ueda et al., 1987a,b). This information led to the proposal of a structural working model for Pgp, with 12 transmembrane regions and 2 ATP binding/utilization domains (Gottesman and Pastan, 1988) (Fig. 1). The multidrug transporter shares homology with a multigene family of ATP binding cassette (ABC) membrane transporters, which includes members in prokaryotes and lower and higher eukaryotes (Chen et al., 1986; Higgins, 1992). Posttranslational modifications of Pgp include glycosylation (Richer et al., 1988; Schinkel et al., 1993) and phosphorylation (Chambers et al., 1993; Germann et al., 1996), although none of them has proved essential for its activity as a drug transporter. There are two genes homologous to the human MDR1 gene in rodents (mdr1a and mdr1b) capable of conferring the multidrug-resistance phenotype (Ng et al., 1989; Gros et al., 1986). Figure 1 Two-dimensional topology of the human multidrug transporter P-glycoprotein. A 12-transmembrane domain model is predicted by the hydropathy profile and amino acid sequence comparison of P-glycoprotein with bacterial transport proteins. The ATP-binding/utilization domains are circled and putative N-linked carbohydrates are shown as curly lines. Heavy bars indicate the regions labeled with photoaffinity analogs. Serine residues clustered in the linker region located between the two halves of P-glycoprotein have been shown to be phosphorylated by protein kinases. The filled circles scattered mainly throughout the transmembrane domains represent point mutations affecting amino acid residues which have been shown to alter drug transport specificity. (adapted from Gottesman et al., 1995) Several biochemical studies have contributed to the actual picture of P-glycoprotein as an ATP-dependent efflux pump able to extrude a wide range of structurally diverse, hydrophobic, amphipathic compounds from the cell. These compounds include natural product-derived anticancer drugs such as anthracyclines, Vinca alkaloids, epipodophyllotoxins, and taxol (Table 1), but not antimetabolites or alkylating agents. Table 1 Agents That Interact with P-Glycoprotein Vinca alkaloids Vincristine, vinblastine Antimicrotubule drugs Colchicine Calcium channel blockers Verapamil, diltiazem, nifedipine, azidopine Anthracyclines Daunorubicin, doxorubicin, mitoxantrone Protein synthesis inhibitors Puromycin, emetine, homoharringtonine Antiarrhythmics Quinidine,...