Molecular and Cellular Biology of Multidrug Resistance in Tumor Cells

The ability of neoplastic cells to survive exposure to various chemotherapeutic drugs represents the main obstacle to successful cancer chemotherapy. This book deals with a particular type of resistance in tumor cells that represents a single but especially important aspect of the multifaceted problem of cancer drug resistance. This type of resistance, known as multidrug or pleiotropic drug resistance, is characterized by cross-resistance of cells to several different classes of cytotoxic drugs, including some of the most commonly used anticancer agents. Over the last several years, there has been a veritable explosion of genetic, biochemical, and clinical information on multidrug resistance, which followed the identification and cloning of the genes responsible for this phenotype and the isolation of monoclonal antibodies against P-glycoproteins, the products of these genes. Elucida­ tion of the molecular mechanism of multidrug resistance has led to the formulation of novel approaches to the prediction of tumor response to chemotherapeutic drugs and increasing the efficacy of cancer therapy. Analysis of the structure and function of P­ glycoproteins from multidrug-resistant mammalian cells has also established a prototype for a novel class of eukaryotic membrane proteins, which have now been associated with a variety of transport processes in different organisms. This book summarizes the results of molecular biological, pharmacological, bio­ chemical, cytogenetic, immunological, and pathological studies on multidrug resistance in mammalian cells. Most of the chapters deal at least to some extent with the structure and expression of P-glycoprotein and its role in multidrug resistance. Front Matter....Pages i-xviii Front Matter....Pages 1-1 Characteristics of Multidrug Resistance in Human Tumor Cells....Pages 3-55 Development of Multidrug Resistance in Rodent Cell Lines....Pages 57-70 Front Matter....Pages 71-71 Cloning and Characterization of Mouse mdr Genes....Pages 73-89 Isolation and Characterization of the Human MDR (P-Glycoprotein) Genes....Pages 91-106 Amplification of Several Different Genes in Multidrug-Resistant Chinese Hamster Cell Lines....Pages 107-116 Molecular and Cytogenetic Analysis of Multidrug Resistance-Associated Gene Amplification in Chinese Hamster, Mouse Sarcoma, and Human Neuroblastoma Cells....Pages 117-145 Karyotype and Amplicon Evolution during Stepwise Development of Multidrug Resistance in Djungarian Hamster Cell Lines....Pages 147-168 Chromosome Localization of P-Glycoprotein Genes in Drug-Sensitive and -Resistant Human Cells....Pages 169-188 Structure and Evolution of P-Glycoproteins....Pages 189-211 Front Matter....Pages 213-213 Drug Accumulation and Binding in P-Glycoprotein-Associated Multidrug Resistance....Pages 215-227 Binding of Drugs and ATP by P-Glycoprotein and Transport of Drugs by Vesicles from Human Multidrug-Resistant Cells....Pages 229-242 Protein Changes in Multidrug-Resistant Cells....Pages 243-261 Membrane Lipids of Multidrug-Resistant Cells: Chemical Composition and Physical State....Pages 263-276 Front Matter....Pages 277-277 Expression of the MDR 1 Gene in Normal Human Tissues....Pages 279-289 Expression of the Multidrug Resistance Gene in Human Cancer....Pages 291-301 Immunohistochemical Analysis of P-Glycoprotein Expression in Normal and Tumor Tissues in Humans....Pages 303-318 Quantitative Estimation of MDR 1 mRNA Levels by Polymerase Chain Reaction....Pages 319-333 Front Matter....Pages 335-335 Collateral Sensitivity of Multidrug-Resistant Cells....Pages 337-347 Reversal of Multidrug Resistance by Calcium Channel Blockers and Other Agents....Pages 349-372 Growth Inhibition of Multidrug-Resistant Cells by Monoclonal Antibodies against P-Glycoprotein....Pages 373-391 Front Matter....Pages 393-393 P-Glycoprotein-Mediated Drug Resistance: Puzzles and Perspectives....Pages 395-402 Back Matter....Pages 403-406 1 Characteristics of Multidrug Resistance in Human Tumor Cells.- 2 Development of Multidrug Resistance in Rodent Cell Lines.- 3 Cloning and Characterization of Mouse mdr Genes.- 4 Isolation and Characterization of the Human MDR (P-Glycoprotein) Genes.- 5 Amplification of Several Different Genes in Multidrug-Resistant Chinese Hamster Cell Lines.- 6 Molecular and Cytogenetic Analysis of Multidrug Resistance-Associated Gene Amplification in Chinese Hamster, Mouse Sarcoma, and Human Neuroblastoma Cells.- 7 Karyotype and Amplicon Evolution during Stepwise Development of Multidrug Resistance in Djun