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.

Springer Book Archives

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 Djungarian Hamster Cell Lines.- 8 Chromosome Localization of P-Glycoprotein Genes in Drug-Sensitive and -Resistant Human Cells.- 9 Structure and Evolution of P-Glycoproteins.- 10 Drug Accumulation and Binding in P-Glycoprotein-Associated Multidrug Resistance.- 11 Binding of Drugs and ATP by P-Glycoprotein and Transport of Drugs by Vesicles from Human Multidrug-Resistant Cells.- 12 Protein Changes in Multidrug-Resistant Cells.- 13 Membrane Lipids of Multidrug-Resistant Cells: Chemical Composition and Physical State.- 14 Expression of the MDR1 Gene in Normal Human Tissues.- 15 Expression of the Multidrug Resistant Gene in Human Cancer.- 16 Immunohistochemical Analysis of P-Glycoprotein Expression in Normal and Tumor Tissues in Humans.- 17 Quantitative Estimation of MDR1 mRNA Levels by Polymerase Chain Reaction.- 18 Collateral Sensitivity of Multidrug-Resistant Cells.- 19 Reversal of Multidrug Resistance by Calcium Channel Blockers and Other Agents.- 20 Growth Inhibition of Multidrug-Resistant Cells by Monoclonal Antibodies against P-Glycoprotein.- 21 P-Glycoprotein-Mediated Drug Resistance: Puzzles and Perspectives.