Drug Resistance As a Biochemical Target in Cancer Chemotherapy

Drug Resistance As a Biochemical Target in Cancer Chemotherapy

1st Edition - November 12, 1991

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  • Editor: Makoto Ogawa
  • eBook ISBN: 9780323153881

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Drug Resistance as a Biochemical Target in Cancer Chemotherapy covers the proceedings of the 13th Bristol-Myers Squibb Symposium on Cancer Research, entitled ""Drug Resistance as a Biochemical Target in Cancer Chemotherapy"", hosted by the Japanese Foundation for Cancer Research in Tokyo. This book is divided into four parts encompassing 18 chapters that summarize the results of both preclinical and clinical research on circumvention of drug resistance. The first two parts discuss the genetic aspects of multidrug resistance and the proteins involved in drug resistance. These parts also examine the structure, function, and expression of P-glycoproteins, with an emphasis on the role of these proteins as targets for cancer chemotherapy. The third part describes the methods for detection of P-glycoprotein and its antagonists to counter clinical drug resistance. This topic is followed by a discussion on the interactions among steroid hormones, steroid hormone receptors, antiandrogens, biological-response modifiers, and cytotoxic drugs in human breast cancer. The concluding part explores the clinical applications of chemosensitizers in cancer therapy. This part also considers the alternative clinical approaches against drug failure, including non-crosss-resistant therapies, autologous bone marrow transplantation, dose-intensive therapy, and high-dose chemotherapy. Biomedical scientists and researchers and clinicians will find this book invaluable.

Table of Contents

  • Contributors

    Editor's Foreword



    Introduction to the Bristol-Myers Squibb Drug Resistance in Cancer Symposium



    Part I Genetic Aspects of Multidrug Resistance

    1 The P-glycoprotein Gene Family

    I. Introduction

    II. P-glycoprotein Genes in Unicellular Eukaryotes

    III. P-glycoprotein Genes in Simple Multicellular Eukaryotes

    IV. The P-glycoprotein Genes of Mammals

    V. The Human MDR3/2 Gene

    VI. Outlook


    2 Molecular Genetic Analysis of P-glycoprotein Function and Expression in Human Cells

    I. Introduction

    II. Human MDR Genes: Structure and Expression

    III. The Role of the MDR1 Gene in Multidrug Resistance

    IV. Structural and Mutational Analysis of P-glycoprotein Function

    V. Diagnostics of MDR1 Expression in Human Cancer by Polymerase Chain Reaction


    3 Function of the Multidrug Transporter

    I. Introduction

    II. The Localization of P-glycoprotein in Normal Tissues Suggests a Role in Transepithelial Transport

    III. Model Systems In Which P-glycoprotein Acts as an Energy-dependent Drug Transporter

    IV. Multidrug Transport May Involve Extraction of Hydrophobie Drugs from Lipid Bilayers

    V. Transgenic Mice Expressing the MDR1 Gene in Bone Marrow

    VI. Conclusions


    4 A Comparison of the Structure, Function, and Expression of P-glycoproteins Encoded by mdrla in mdr1b in Mouse

    I. Introduction

    II. Structural Differences between P-glycoprotein Family Members

    III. Functional Differences Associated with mdr1a and mdr1b

    IV. Differences in Expression between mdr1a and mdr1b

    V. Conclusions


    Part II Proteins Involved in Drug Resistance as Targets for Cancer Chemotherapy

    5 Multidrug Resistance: Basic Approaches for Reversal

    I. Introduction

    II. Basic Properties of the P-glycoprotein of MDR Cells

    III. P-glycoprotein as a Target of Cancer Chemotherapy

    IV. Application of Monoclonal Antibodies for Therapy of Human Resistant Cells

    V. Search for New Agents to Reverse Drug Resistance

    VI. Development and Evaluation of New Antitumor Agents Effective against Human Drug-resistant Tumors

    VII. Conclusion


    6 Expression of P-glycoprotein Isoforms

    I. Introduction

    II. P-glycoprotein Gene Family Members in Different Species

    III. Localization of P-glycoprotein Isoforms in Chinese Hamster

    IV. Concluding Remarks


    7 The Use of Yeast and Yeast Strains Expressing Human DNA Topoisomerases in the Study of Anticancer Drugs

    I. Introduction

    II. DNA Topoisomerases as Targets of Therapeutics

    III. Yeast as a Genetic System for the Study of DNA Topoisomerase-targeting Anticancer Drugs

    IV. Expression of Human DNA Topoisomerases I and II in Yeast for Drug Screening or for the Construction of Drug-resistant Mutant Human Enzymes

    V. A Unique Feature of Topoisomerasetargeting Drugs That Interfere with Transesterification

    VI. Potential Targets for the Development of New Therapeutics

    VII. Drugs of the Same Theme but Different Colors

    VIII. Concluding Remarks


    8 Mechanisms of Tumor Cell Killing by Topoisomerase Poisons

    I. Introduction

    II. Topoisomerase I Poisons

    III. Topoisomerase II Poisons


    9 Regulation of Glutathione Transferase P Gene: Implications in Carcinogenesis and Drug Resistance

    I. Introduction

    II. Results and Discussion

    III. Concluding Remarks


    Part III Approaches Against Clinical Drug Resistance

    10 Clinical Detection and Role of Differentiation in Multidrug Resistance

    I. Introduction

    II. Methods of P-glycoprotein Detection

    III. Role of Differentiation in Multidrug Resistance

    IV. Use of P-glycoprotein Antagonists


    11 Detection of Multidrug-Resistant Human Cancer Cells by Monoclonal Antibodies

    I. Introduction

    II. Sensitivity and Specificity of Monoclonal Antibodies, MRK16-F(ab')2 and MRK20-F(ab')2

    III. Reactivity of Monoclonal Antibodies with Normal Leukocytes in Peripheral Blood

    IV. Reactivity of MRK16-F(ab')2 and MRK20-F(ab')2 with Clinical Samples

    V. Summary


    12 Molecular Analysis of Human IL-2 and IL-2 Receptors

    I. Introduction

    II. Structure of Human IL-2

    III. Structure of the IL-2 Receptor Complex

    IV. IL-2Rß Chain and Signal Transduction

    V. IL-2Rß Is Functional in a Neural Cell Line

    VI. Summary


    13 The Interactions among Steroid Hormones, Steroid Hormone Receptors, Antiestrogens, Biological-response Modifiers and Cytotoxic Drugs in Human Breast Cancer

    I. Introduction

    II. Effects of Biological-response Modifiers and Cytotoxic Drugs on Steroid Hormone—Receptor Expression and Response to Antiestrogens

    III. Effects of Hormonal Therapies on Response to Cytotoxic Drugs

    IV. Effects of Cytotoxic Drugs on Serum Hormones

    V. Conclusions


    Part IV Clinical Approaches Against Drug Failure

    14 Clinical Detection of Multidrug Resistance and Reversal with Chemosensitizing Agents

    I. Introduction

    II. Clinical Applications of Chemosensitizers in Cancer Therapy

    III. Further Studies of Chemosensitizers


    15 Clinical Evaluation of Non-cross-resistant Therapies in Advanced Hodgkin's Disease

    I. Introduction

    II. Rise of ABVD and Non-cross-resistant Regimens

    III. Attempts to Overcome Drug Resistance by Alternating MOPP and ABVD

    IV. More Recent Findings with Non-crossresistant Regimens

    V. Attempts to Overcome Drug Resistance by High-dose Therapy

    VI. Comment


    16 Autologous Bone Marrow Transplantation for Hematologic Malignancy

    I. Overview

    II. Rationale

    III. Critical Issues

    IV. Clinical Studies

    V. Future Directions

    VI. Conclusion


    17 Dose-intensive Therapy: A Strategy to Avoid Drug Resistance in Solid Tumors

    I. Considerations in the Design of a Highdose Regimen for Solid Tumors

    II. Breast Cancer

    III. Bone Marrow Transplantation in Breast Cancer

    IV. Bone Marrow Involvement

    V. Supportive Care

    VI. Summary of ABMT in Breast Cancer


    18 High-dose Chemotherapy with Autologous Bone Marrow Transplantation in Malignant Lymphomas and Breast Cancer

    I. Background

    II. Materials and Methods

    III. Results

    IV. Discussion



Product details

  • No. of pages: 368
  • Language: English
  • Copyright: © Academic Press 1991
  • Published: November 12, 1991
  • Imprint: Academic Press
  • eBook ISBN: 9780323153881

About the Editor

Makoto Ogawa

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