Drug Resistance As a Biochemical Target in Cancer Chemotherapy - 1st Edition - ISBN: 9780127022956, 9780323153881

Drug Resistance As a Biochemical Target in Cancer Chemotherapy

1st Edition

Editors: Makoto Ogawa
eBook ISBN: 9780323153881
Imprint: Academic Press
Published Date: 12th November 1991
Page Count: 368
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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


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




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© Academic Press 1992
Academic Press
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About the Editor

Makoto Ogawa

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