Mechanisms of Drug Resistance in Neoplastic Cells - 1st Edition - ISBN: 9780127633626, 9781483220758

Mechanisms of Drug Resistance in Neoplastic Cells

1st Edition

Bristol-Myers Cancer Symposia, Vol. 9

Editors: Paul V. Woolley Kenneth D. Tew
eBook ISBN: 9781483220758
Imprint: Academic Press
Published Date: 28th June 1988
Page Count: 416
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Bristol-Myers Cancer Symposia, Volume 9: Mechanisms of Drug Resistance in Neoplastic Cells provides information on both basic scientific and clinical studies on the causes and implications of tumor cell resistance to common antineoplastic agents. The book describes the colon cancer as a model for resistance to antineoplastic drugs; mathematical modeling of drug resistance; and the mechanism of induced gene amplification in mammalian cells. The text also discusses the cellular concomitants of multidrug resistance; resistance to alkylating agents; and the phosphoprotein and protein kinase C changes in human multidrug-resistant cancer cells. Novel drugs that affect glutathione metabolism; the regulation of genes encoding drug-metabolizing enzymes in normal and preneoplastic tissues; and the relevance of glutathione S-transferases to anticancer drug resistance are also considered. The book further tackles the cellular resistance to cyclophosphamide; the preclinical and clinical experiences with drug combinations designed to inhibit DNA repair in resistant human tumor cells; and the modification of the cytotoxicity of DNA-directed chemotherapeutic agents by polyamine depletion. The text also demonstrates multidrug resistance and the circumvention of resistance. Oncologists, molecular biologists, biochemists, geneticists, and pharmacologists will find the book invaluable.

Table of Contents


Editor's Foreword



Part I General Considerations of Drug Resistance

1 Colon Cancer as a Model for Resistance to Antineoplastic Drugs

I. Introduction

II. Types of Resistance: Intrinsic and Acquired

III. Clinical Resistance of Colon Cancer

IV. Behavior of Colon Cancer Cells in the Human Tumor Stem Cell Assay

V. Effects of Radiation and Oxygen Radicals on Colon Carcinoma Cells

VI. A Model of Colon Cancer Resistance

VII. Circumventing Resistance


2 Mathematical Modeling of Drug Resistance

I. Introduction

II. A Model for the Appearance of a Single Resistant Phenotype

III. Implications of a Stem-Cell Model of Tumor Growth for the Acquisition of Drug Resistance

IV. Effect of Variability on the Mean Value of the Mutation Rate in the System

V. Effect of Treatment Sequencing and the Question of Dose Intensity

VI. Partial Resistance

VII. Summary and Conclusions


3 On the Mechanism of Induced Gene Amplification in Mammalian Cells

I. Introduction

II. Enhancement of the Frequency of Gene Amplification by Hypoxia

III. Overreplication of DNA Following Inhibition of DNA Synthesis

IV. On the Mechanism of Overreplication of DNA

V. Overreplication-Recombination and the Generation of Amplifications and Chromosomal Aberrations-Mutations

VI. Consequences for Tumor Progression and Chemotherapy Resistance


4 Cellular Concomitants of Multidrug Resistance

I. Introduction

II. Plasma Membrane Glycoprotein (gp 150-180/P-Glycoprotein)

III. Chromosomal Organization of Amplified MDRA Genes

IV. Low-Molecular-Weight Cytosolic Protein (Sorcin/V19)

V. EGF Receptor

VI. Summary and Overview


5 Resistance to Alkylating Agents: Basic Studies and Therapeutic Implications

I. Introduction

II. Development of Resistance to Alkylating Agents

III. High-Dose Effect of Alkylating Agents-Experimental Model

IV. Cross-Resistance among Alkylating Agents

V. Resistance Mechanisms—Heterogeneity

VI. Other Studies of Resistance Mechanisms

VII. Multilog Cell Kill by Drug and Tumor Type

VIII. Multilog Cell Kill for Alkylating Agents and Nonalkylating Agents against Sensitive Tumors

IX. Cross-Resistance among Alkylating Agents as Determined from Multilog Kill Analyses

X. Multilog Survival Analysis—Duration of Drug Exposure

XI. Synergism

XII. Conclusions


6 Phosphoprotein and Protein Kinase C Changes in Human Multidrug-Resistant Cancer Cells

I. Introduction

II. Human Breast Cancer Lines

III. Human Small-Cell Lung Cancer Lines

IV. Protein Kinase C

V. Conclusions


Part II Enzymatic Basis of Drug Resistance

7 Novel Drugs That Affect Glutathione Metabolism

I. Introduction

II. Summary of Glutathione Metabolism and Transport

III. Decrease of Cellular Glutathione by Inhibition of 7-Glutamylcysteine Synthetase

IV. Methods for Increasing Cellular Levels of Glutathione

V. Prospects for More Effective Agents and for the Development of Other Approaches to the Modulation of Glutathione Metabolism


8 Regulation of Genes Encoding Drug-Metabolizing Enzymes in Normal and Preneoplastic Tissues

I. Introduction

II. Rat Liver Glutathione 5-Transferase

III. Analysis of a Rat Liver Glutathione S-Transferase Ya Structural Gene

IV. Regulation of Rat Liver Glutathione S-Transferase mRNAs by Xenobiotics

V. Expression of Glutathione S-Transferases, Epoxide Hydrolase, and Quinone Reductase Genes during Chemical Carcinogenesis

VI. Conclusions


9 Glutathione S-Transferases and Anticancer

I. Introduction

II. The Resistant Phenotype in Walker 256 Rat Breast Carcinoma Cells

III. Drug Resistance and an Altered Glutathione STransferase Phenotype in Cell Culture

IV. Subcellular Compartmentalization of Glutathione S-Transferases

V. Glutathione S-Transferases in Human Biopsies

VI. Discussion


10 Cellular Resistance to Cylcophosphamide

I. Cyclophosphamide Metabolism

II. Tumor-Cell Resistance Due to Aldehyde Dehydrogenase

III. Normal Tissue Resistance Due to Aldehyde Dehydrogenase

IV. Tumor-Cell Resistance Due to Glutathione S-Transferase

V. Other Potential Mechanisms of Resistance to Cyclophosphamide


11 Preclinical and Clinical Experiences with Drug Combinations Designed to Inhibit DNA Repair in Resistant Human Tumor Cells

I. Introduction

II. Materials and Methods

III. Results

IV. Discussion


12 Modification of the Cytotoxicity of DNA-Directed Chemotherapeutic Agents by Polyamine Depletion

I. Introduction

II. Polyamine Biosynthesis and Inhibition of Pathways

III. Binding of Polyamines to Nucleic Acids

IV. Effect of Polyamine Depletion on Nitrosourea Cytotoxicity

V. Effects of Polyamine Depletion on CIS-Platinum Cytotoxicity

VI. Effects of Polyamine Depletion on Other Cytotoxic Agents

VII. Other Effects


Part III Multidrug Resistance

13 Multidrug Resistance and P-Glycoprotein Expression

I. Introduction

II. Overexpression of P-Glycoprotein

III. P-Glycoprotein Gene Amplification

IV. P-Glycoprotein Gene Transfection

V. Structure of P-Glycoprotein

VI. Does P-Glycoprotein Cause Multidrug Resistance?


14 Different Mechanisms of Multiple Drug Resistance in Two Human Leukemic Cell Lines

I. Introduction

II. Results and Discussion

III. Summary and Conclusions


15 Multidrug Resistance in the Mouse Macrophage-Like Cell Line J774.2

I. Introduction

II. Isolation of Drug-Resistant Cell Line

III. Characterization of Resistant-Specific Proteins

IV. Gene Amplification

V. Summary


16 Expression, Amplification, and Transfer of DNA Sequences Associated with Multidrug Resistance

I. The Biological Problem of Multidrug Resistance

II. Development of a Genetic System for the Study of Multidrug Resistance in Human KB Cells

III. Drug Binding by P-Glycoprotein

IV. Clinical Implications: Expression of the mdrl Gene Product in Normal Tissues and Tumors


17 Cytogenetic and Molecular Biologic Alterations Associated with Anthracycline Resistance

I. Introduction

II. Properties of Resistant Cell Lines

III. Cytogenetic Alterations Associated with the Acquisition of Anthracycline Resistance

IV. Molecular Alterations Associated with Anthracycline Resistance

V. Conclusions


18 Roles of DNA Topoisomerases in Drug Cytotoxicity and Drug Resistance

I. DNA Topoisomerase II as a Therapeutic Target in Cancer Chemotherapy

II. DNA Topoisomerase I as a Possible Therapeutic Target in Cancer Chemotherapy


Part IV Circumvention Resistance

19 Manipulation of Cellular Thiols to Influence Drug Resistance

I. Introduction

II. Glutathione Levels and Drug Resistance

III. Experimental Model Systems of Human Ovarian Cancer

IV. GSH Metabolism and Effects of BSO in Vitro and in Vivo

V. DNA Repair in Drug-Resistant Cells

VI. Discussion


20 Drug Resistance as a Focus for New Drug Design

I. Introduction

II. Background

III. Implications for Further Drug Development

IV. Relevance of Several Antitumor Screening Models for Analog Development

V. Summary


21 Manipulation of Drug Accumulation: Mechanisms to Overcome Resistance

I. Introduction

II. Multiple Acquired Drug Resistance (MADR): Patterns of Cross-Resistance Related to decreased Drug Accumulation

III. Multiple Intrinsic Drug Resistance (MIDR): Selective Cellular Sensitivity Related to Drug Accumulation

IV. Circumvention of MADR and MIDR

V. Conclusions


22 Manipulation of Antineoplastic Drug Sensitivity and Resistance by DNA Transfection

I. Introduction

II. Strategies for Circumvention of Drug Resistance with Gene-Insertion Methodologies

III. Intrinsic Construct and Target Requirements for Successful DNA Transfections

IV. Gene Insertion Methodologies

V. Therapeutic Perspectives for Gene Therapy in Circumventing Drug Resistance


23 Potential Use of Monoclonal Antibody-Drug Conjugates to Prevent Drug Resistance





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© Academic Press 1988
Academic Press
eBook ISBN:

About the Editor

Paul V. Woolley

Kenneth D. Tew

Affiliations and Expertise

Department of Cell & Molecular Pharmacology, Medical University of South Carolina, USA

Ratings and Reviews