Part II Table of ContentsSection C: Alkylating Agents

Chapter 30Chemistry of Alkylation. CHABLBS C. PRICE

Introduction 1Reaction Mechanism 1

References 6

Chapter 31

Molecular Biology ol Alkylation: An Overview. DAVID B. LOTLUM. With 5 Figures

Introduction 6

Alkylation of DNA 6

Effects of Alkylating Agents on Bacteriophage 9

Cellular Modification of Damaged DNA 11

Functional Capacity of Alkylated Template 14

References 15

Chapter 32

Mechanism of Action of 2-ChIoroethyIamine Derivatives, Sulfur Mustards, Epoxides, andAziridines. T. A. CONNOBS. With 2 Figures

Introduction 18

The Mechanism of Alkylation 19Mechanism of Action at the Cellular Level 20

A. Long Term Effects of the Alkylating Agents 22B. Antineoplastic Effects 22C. Effects on Hemopoietic Tissue 23D. Effects on Spermatogenesis 23E. Effects on the Immune Response 24

Mechanism of Action at the Macromolecular Level 24A. Reactions with Enzymes and Coenzymes 25B. Reaction with Nucleic Acids 25

Distribution and Metabolism of Alkylating Agents 28

Conclusions 29References 30

Chapter 33

Mechanism of Action of Methanesulfonates. BRIAN W. FOX. With 1 Figure

Introduction 35

Whole Tissue Studies 35A. Antitumor Activity 35B. Spermatogenesis 37

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VIII Table of Contents

C. Hemopoietic Effects 37D. Immunosuppressive Properties 38E. Miscellaneous Effects 38

Metabolism and Distribution Studies 39

Cellular Studies 40

Studies at the Molecular Level 41Mutagenic Action 41Conclusions 42References 42

Chapter 34Mechanism of Action of Mitomycins. HELGA KEBSTEN. With 7 Figures

Introduction 47Molecular Mechanism of Action 48

A. Interaction with DNA in Vitro 48B. Interaction with DNA in Intact Cells (DNA Damage and Repair) 52C. DNA Synthesis and Degradation 53D. RNA Metabolism 54E. Synthesis of Enzymes 56

Biological Effects of Mitomycins Related to Molecular Mechanism of Action 56A. Mutagenicity 56B. Chromosome Breakage 56C. Viruses, Phage, and Episomal DNA 57D. Mitosis 59E. Immunological Aspects 59

References 60

Chapter 35

Mechanism of Action of Nitrosoureas. GLYNN P. WHEELEB

Introduction 65Chemistry 65Pharmacological Considerations 69Reactions with Biological Materials 69

A. Alkylation 69B. Carbamoylation 72

Biochemical Effects 73A. Synthesis of Macromolecules 73B. Enzyme Levels and Inactivation of Enzymes 75

Biological Effects 76A. Effects upon Cell Cycle and Cytotoxicity during the Cycle 76B. Genetic Effects 78

Conclusions 79

References 79

Section D: Hormones

Chapter 36

Mechanism of Action of Glucocorticoids. FBED ROSEN and RICHABD J. MILHOLLAND

Introduction 85

Table of Contents IX

Biochemical Effects of Glucocorticoids on Lymphoid Tissues 86A. DNA Metabolism 86B. RNA and Protein Metabolism 88C. Carbohydrate Metabolism 91D. Changes in Enzyme Activity 94

Glucocorticoid Receptors 94A. Studies in Animals 96B. Whole Cell Studies in Vitro 96C. Broken-Cell System 98

Possible Mechanism of Action and Basis for Resistance to Glucocorticoids 98References 100

Chapter 37

Mechanisms of Action of Estrogens. RTJSSELL HILF and JAMES L. WITTLHT. With 5 Figures

Introduction 104

Chemical Structure and Steroidogenesis 104

Actions on Target Organs 108A. Accessory Sex Organs 108B. Pituitary and Hypothalamus 108C. Lipogenesis and Cholesterol 109D. Antiestrogens 109E. Breast and Breast Cancer I l lF. Additional Effects of Estrogens 113

Biochemical Basis of Action 113A. Specific Estrogen Binding Proteins 113B. Macromolecular Synthesis 118C. Carbohydrate Metabolism 122

References 125

Chapter 38Mechanism of Action of Androgens. RTJSSELL HILF. With 1 Figure

Introduction 139

Biosynthesis of Androgens 139

Relative Potency of Androgens 142

Actions on Target Organs 142A. Testis and Male Accessory Sex Organs 142B. Ovaries and Female Accessory Sex Organs 143C. Pituitary 143D. Breast and Breast Cancer 144E. Metabolic Actions 145F. Antiandrogens 145

Mechanisms of Action 146A. Effects of Androgens on Synthesis of Macromolecules 147B. Androgen Receptor Macromolecules 149C. Energy Metabolism and Enzyme Changes 151

References 153

X Table of Contents

Chapter 39Mechanism of Action of Progesterone. BEET W. O'MALLEY and CHARLES A. STBOTT.

With 1 Figure

Biologic Responses to Progesterone 158

The Uptake and Metabolism of Progesterone 159

Binding of Progesterone to Target Cells 162

Sequence of Events in the Action of Progesterone 163

References 167

Chapter 40Pharmacology and Clinical Utility of Hormones in Hormone Belated Neoplasms.

THOMAS L. DAO

Introduction 170

Hormone-Induced Tissue Growth and Neoplasia 171

Antineoplastic Property of Steroid Hormones as Related to Their Biological Activities. 172A. Estrogens and Antiandrogenic Effect 172B. Androgen and its Antiestrogenic Effect 173C. Antineoplastic Effect of Estrogen and Hypothalamic-Pituitary Regulation of

Prolactin 174D. Effect of Progestogens on Endometrium, Mammary Gland, and Kidney, and Their

Antitumor Activity 174E. Corticosteroids and Their Antitumor Activity 175F. Direct Effect of Steroid Hormones on Tumor Growth 176

Metabolism of Steroids in Cancer 177A. Metabolism of Estrogens 177B. Metabolism of Androgens 179

Clinical Use of Hormonal Steroids in the Treatment of Cancer 179A. Cancer of the Prostate 179

I. Diethylstilbestrol (a,a'-diethyl-4,4'-stilbenediol) 179II. Chlorotrianisene (tri-p-anisylchloroethylene, TACE) 180

III. Corticosteroid Therapy 180B. Cancer of the Breast 180

I. Androgen Therapy 1811. Testosterone 1812. Dihydrotestosterone (Stanolone, Androstanolone, Androstan-17j?-ol-3-one) 1813. 17a-Methyltestosterone 1824. Fluoxymestrone (9a-nuoro-llj?-hydroxy-17a-methyltestosterone, Halo-

testin) 1825. 19-Nor-Testosterone 1826. Zl'-Testololactone (Teslac) 1827. Other Synthetic Androgens 183

II. Estrogen Therapy 183III. Adrenocorticoid Therapy 184IV. Progesterone 185

C. Endometrial Carcinoma 186D. Carcinoma of the Kidney 186E. Lymphomas and Leukemia 187

Conclusions 187

References 188

Table of Contents XI

Section E: Antimetabolites

Chapter 41Fluorinated Pyrimidines and Their Nucleosides. CHARLES HEIDELBERGER. With 10 Figures

Introduction 193

Rationale 193

Syntheses 195

Physical, Chemical, and Conformational Properties 197Tumor-Inhibitory Properties 198Other Biological Effects 199

A. Inhibition of the Growth of Cultured Cells 199B. Antiviral Activity 199C. Mutagenic Activity 200D. Teratogenic Activity 200E. Effects on Chromosomes 200F. Effects on Bacterial Cell Walls 201G. Antifungal Effects 201H. Immunosuppression 201

Biochemical Summary 201A. Metabolic Degradation of the Pyrimidine Ring 202B. Anabolic Reactions along the Ribonucleotide Pathway 202C. Anabolic Reactions along the Deoxyribonucleotide Pathway 203D. Nucleoside Catabolic Reactions 203

Inhibition of DNA Synthesis 203A. Cellular 203B. Enzymatic Mechanism 204

Incorporation into DNA 204Effects on RNA Synthesis 205

A. Mammalian 205B. Microorganisms 206C. Effects on Ribosome Biosynthesis 206

Incorporation into RNA 207A. Total Cellular 207B. Viral RNA 208C. Transfer RNA 209D. Ribosomal RNA 210E. Messenger RNA 210

Consequences of Incorporation into RNA 211A. Mutagenesis to RNA Viruses 211B. Effects on Protein Synthesis 211C. Effects on Enzyme Induction 212D. Coding Properties 213E. Translational Errors 214

Pathways of Activation and Resistance 215A. Role of Catabolism 215B. Activation 216C. Resistance 217

Effects on the Cell Cycle 217

XII Table of Contents

Preclinical Pharmacology 219

Clinical Use 219

Clinical Pharmacology 221

References 223

Chapter 4

Table of Contents XIII

B. Effect of Dose and Schedule on Pharmacological Findings 262I. Dose 262

II. Schedule 262C. Clinical Results for Acute Leukemia and the Relationship of Schedule to Effec-

tiveness 263

Combination Chemotherapy 263A. Ara-C and Cyclophosphamide 263B. Ara-C and l,3-6is(2-Chloroethyl)-l-Nitrosourea (BCNU) 264C. Ara-C and 6-Thioguanine (TG) 264D. Ara-C and Methyl Mitomycin (Porfiromycin) 264

Resistance to Ara-C as Related to Kinase: Deaminase Ratios and to Intracellular Ribo-nucleotide Concentrations 264

Perspectives 266A. Tetrahydrouridine (THU) 266B. 1-yS-D-Arabinofuranosylcytosine 5'-Adamantoate (AdO-Ara-C) 266C. Other Ara-C Analogs 266

I. 2,2'-O-Cyclocytidine (Cyclocytidine) 266II. Arabinosylcytosine 3-N-0xide (Ara-C-3-N-0xide) 267

D. Sparing Action by Uridine 267References 267

Chapter 44

Halogenated Pyriniidine Deoxyribonuclcosides. WILLIAM H. PRUSOIT and BARRY GOZ.With 4 Figures

Introduction 272

Chemistry 272A. Synthesis 272

I. Synthesis of Nucleosides Halogenated in the Pyrimidine Moiety 272II. Synthesis of Radioactive Halogenated Nucleosides and Nucleotides . . . . 273

III. Synthesis of Nucleosides Halogenated in the Sugar Moiety 273IV. Synthesis of Nucleotides Halogenated in the Pyrimidine Moiety 274V. Synthesis of Halogenated Nucleic Acid 274

B. Stability of Nucleosides 275C. Steric Effects 277D. Ionization Effects 277E. Molecular Conformation 278

Metabolism 279A. Anabolism 279B. Catabolism 282C. Enzyme Inhibition ; 285D. Augmentation of Utilization of Halogenated Deoxyribonucleosides 288

I. Inhibition of Thymidylate Synthetase 288II. Inhibition of Nucleoside Phosphorylase 289

III. Inhibition of Pyrimidine Degradation 290IV. Complex Formation 291V. Alteration of Structure 291

VI. Improved Regimens 291

Physical Effects of Incorporation of Halogenated Uracil Derivatives into DNA . . . . 292A. Increased Lability to Stress 292B. Increased Density 292C. Increased Temperature (Tm) for DNA Denaturation 292D. Decreased pH for DNA Denaturation 294E. Increased Sensitivity to Heat Degradation 294

XIV Table of Contents

Biological Consequences of Incorporation of Halogenated Uracil Derivatives into DNA 295A. Mutagenic Effects 295B. Inhibition of Cellular Division 297

I. Cell Culture 297II. Animals 300

C. Inhibition of Viral Replication 302D. Effect on Oncogenic Viruses 307E. Effects on Transformation, Conjugation, and Transduction 308F. Inhibition of Antibody Production 309G. Effects on Embryonic Development and Differentiation 310H. Toxicity 313

Marker Function 314

Radiosensitization 318

Clinical Use 322

Mode of Inhibition 325

Conclusions 326

References 327

Chapter 45

Azapyrimidine Nucleosides. J. SKODA. With 3 Figures

Introduction 348

Review of Existing Azapyrimidine Nucleosides 348A. 6-Azapyrimidine Nucleosides 348B. 5-Azapyrimidine Nucleosides 350C. 6-Azauridine 351

I. Molecular Mechanism of Inhibitory Effects 351II. Biological Effects 354

1. Virostatic Activity 3542. Antineoplastic Effects 3553. Immunosuppressive Activity 3564. Cholesterol and Lipid Changes Induced by 6-Azauridine 3565. Embryotoxic Effects 356

III. Pharmacological Studies 358IV. Clinical Application 360

1. Virostatic Effects 3602. Antineoplastic and Antihyperplastic Effects 3603. Effect on Psoriasis 361

D. 5-Azacytidine 361I. Molecular Mechanism of Inhibitory Action 361

II. Biological Effects in Animal Systems 362III. Clinical Studies 363

References 364

Chapter 46

Showdomycin, 5-Hydroxyuridine, and 5-Aminouridine. D. W. VISSEB. With 1 Figure

Introduction 373

Chemistry of Showdomycin 373

Metabolism of Showdomycin 373

Inhibitory Effects of Showdomycin 374

Chemistry and Metabolism of 5-Hydroxyuridine 376

Inhibitory Effects of 5-Hydroxyuridine 377

Table of Contents XV

Chemistry, Metabolism, and Inhibitory Effects of 5-Aminouridine 379

References 381

Chapter 47

6-Thiopurines. A. R. P. PATEBSON and DAVID M. TIDD. With 1 Figure

Introduction 384

Metabolism of 6-Mercaptopurine and 6-Methylthioinosine 385A. Anabolism 385

I. 6-Thioinosinate 385II. 6-Methylthioinosinate 385

III. 6-Thioxanthylate 386IV. Other Anabolites of 6-Mercaptopurine 386V. 6-Thioinosine 387

B. Catabolism 387Metabolism of 6-Thioguanine 387

A. Anabolism 387I. 6-Thioguanosine Phosphates 387

II. Deoxythioguanosine Phosphates 388III. Other Anabolites of 6-Thioguanine 388IV. 6-Thioguanosine and ;3-2'-Deoxythioguanosine 388

B. Catabolism 389Metabolic Effects of 6-Mercaptopurine and 6-Methylthioinosine 389

A. The Free Base, 6-Mercaptopurine 389B. Nucleotide Anabolites 390

I. Inhibition of Purine Ribonucleotide Synthesis de novo 390II. Inhibition of Purine Ribonucleotide Interconversions 392

III. Incorporation into DNA 392IV. Resistance to 6-Mercaptopurine 393V. Conclusions 393

Metabolic Effects of 6-Thioguanine 393A. The Free Base, 6-Thioguanine 394B. Nucleotide Anabolites 394

I. Inhibition of Purine Ribonucleotide Synthesis de novo 394II. Inhibition of Purine Ribonucleotide Interconversions 395

III. Incorporation into DNA 395IV. Delayed Cytotoxicity 396V. Conclusions 396

Combination Chemotherapy 397

References 397

Chapter 48

Azathioprine. GERTBTTDE B. ELION and GEOEGE H. HITCHINGS

Introduction (Basic Aspects) 404

Biochemical Effects 404

Biological Effects 405A. Classes of Lymphocytes and Their Interactions 405B. Effects on Cells in Vitro 405C. Effects on the Immune Response 407

I. Antibody Formation 407II. Cell-Borne Immunity 407

D. Antitumor Effects 408I. In Rodents 408

II. In Man 408E. Comparison of 6-Mercaptopurine and Azathioprine 409

XVI Table of Contents

Clinical Pharmacology 409A. Toxicity 409B. Tissue Distribution 411C. Metabolism of Azathioprine 411

I. Introduction 411II. Urinary Metabolites 411

1. 35S-Azathioprine 4112. "C-Azathioprine 412

III. Blood Levels 4131. a5S-Azathioprine 4132. 14C-Azathioprine 4133. Rosette Inhibitory Activity (RIA) 413

IV. Effect of Disease Conditions 4141. Renal Insufficiency 4142. Gout 4143. Lesch-Nyhan Syndrome 4144. Liver Disease 414

D. Teratology 415I. Chromosome Studies 415

II. Teratogenesis in Laboratory Animals 415III. Clinical Experience 415

E. Effects on Immunological Status 416I. Tests for Immunological Reactivity 416

II. Infections 416III. Carcinogenesis 417

Conclusions 418

References 419

Chapter 49

Purine Arabinosides, Xylosides, and lyxosides. G. A. LEPAGE. With 1 Figure

Introduction 426

9-/?-D-Arabinofuranosyladenine (Ara-A) 427

9-/S-D-Arabinofuranosylguanine (Ara-G) 428

9-jS-D-Arabinofuranosylhypoxanthine (Ara-H) 429

9-^-D-Arabinofuranosyl-6-Mercaptopurine (Ara-6-MP) 429

9-jS-D-Arabinofuranosyl-6-Thioguanine (Ara-TG) 430

9-j3-D-Xylofuranosyladenine (Xyl-A) 430

9-j3-D-Xylofuranosyl-6-Mercaptopurine (Xyl-6-MP) 430

9-/3-D-Xylofuranosyl-6-Thioguanine (Xyl-TG) 431

9-/?-D-Lyxofuranosyladenine (Lys-A) 431

9-/S-D-Lyxofuranosyl-6-Mercaptopurine (Lyx-6-MP) 431

References 431

Chapter 50

Antibiotics Resembling Adenosine: Tubercidin, Toyocamycin, Sangivamycin, Formycin,Psicofuranine, and Decoyinine. CHARLES A. NICHOL. With 3 Figures

Introduction 434Pyrrolopyrimidine Nucleosides: Tubercidin, Toyocamycin, and Sangivamycin 435

A. Common Pathway of Biosynthesis 435B. Tubercidin: An Anabolic Analog of Adenosine 436C. Biochemical Basis for the Cytotoxicity of Tubercidin 437

Table of Contents XVII

I. Feedback Inhibition of Purine Nucleotide Biosynthesis by Tubercidin Mono-phosphate 437

II. Impairment of Some Vital Function of ATP 437III. Formation of an Analog of Cyclic AMP 438IV. Impairment of Some Reaction Depending on NAD Cofactors 438V. Formation of Fraudulent Macromolecules that can Impede Protein or Nucleic

Acid Synthesis 438VI. Different Action of Tubercidin in Cells of Different Origin 439

D. Comparison of Toyocamycin and Sangivamycin with Tubercidin 439E. Potential for Chemotherapy 440

Formycin 441A. Enzymatic Studies 442B. Biopolymers Containing Formycin 443C. Potential for Chemotherapy 444

Inosine Analogs: Formycin B and 7-Deazainosine 444A. Formycin B 444B. 7-Deazainosine 445

Psicofuranine, Decoyinine, and Mycophenolic Acid 445A. Rediscovered Antibiotics 446B. Biochemical Sites of Action 447

I. Psicofuranine 448II. Decoyinine 449

III. Mycophenolic Acid (MPA) 449C. Potential for Chemotherapy 451

Concluding Comments 451

References 452

Chapter 51

8-Azaguanine. R. E. PARKS, JB. , and K. C. AGARWAL

Introduction 458

Early Investigations 458

Pharmacological Behavior 459

Effect of 8-Azaguanine and Its Derivatives on Enzymes 459A. Degradative Enzymes 459B. Anabolic Enzymes 460C. Metabolic Enzymes 461D. RNA Polymerase, DNA Polymerase, and Ribonuclease (RNAase) 462

Effects of 8-Azaguanine on Protein Synthesis 463

Incorporation of 8-Azaguanine into Nucleic Acids 463

References 464

Chapter 52

Folate Antagonists. JOSEPH R. BEBTINO. With 2 Figures

Basic Considerations 468A. Structure and Mechanism of Action of Folate Antagonists 468B. Mechanism of Cell Death 469

Pharmacology of Folate Antagonists 471A. Absorption 471B. Transport 471C. Distribution of Folate Antagonists 472D. Metabolism 472

XVIII Table of Contents

E. Excretion 473F. Mechanisms of Drug Resistance 473

Clinical Application 474A. General Considerations 474B. Toxic Effects 474C. Treatment of Neoplastic Disease: General Principles 475D. Treatment of Specific Tumors 476

I. Choriocarcinoma 476II. Acute Leukemia 476

III. Head and Neck Cancer 477IV. Breast Cancer 477V. Lung Cancer 477

VI. Lymphoma 478VII. Brain Tumors 478

VIII. Primary or Metastatic Liver Tumors 478IX. Mycosis Fungoides 478X. Miscellaneous Solid Tumors 478

XI. Nonneoplastic Diseases 479

References 479

Chapter 53

Glutamine Antagonists. L. L. BENNETT, J B .

Introduction 484

Metabolic Effects of Glutamine Analogs 485A. Azaserine and DON 485

I. Isolation and General Biological Activity 485II. Inhibition of Purine Biosynthesis 486

III. Inhibition of Pyrimidine Biosynthesis 489IV. Inhibition of Synthesis of NAD 491V. Inhibition of Synthesis of Glucosamine 491

VI. Inhibition of Synthesis of Asparagine 491VII. Inhibition of Synthesis of Anthranilic Acid and p-Aminobenzoic Acid . . 492

VIII. Synthesis of Histidine 492IX. Effects on Glutaminase and Glutamine Synthetase 492X. Other Actions 493

XI. Mechanism of Growth Inhibition by Azaserine and DON 494B. Conjugates of DON 496C. Amide Derivatives of Glutamine: y-Glutamylhydrazide and y-Ar-Benzylglutamine 496D. O-Carbamyl-L-Serine and O-Carbazyl-L-Serine 497E. /S-Carbamyl-L-Cysteine 497F. Albizziin 498

Agents Affecting Synthesis and Degradation of Glutamine 498A. Inhibitors of Glutamine Synthetase 498B. Glutaminase 499

Glutamine Analogs as Antitumor Agents 499

Glutamine Analogs as Immunosuppressive Agents 502

References 502

Chapter 54

Cytotoxic Amino Acid Analogs. PAUL F. KBUSE, JR.

Introduction 512

Amino Acid Analogs and Anticancer Properties 513

A. Aspartic Acid and Asparagine 513

Table of Contents XIX

B. Basic Amino Acids 515I. Arginine 515

II. Histidine 517III. Lysine 518

C. Aromatic Amino Acids 519I. Phenylalanine 519

II. Tyrosine 520III. Tryptophan 521

D. Sulfur-Containing Amino Acids 521I. Methionine 521

II. Cysteine and Cystine 522E. Leucine, Isoleucine, Valine, and Other Amino Acids 523

I. Leucine, Isoleucine, and Valine 523II. Other Amino Acids 524

Amino Acid Analogs and Immunosuppression 525

Future Considerations 528

References 529

Chapter 55

Cytotoxic Analogs of Pyridine Nucleotide Coenzymes. L. S. DIETRICH. With 2 FiguresIntroduction 539Analogs of NAD 540References 542

Chapter 56

Triazenoimidazole Derivatives. Ti Li Loo. With 3 Figures

Introduction 544Chemistry 5445-(3,3-Dimethyl-l-Triazene) Imidazole-4-Carboxamide (DIC, NSC-45388) 5455-[3,3-6is(2-Chloroethyl)-l-Triazeno]Imidazole-4-Carboxamide (BIC, NSC-82196) . . . 548Structure-Activity Relationships 549References 550

Section F: Additional Cytotoxic Agents

Chapter 57

Cytotoxic Inhibitors of Protein Synthesis. ABTHUB P. GBOLLMAN. With 10 FiguresIntroduction 554Classification of Inhibitors 554Effects on Protein Synthesis and Polyribosome Structure 555Inhibitors 556

A. Harringtonine 556I. General 556

II. Mechanism of Action 556III. Other Cephalotaxus Alkaloids 557

B. Pactamycin 557I. General 557

II. Mechanism of Action 557C. Emetine 558

I. General 558II. Mechanism of Action 559

III. Structure-Activity Relationships 560

XX Table of Contents

IV. Effects on Synthesis of RNA 560V. Mechanism of Cytotoxicity 560

D. Cycloheximide 561I. General 561

II. Mechanism of Action 561III. Structure-Activity Relationships 562IV. Topological Similarity to the Ipecac Alkaloids 562V. Effects on Synthesis of RNA 563

E. Tylocrebrine 564I. General 564

II. Mechanism of Action 564F. Anisomycin 564

I. General 564II. Mechanism of Action 565

III. Structure-Activity Relationships 565G. Sparsomycin 565

I. General 565II. Mechanism of Action 566

H. Paederin 566I. General 566

II. Mechanism of Action 566References 567

Chapter 58Selective Interruption of BNA Metabolism by Chemotherapeutic Agents. HERBERT T.

ABELSON and SHELDON PENMAN. With 2 Figures

Introduction 571

Nucleolus 572

Nuclear Heterogeneous RNA (HnRNA) and Messenger RNA (mRNA) 574

4Sand5SRNA 576

Mitochondrial RNA 577

Some Examples of the Use of Selective Inhibitors 578

References 579

Chapter 59

Actinomycin D. IRVING H. GOLDBERG. With 2 Figures

Introduction 582

Site of Action in Mammalian Cells 583

Structural Features Required for Biological Activity 584

Models of Actinomycin Binding Site on DNA 586

Clinical Uses of Actinomycin D 589

Carcinogenicity of Actinomycin D 589

References 589

Chapter 60

Daunomycin (Daunorubicin) and Adriamycin. A. DIMABCO. With 17 Figures

Introduction 593

Chemistry 593

Activity on Normal and Neoplastic Cells in Vitro 594

Activity on Experimental Tumors 597

Table of Contents XXI

Biochemical Effects and Mechanisms of Action 597

Resistance to Daunomycin 606

Antiviral Activity 606

Pharmacological and Toxicological Studies 608

References 611

Chapter 61Chromomyctn, Olivomycin, and Mithramycin. G. F. GAUSE. With 2 Figures

Chemistry and Mechanism of Action 615Antitumor Activity 617

Pharmacology 619

Clinical Investigations 621References 621

Chapter 62Nogalamycin. B. K. BHUYAN and C. G. SMITH. With 1 Figure

Introduction 623Chemistry of Nogalamycin 623In Vitro Studies 623

A. Antibacterial Activity 623B. Cytotoxicity to Mammalian Cells 624C. Characteristics of Nogalamycin •— DNA Interaction 624D. Effects of Nogalamycin on RNA Synthesis 628E. Other Activities Inhibited by Nogalamyein 629F. Phase Specificity of Nogalamycin 629G. Comparative Biological Activity of Nogalamycin and Its Derivatives 629

In Vivo Studies 630A. Enzyme Synthesis in Regenerating Liver 630B. Whole Animal Toxicity 631C. Antitumor Activity 631

References 631

Chapter 63Streptonigrin. WILLIAM B. KREMER and JOHN LASZLO. With 4 Figures

Introduction 633

Biological Properties 634

Biochemical Effects 634Clinical Studies 638

Derivatives of Streptonigrin 639

References 640

Chapter 64Anthramycin. SUSAN B. HORWITZ. With 2 Figures

Introduction 642

Cytotoxic, Antimicrobial, and Chemosterilant Properties 642

XXII Table of Contents

Effects on Macromolecular Synthesis in Cultured Cells 644

Interaction of Anthramycin with DNA 644

Structure-Activity Relationships 646

Conclusions 647

References 647

Chapter 65

Camptothccin. SUSAN B. HoRwrrz. With 5 Figures

Introduction 649

Pharmacokinetics 650

Antitumor Properties 650

Effects on Cultured Cells 651

Effects on Mammalian Viruses 654

Structure-Activity Relationships 654

Mechanism of Action 654

Conclusions 655

References 655

Chapter 66

3'-Deoxyadenosine and Other Polynneleotide Chain Terminators. SUNE FBEDERIKSEN andHANS KLENOW

Introduction 657

Enzymatic Studies 658A. Deamination 658B. Phosphorylation 658

Effects of Phosphorylated Derivatives 659

Effects on Whole Cells 660A. Growth 660

I. 3'-Deoxyadenosine and 3'-Amino-3'-Deoxyadenosine 660II. 3'-Deoxyinosine and 3'-Deoxyadenosine NJ-Oxide 661

III. Other 3'-Deoxyribonucleosides 661IV. 3'-Amino Substituted Compounds 661V. 3'-Halogen Substituted Compounds 661

VI. 2',3'-Dideoxyribonucleosides 662B. Mitosis and Chromosomes 662C. Uptake and Metabolism 662

RNA Synthesis 663A. Ehrlich Ascites Cells 663B. HeLa Cells 664C. H.Ep. Cells 664

References 664

Chapter 67

Vinca Alkaloids and Colchicine. WILLIAM A. CREASEY. With 2 Figures

Introduction 670

Basic Considerations 671A. Chemical Nature and Structure-Activity Relationships 671

Table of Contents XXIII

I. Vinca Alkaloids 671II. Colchicine Derivatives 672

III. Podophyllotoxin and Griseofulvin 673B. Biological Activity 673

I. Mitotic Arrest 673II. Antitumor Effects 675

III. Anti-Inflammatory Action 675VI. Other Biological Effects 675

C. Microtubule Interaction 676D. Biochemical Effects 679

I. Nucleic Acid Biosynthesis 679II. Protein Biosynthesis 681

III. Lipid Metabolism 682IV. Miscellaneous Biochemical Effects 682

E. Metabolism and Distribution 683

Clinical Considerations 684A. Drugs, Dosage, and Administration 685B. Toxicity 686

The Place of the Vinca Alkaloids in the Chemotherapy of Cancer 687References 687

Chapter 68L-Asparaginase: Basic Aspeets. M. K. PATTERSON, JR.Introduction 695

Assay of Enzyme Activity 696

Distribution and Antitumor Activity 697Isolation and Purification 698

Properties and Structure 699A. D-Asparagine 700B. Glutamine 701C. 5-Diazo-4-Oxo-L-Norvaline (DONV) 701D. L-/?-Cyanoalanine 701E. /3-Aspartylhydroxamate 701F. jS-Methyl-L-Aspartate 701G. Macromolecules 701

Pharmacological Effects 703

Immunological Studies 705

Biochemical Studies 708

Toxicological Effects 710

Asparagine Synthetase 711

References 713

Chapter 69

L-Asparaginase: Current Status of Clinical Evaluation. HERBERT F. OETTGEN

Introduction 723

Properties of the Enzyme Preparation 723

Distribution and Elimination 724

Dose and Route of Administration 725

Effects of Asparaginase Therapy on Plasma Amino Acid Levels 725

Therapeutic Effects 725

XXIV Table of Contents

A. Spectrum of Response 725B. Relation of Incidence and Duration of Remissions to Dose and Schedule of Ad-

ministration of Asparaginase 730C. Central Nervous System Leukemia 732

D. Combination Therapy 732E. Resistance 733

Toxic Effects 734

Conclusions 739

Appendix 740

References 742

Chapter 70Procarbazine. DONALD J. REED. With 2 Figures

Introduction 747

Tumor Inhibition 747

Chemical Properties 747

Pharmacology 751

Metabolism 753

Mode of Action of Procarbazine 756

Clinical Aspects 759

References 760

Chapter 71

Bis-Guanylhydrazones. E. MIHICH. With 2 Figures

Introduction 766

Methylglyoxal-Ws-(Guanylhydrazone) and Aliphatic Derivatives 766A. Effects on Experimental Tumors 767

I. Tumor Sensitivity 767II. Structure-Activity Relationships 768

III. Combination Treatments 768B. Effects on Microorganisms 769

I. Bacteria and Protozoa 769II. Viruses 769

C. Pharmacological Studies 769I. Toxicological Effects 769

II. Disposition and Cellular Uptake 770III. Therapeutic Effects in Man 772

D. Mechanism of Action 773I. Relationships to Spermidine 776

II. Relationships to Nucleic Acids 776III. Relationships to Mitochondrial Functions 776

4,4'-Diacetyl-Diphenyl-Urea-6is(Guanylhydrazone) (DDUG) and Other Aromatic bis-(Guanylhydrazones) 777A. Effects on Experimental Tumors 777

I. Spectrum of Tumor Sensitivity 777II. Structure-Activity Relationships 778

III. Combination Treatments 779B. Pharmacological Studies 780

I. Toxicological Effects 780II. Disposition and Cellular Uptake 780

C. Mechanism of Action 781

Conclusions 782

References 783

Table of Contents XXV

Chapter 72

Clinical and Pharmacologie Effects of Hydroxyurea. IRWIN H. KRAKOFF

Introduction 789

Fate and Distribution 789

Teratogenic Effects 790

Mechanism of Action 790

Cell Cycle Specificity 791

Conclusions 791

References 791

Chapter 73

•-(N)-Heterocyclie Carboxaldehyde Thiosemicarbazones. KRISHNA C. AGRAWAL and ALANC. SARTORELLI. With 2 Figures

Introduction 793

Antineoplastic Activity 793A. Correlation of Ring Substitution with Tumor-Inhibitory Potency 795B. Correlative Studies of Chelating Potential with Antitumor Activity 798C. Combination Chemotherapy 799D. Clinical Studies 799

Antiviral Activity 800

Distribution and Metabolism 800

Biochemical Mechanism of Action 802

Conclusions 804

References 804

Chapter 74

l-(o-ChIorophenyl)-l-(p-Chlorophenyl)-2,2-Dichtoroethane (o,p'-DDD), an Adrenocorti-colytic Agent. JAMES A. STRAW and MICHAEL M. HART. With 1 Figure

Introduction 808

Pharmacology 809A. Absorption 809B. Distribution 809C. Metabolism 810D. Excretion 810

Effects on Adrenocortical Tissue 810A. Histologic and Ultrastructural Changes 810B. Effects on Steroid Production 811C. Mechanism of Action of o,p'-DDD 812

Extra-Adrenal Effects 813A. Effects on Steroid Metabolism 813B. Effects on Drug Metabolism 813C. Effects on Thyroxine Binding Globulin 814

Clinical Studies 814A. Patient Population 815B. Drug Treatment 815C. Clinical Results 815D. Side Effects and Toxicity 817

References 817

XXVI Table of Contents

Chapter 75

The Fhthalanilides. DAVID W. YESAIR and CHARLES J. KENSLEB. With 2 Figures

Introduction 820

Tumor-Inhibitory Activity and Toxicity 820

Metabolism 822

Biochemical Mechanism of Action 823

Conclusions 826

References 826

Chapter 76

Platinum Compounds. GLEN R. GALE. With 1 Figure

Introduction 829

Tumor-Inhibitory Activity 830

Toxicity of Platinum Compounds 831

Distribution of Tumor-Inhibitory Platinum Compounds 832

Biochemical Mechanism of Action 833

Addendum 836

References 839

Chapter 77

Metal Chelates of 3-Ethoxy-2-Oxobutyraldehyde bis (Thiosemicarbazone), HaKTS. DAVIDH. PETEBING and HAROLD G. PETERING. With 1 Figure

Introduction 841

Antineoplastic Activity of H8KTS 842

Metal Chelation and Antitumor Activity of H2KTS (Activity of Cu(II) KTS and ZnKTS) 843

Studies on the Mechanisms of Action of Cu(II)KTS 845

References 847

Chapter 78

Phleomycin and Bleomycin. PAUL PIETSCH. With 7 Figures

Introduction 850

General Properties 851A. Composition 851B. Physical Properties 852C. Spectral Features 852D. Permeability 855E. Range of Biological Activity 855

Actions 856A. Selective Inhibition of DNA Synthesis 856B. Receptivity of Target Sites 858C. Selective Inhibition of Cell Division 859D. Inhibition of Replicative RNA 859E. Arrest of Transcription 860F. Toxicity 860G. Effects on Genes 862

Reactions with DNA and Considerations of Mechanisms 862A. Reactions 862

Table of Contents XXVII

B. Polyphleomycin Model 866C. Cleaving of DNA 868

Bleomycin in Cancer Chemotherapy 869References 871

Chapter 79

Pharmacology of Newer Antineoplastic Agents. RICHARD H. ADAMSON. With 9 Figures

Introduction 877

Guanazole 877

Gallium 879

Hycanthone 879

Ellipticine and 9-Methoxyellipticine 881

Alanosine 882

Rifamycin SV and Derivatives 882

Tilorone Hydrochloride 884

ICRF159 885

Isophosphamide 886

Cyclocytidine 886

References 887

Addendum to

Cytotoxic Analogs of Pyrldlne Nueleotide Coenzymes. L. S. DIETRICH 891

Author Index 893

Subjeet Index 1035