Today, the basic mood of researchers and clinical investigators, both at the center and on the periphery of interferon studies, is optimistic regarding the future of interferons as therapeutic substances. Many also feel these polypeptides will prove invaluable probes in unraveling certain fundamental biochemical processes which control the life cycle and developmental pattern of many human cells. In contrast, only a year or two ago, this optimism had given way to an attitude almost of disenchantment as public and scientific expectations were raised steeply, then rapidly waned, as it turns out, prematurely. Both the mUltiple actions of interferons (a virtual cascade of biochemical reactions may be induced, as documented herein) and the high visibility of interferon research provided by the millions of dollars invested both by national health agencies and by multinational pharmaceutical companies, contributed to an upsweep in public attention to drug development probably unprecedented in this century. Virtually every oncologist, it would seem, was plagued by requests for the experimental agent, although they already had therapies of more proven value. As recently as 1980, even though interferon had achieved success against certain cancers and certain viral diseases, the variability in clinical results was seemingly ever present and little evidence emerged to suggest interferons could cure advanced diseases. Why then the resurgence of an optimistic mood? There are almost always many elements which contribute to happiness, and this is certainly true of the broad frontier of interferon and its place in biochemical research and treatment.

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1 Interferons and Their Applications: Past, Present, and Future.- A. Introduction.- B. Interferon Research: The Beginnings.- C. The Current Windfall in Interferon Research.- D. Clinical Applications.- I. Viral Infections.- II. Cancer.- E. Looking Ahead.- I. Tasks for the Laboratory.- II. Challenges for Clinical Investigators.- F. Future Prospects.- G. Possible Socioethical Problems.- H. Conclusion.- References.- 2 Assay of Interferons. With 1 Figure.- A. Introduction.- B. Bioassays.- I. Cytopathic Effect Inhibition Assay.- 1. Subjective Endpoints.- 2. Objective CPE Inhibition Assays.- II. Plaque Reduction Assays.- III. Virus Yield Reduction Assays.- 1. Reduction in Infectious Virus Yield.- 2. Hemagglutinin Yield Reduction.- 3. Inhibition of Retrovirus Reverse Transcriptase.- 4. Neuraminidase Yield Reduction.- 5. Inhibition of Viral RNA Synthesis.- IV. Other Assays.- 1. Hemadsorption Inhibition Assay.- 2. Immunofluorescent Cell-Counting Assay.- 3. Reduction of DNA Synthesis.- 4. Other Assays of Limited Use.- V. A Reference Bioassay.- C. Data Analysis, Unitage, and Standardization.- I. Dose-Response Curves.- 1. Construction of Graphical Representations.- 2. Factors Affecting Slope and Assay Results.- II. Determination of Variability of Assay Results.- III. Standards.- 1. Calibration of Assay.- 2. Use of Laboratory and International Standards.- D. Interferon Standards.- I. Derivation.- II. Quality.- III. Stability and Its Prediction.- IV. Use and Limitations of Standards.- V. Sources of Standards.- E. Radioimmunoassays.- F. Summary.- References.- 3 Evolution of Interferon Genes. With 11 Figures.- A. Introduction.- B. Coding Region Nucleotide Sequence.- C 3? Noncoding Region Nucleotide Sequence.- D. Structural Evolution of the 3? Noncoding Region.- E. Coding Region Amino Acid Sequence.- F. Concluding Remarks.- References.- 4 Comparative Analysis of Interferon Structural Genes With 2 Figures.- A. Introduction.- B. Molecular Cloning of Some Human IFN-? cDNA and Chromosomal Genes.- C. Molecular Cloning of a Human IFN-? cDNA and Its Chromosomal Gene.- D. Comparative Structure of Some IFN-? and -? mRNAs and Proteins Deduced from cDNA Clones.- I. The Coding Regions.- II. The Signal Peptides.- III. The Noncoding Regions.- E. Comparative Structure of Some IFN-? and -?1 Chromosomal Genes.- F. Other Human IFN-? and -? Genes.- G. Chromosomal Localization.- H. IFN Structural Genes in Other Species.- J. Conclusions.- References.- 5 Comparative Structures of Mammalian Interferons With 9 Figures.- A. Introduction.- B. Purification and Characterization of Native Interferons.- I. Human Interferons-?.- 1. Purification.- 2. Characterization.- II. Human Interferon-?.- 1. Purification.- 2. Characterization.- III. Human Interferon-?.- IV. Mouse Interferons.- V. Comparison of Amino Acid Sequences of Human and Mouse Interferons.- C. Purification and Characterization of rDNA-Derived Interferons.- I. Human Interferons-?.- II. Human Interferons-?.- III. Human Interferons-?.- D. Protein Structure and Interferon Activity.- I. Disulfide Bonds.- II. Physical Studies.- 1. rDNA-Derived Interferons.- 2. Interferon Fragments.- III. Effect of Sequence Changes on Activity.- 1. NH2 Terminal Variations.- 2. COOH Terminal Variations.- 3. cDNA-Encoded Analogs.- IV. Carbohydrate Content.- 1. Native Human Interferons-?.- 2. Native Human Interferons-?.- 3. Native Human Interferons-?.- 4. Native Mouse Interferons.- E. Structure Prediction.- References.- 6 Regulatory Control of Interferon Synthesis and Action With 6 Figures.- A. Regulatory Control of IFN Synthesis.- I. Introduction.- II. Human IFN Genes.- 1. A Multigene Family.- 2. Location of IFN Genes.- III. Regulation of IFN Synthesis.- 1. Superinduction.- 2. Cellular RNA Metabolism During Induction.- IV. Virus-Resistant Cell Mutants.- B. Regulatory Control of IFN Action.- I. Introduction.- II. Genetic Factors Controlling Sensitivity to ifN.- 1. Human Chromosome 21.- 2. Mouse Genes for Sensitivity to ifN.- III. Other Factors Influencing IFN Action.- 1. Antiviral Activity.- 2. Nonantiviral Activities.- IV. Clinical Considerations.- 1. IFN Therapy.- 2. Combination Therapy.- 3. "Misregulation" of IFN Action.- References.- 7 Application of Recombinant DNA Technology to Expression of Human Interferon Genes.- A. Introduction.- B. General Comments on the Experimental Strategies for Cloning IFNs.- I. Specific Comments on Cloning IFN-?.- II. Specific Comments on Cloning IFN-?.- III. Cloning IFN-7.- C. Comments on Strategies for IFN Production in rDNA Hosts.- D. Examples of Findings Directly Derived from Cloning Experiments.- I. Multigene Families.- II. Chromosomal Clustering of IFN-? and IFN-?.- III. Absence of Introns in IFN-? and IFN-?1.- IV. Species and Tissue Specificity of IFNs.- References.- 8 The Molecular Mediators of Interferon Action With 2 Figures.- A. Introduction.- B. The Inhibition of Protein Synthesis by Double-Stranded RNA.- C. 2?,5?-01igo(A).- I. 2?,5?-01igo(A) Polymerase.- II. 2?,5?-01igo(A)-Activated Endonuclease (RNAse L).- III. Degradation of 2?,5?-01igo(A).- D. Degradation of Viral RNA in Infected Cells.- I. The Localized Activation of 2?,5?-01igo(A) Polymerase-RNAse L.- II. The Requirement for Double-Stranded RNA.- E. Other Antiviral Mechanisms.- I. Protein Kinase Activated by Double-Stranded RNA.- II. Other Metabolic Changes in Interferon-Treated Cells.- F. Conclusions.- References.- 9 The Cellular Effects of Interferon.- A. Introduction.- B. Cell Growth Inhibition by IFN.- I. Assay Systems.- 1. Viable Cell Counts.- 2. Colony Formation.- 3. Measurement of Macromolecular Synthesis.- II. Variables in Analysis of Growth Inhibition by IFN.- 1. Cell Type.- 2. Type of IFN.- 3. Conditions of IFN Treatment.- 4. Reversibility of IFN Effect.- III. Proof That Cell Growth Inhibitor Is IFN.- 1. Physical/Chemical Proof.- 2. Neutralization by Antiserum.- 3. Purification.- 4. Cell Mutants Resistent to IFN.- C. Effects of IFN on Cell Cycle.- D. Other Cellular Effects of IFN.- I. Morphology.- II. Mobility.- III. Physiologic Cell Responses to IFN.- IV. Phagocytosis.- V. Interaction with Chemicals or Factors Affecting Growth.- VI. Anticellular Effects of 2?,5?-01igonucleotide.- VIL Effect on Synthesis of Specific Proteins.- VIII. Cell Membrane-Associated Changes.- IX. IFN Effects on Cyclic Nucleoti…