The Pineal Gland and Cancer

Section I: Significance of the Pineal Gland and Its Hormone Melatonin.- 1 Some Historical Remarks Concerning Research on the Pineal Gland and Cancer.- References.- 2 Biology of the Pineal Gland and Melatonin in Humans.- 2.1 Introduction.- 2.2 The Pineal Gland in Animal Species.- 2.2.1 Structural Aspects, Innervation, and Pinealocyte Receptors.- 2.2.2 Melatonin (MEL) Synthesis and the Regulation of Its Day/Night Rhythm.- 2.2.3 The Influence of Light and Darkness on MEL Formation.- 2.2.4 The Function of MEL in Non-Human Mammals.- 2.2.5 Influence of Magnetic and Electromagnetic Fields on the Pineal Gland.- 2.3 The Human Pineal Gland and MEL.- 2.3.1 General Aspects.- 2.3.2 Release and Fate of MEL.- 2.3.3 Interindividual Variation of MEL Secretion.- 2.3.4 Day/Night Rhythm of MEL Formation in Humans.- 2.3.5 Influence of Light and Dark on MEL Secretion.- 2.3.6 Seasonal Differences in MEL Secretion.- 2.3.7 MEL Secretion in Old Age and Pineal Calcification.- 2.3.8 Various Factors Influencing MEL Secretion.- 2.3.9 MEL and Seasonal Affective Disorder.- 2.3.10 Electromagnetic and Magnetic Fields.- 2.3.11 Function of MEL in Humans.- 2.4 Conclusions.- References.- 3 The Role of Melatonin in the Neuroendocrine System: Multiplicity of Sites and Mechanisms of Action.- 3.1 Melatonin Is a Universal Time-Related Signal.- 3.2 Sites of Melatonin Action Are Multiple.- 3.3 Melatonin Promotes GABAergic Responses in SCN and the Brain.- 3.4 Melatonin Acts on Cells Through cAMP- and Non-cAMP-Signal Transduction Pathways.- 3.5 Melatonin Interacts with Cytoskeletal Proteins.- 3.6 Melatonin Exerts Antioxidant Effects.- 3.7 Melatonin Restores Amplitude of Circadian Rhythm in Chronic Inflammation or Aging.- 3.8 Concluding Remarks.- References.- 4 The Pineal Gland and Chronobiologic History: Mind and Spirit as Feedsidewards in Time Structures for Prehabilitation.- 4.1 Introduction.- 4.2 Render Measurable What as Yet Is Not: Emotion, Mind, and Spirit.- 4.3 Let Us Learn That We Do Not Know Even What We Should Know.- 4.4 Tarquini and Pineal Gland History.- 4.5 Anatomical-Clinical Associations.- 4.6 The Homeostatic Melatonin Era.- 4.7 Sampling and Assessing Chronomes.- 4.8 Subtle Human Melatonin Rhythms.- 4.9 Pineal Gland and Adrenal Cortex, Feedsidewards.- 4.10 Circaseptans.- 4.11 The Need for Dense Sampling Before the Ruling Out of Rhythms and Presence of Melatonin.- 4.12 A Controversy Resolved.- 4.13 Summary.- References.- 5 Melatonin Involvement in Cancer: Methodological Considerations.- 5.1 Introduction.- 5.2 Chronoradiotherapy.- 5.3 Historical Perspective.- 5.4 Chronochemotherapy.- 5.5 Need for Marker Rhythmometry.- 5.6 Chronorisk.- 5.7 Rhythm Scrambling.- 5.8 Lessons from Studies on Pituitary Grafts With and Without a Hypothalamus.- 5.9 Methodological Considerations.- 5.9.1 Specificity.- 5.9.2 Risk Versus Disease.- 5.9.3 Melatonin as an Oncostatic Drug: Importance of Timing.- 5.9.4 Coordination Via Feedsidewards: Importance of Circaseptans.- 5.9.5 Environmental Effects from Near and Far.- 5.10 Concluding Remarks.- References.- Section II: Effect of Tumor Growth on the Production and Secretion of Pineal Melatonin.- 6 Analysis of Melatonin in Patients with Cancer of the Reproductive System.- 6.1 Introduction.- 6.2 Methodological Considerations and Problems Encountered in Estimating the Function of the Pineal Gland in Cancer Patients.- 6.2.1 Analytical Methods.- 6.2.2 Parameters Interfering with the Estimation of Pineal Function in Patients.- 6.3 Studies on Patients with Breast Cancer.- 6.4 Studies on Patients with Gynecological Cancers.- 6.4.1 Endometrial Cancer.- 6.4.2 Ovarian Cancer.- 6.5 Studies on Patients with Prostate Cancer.- References.- 7 Melatonin in Patients with Cancer of Extra-Reproductive Location.- 7.1 Introduction.- 7.2 Patients and Methods.- 7.3 Results.- 7.3.1 Nocturnal Urinary aMT6s Excretion in Cancer Patients.- 7.3.2 Correlations of Nocturnal Urinary aMT6s Excretion with Immunocytochemical Parameters Measured in Gastrointestinal and Lung Cancer.- 7.3.3 Correlations Among Intratumoral Parameters in Gastrointestinal Cancers.- 7.4 Discussion.- 7.4.1 Melatonin Secretion in Human Cancer Patients.- 7.4.2 Correlation Between MT Production and Proliferative Activity in Tumor Cells.- 7.4.3 Correlation Among Tumoral Parameters.- 7.5 Conclusion.- References.- 8 The Modulation of Melatonin in Tumor-Bearing Animals: Underlying Mechanisms and Possible Significance for Prognosis.- 8.1 Introduction.- 8.2 Studies with Chemically-Induced Mammary Cancers.- 8.2.1 Acute Effects of DMBA-Administration on Circulating Melatonin: Evidence for an Induction of the Hepatic Degradation of the Hormone.- 8.2.2 The Effects of DMBA-Induced Mammary Tumor Growth on Circulating Melatonin and the Pineal Melatonin Biosynthetic Pathway.- 8.3 Studies with Serial Transplants Derived from DMBA-Induced Mammary Cancers.- 8.3.1 Early Passage: Localized Carcinosarcoma.- 8.3.2 Late Passages: Metastasizing Sarcoma.- 8.4 Studies with Chemically Induced Colon Cancers.- 8.5 Conclusions and Considerations.- References.- 9 The Pineal Gland, Melatonin, and Neoplastic Growth: Morphological Approach.- 9.1 Introduction.- 9.2 Morphological Studies of Tumors Following Melatonin Treatment and Pinealectomy.- 9.3 Pineal Morphology in Tumor-Bearing Animals.- 9.4 Pineal Morphology in Human Malignancy.- References.- Section III: Effects of Melatonin and of Unidentified Pineal Products on Tumor Growth.- 10 In Vitro Effects of Melatonin on Tumor Cells.- 10.1 Introduction.- 10.2 Effects of Melatonin on Breast Cancer Cells.- 10.2.1 Effects of Melatonin on Proliferation of Breast Cancer Cells In Vitro.- 10.2.2 Effects of Melatonin on the Metastatic Behavior of Breast Cancer Cells.- 10.2.3 Influence of Melatonin on Active Cell Death of Mammary Cancer Cells.- 10.2.4 Mechanisms of the Oncostatic Action of Melatonin In Vitro.- 10.3 Effect of Melatonin on Melanoma Cells.- 10.4 Effect of Melatonin on Cancer Cells from Female Reproductive Organs.- 10.5 Effect of Melatonin on Other Neoplasms.- 10.6 Conclusions.- References.- 11 Melatonin and Colon Carcinogenesis.- 11.1 Introduction.- 11.2 Effect of Melatonin on Colon Carcinoma Development.- 11.2.1 Inhibitory Effect of Melatonin on 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis in Rats.- 11.2.2 Effect of Melatonin on Colon Tumor Growth In Vitro and In Vivo.- 11.3 Early Stages of 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis As Targets for the Effect of Melatonin.- 11.3.1 Effect of Melatonin on the Genotoxic Action of 1,2-Dimethylhydrazine.- 11.3.2 Effect of a Single 1,2-Dimethylhydrazine Administration on Free Radical Processes in Rats.- 11.3.3 Effect of Melatonin on Free Radical Processes in Rats.- 11.3.4 Carbohydrate and Lipid Metabolism in Rats Exposed to a Single Dose of 1,2-Dimethylhydrazine.- 11.3.5 Effect of 1,2-Dimethylhydrazine on the Neuroendocrine System of Rats.- 11.4 Effect of Melatonin on Late Stages of 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis.- 11.4.1 Free Radical Processes in Rats with Colon Tumors Induced by 1,2-Dimethylhydrazine: Effect of Melatonin.- 11.4.2 Effect of Melatonin on Proliferative Activity and Apoptosis in Colon Mucosa and Colon Tumors Induced by 1,2-Dimethylhydrazine in Rats.- 11.4.3 Pineal Function in Rats with Colon Tumors Induced by 1,2-Dimethylhydrazine.- 11.4.4 Melatonin-Containing Cells in the Intestinal Mucosa of Rats with 1,2-Dimethylhydrazine-Induced Colon Tumors: Effect of Exogenous Melatonin.- 11.4.5 Disturbances in Carbohydrate and Lipid Metabolism During Carcinogenesis Induced by 1,2-Dimethylhydrazine in Rats.- 11.4.6 Effect of Melatonin on Carbohydrate and Lipid Metabolism in Rats with Colon Tumors Induced by 1,2-Dimethylhydrazine.- 11.4.7 Possible Effect of Melatonin on the Immune System in Rats Exposed to 1,2-Dimethylhydrazine.- 11.5 Conclusion.- References.- 12 Role of Extrapineal Melatonin and Related APUD Series Peptides in Malignancy.- 12.1 Introduction.- 12.2 Extrapineal Melatonin: Cellular Localization, Role, and Significance Within the Diffuse Neuroendocrine System.- 12.3 Extrapineal MT and APUD Series Peptides: Possible Participation in Endogenous Mechanisms of Tumor Growth.- 12.4 Extrapineal Melatonin and Tumor Radiosensitivity: New Approaches for Modification of Antitumor Therapy.- 12.5 General Conclusion and Future Perspectives.- References.- 13 A Survey of the Evidence That Melatonin and Unidentified Pineal Substances Affect Neoplastic Growth.- 13.1 Introduction.- 13.2 The Role of the Pineal Hormone Melatonin.- 13.2.1 The Effects of Melatonin in Relation to Malignant Growth.- 13.2.2 The Effects of Melatonin in Relation to the Immune System and Stress.- 13.3 Effects of Yet Unknown Pineal Substances on Malignant Cells in Culture.- 13.3.1 Extracts of Ovine Pineal Glands.- 13.3.2 Extracts of Rat Pineals.- 13.3.3 Studies on an Unidentified Bovine Pineal Substance Which Inhibits MCF-7 Cell Growth in Vitro.- 13.4 Possible Presence of Kynurenines and Kynurenamines in Pineal Extracts.- 13.5 The Possible Significance of a Bovine Pineal Gland-Derived Decapeptide for the Growth of Malignant Cells in Vivo.- 13.6 Summary.- References.- 14 Experimental Studies of the Pineal Gland Preparation Epithalamin.- 14.1 Introduction.- 14.2 Epithalamin - a Low Molecular Weight Peptide Preparation.- 14.3 Effect of Epithalamin on the Life Span of Mice, Rats, and Drosophila melanogaster.- 14.4 The Influence of Epithalamin on the Function of the Nervous, Endocrine, and Immune Systems of Young and Old Rats.- 14.5 The Effect of Epithalamin on Spontaneous Tumor Development in Rats and Mice.- References.- Section IV: Mechanisms of Action of Melatonin on Tumor Cells.- A. Actions Via the Endocrine System.- 15 An Overview of the Neuroendocrine Regulation of Experimental Tumor Growth by Melatonin and Its Analogues and the Therapeutic Use of Melatonin in Oncology.- 15.1 Introduction.- 15.2 Effects of Melatonin and Its Analogues on Experimental Cancer Growth.- 15.2.1 Melatonin and Breast Cancer.- 15.2.2 Melatonin and Melanoma.- 15.2.3 Melatonin and Sarcoma.- 15.2.4 Melatonin and Other Tumors.- 15.3 Melatonin Binding in Neoplastic Tissues.- 15.3.1 Mouse Melanoma.- 15.3.2 Hamster Melanoma.- 15.3.3 Human Melanoma.- 15.3.4 Murine Mammary Cancer.- 15.3.5 Human Breast Cancer.- 15.3.6 Human Benign Prostatic Hyperplasia.- 15.3.7 Other Immortalized Cell Lines.- 15.4 Potential Melatonin Signal Transduction Mechanisms in Neoplastic Cells.- 15.4.1 Cyclic AMP and G Proteins.- 15.4.2 Phosphoinositide Metabolism.- 15.4.3 Nonmelatonin Receptor Expression.- 15.4.4 Transcriptional Regulation.- 15.4.5 Genomic Interactions.- 15.4.6 Calcium/Calmodulin (Ca2+/CaM) and the Cytoskeleton.- 15.4.7 Redox Mechanisms: Glutathione and Nitric Oxide.- 15.4.8 Tumor Linoleic Acid Uptake and Metabolism.- 15.5 Melatonin in the Chemoendocrine Therapy of Human Malignancies.- 15.6 Conclusions.- References.- 16 Modulation of the Estrogen Response Pathway in Human Breast Cancer Cells by Melatonin.- 16.1 Introduction.- 16.2 Melatonin and Breast Cancer.- 16.3 Melatonin Receptors.- 16.3.1 Membrane-Associated, G Protein-Linked Melatonin Receptors.- 16.3.2 Nuclear Melatonin Receptors.- 16.4 Melatonin and the Estrogen Response Pathway.- 16.4.1 Melatonin Modulation of ER Expression.- 16.4.2 Melatonin Modulation of Estrogen-Regulated Genes.- 16.4.3 Melatonin Modulation of ER Transactivation.- 16.5 Conclusions.- References.- 17 Benign and Tumor Prostate Cells as Melatonin Target Sites.- 17.1 Effects of Melatonin on the Prostate Gland In Vivo.- 17.2 Melatonin Action in Prostate Epithelial Cells In Vitro.- 17.2.1 Benign Prostate Hypertrophy Cells.- 17.2.2 Prostate Cancer Cells.- 17.3 Melatonin Action in Prostate Epithelial Cells: Towards a Unifying Hypothesis.- References.- B. Actions Via the Immune System.- 18 Neuroimmunomodulation Via the Autonomic Nervous System.- 18.1 Introduction.- 18.2 Adrenergic In Vivo Effects on Immune Functions.- 18.3 Cholinergic Immunomodulation.- 18.4 Conclusions.- References.- 19 Melatonin and Immune Functions.- 19.1 Evidence of an Immunoregulatory Role of Melatonin (MEL).- 19.2 Protective Effects of MEL on ?2-Adrenergic Immunosuppression in Rats.- 19.3 CD4+ Lymphocytes and Monocytes/Macrophages as Targets of MEL Activity.- 19.4 Possible Mechanisms of Action of MEL on Immune Cells.- 19.4.1 MEL Membrane Receptors on Immune Cells.- 19.4.2 MEL as a Ligand for the Nuclear Receptors RZR-? and RZR-?.- 19.4.3 MEL as a Calmodulin Antagonist.- 19.4.4 MEL as Antioxidant.- 19.5 Conclusion.- References.- 20 Melatonin and the Immune System: Therapeutic Potential in Cancer, Viral Diseases, and Immunodeficiency States.- 20.1 Neuroimmune Interactions with the Environment.- 20.2 Melatonin and the Immune-Hematopoietic System.- 20.2.1 Functional Effects.- 20.2.2 Cytokines Which Mediate the Effect of Melatonin.- 20.2.3 Melatonin Receptors.- 20.2.4 Clinical Trials.- 20.2.5 Mechanism of Action.- 20.3 Conclusion.- References.- 21 Melatonin Rhythms in Mice: Role in Autoimmune and Lymphoproliferative Diseases.- 21.1 Introduction.- 21.2 Melatonin Endogenous Rhythm in Mice.- 21.3 The Role of Pineal Gland and Melatonin in Autoimmune and Lymphoproliferative Diseases.- 21.3.1 Autoimmune Diabetes.- 21.3.2 Collagen-Induced Arthritis.- 21.3.3 Induced T Cell Leukemia.- 21.4 Conclusions.- References.- 22 Mechanisms Involved in the Immunomodulatory Effects of Melatonin on the Human Immune System.- 22.1 Introduction.- 22.2 Effects of Melatonin on the Immune System.- 22.3 Mechanisms of Action of Melatonin: The Membrane Receptor.- 22.4 Nuclear Receptors for Melatonin in the Immune System.- 22.5 The Physiological Role of Membrane Receptors Versus Nuclear Receptors.- References.- C Actions Via Neural Pathways.- 23 The Role of the Pineal Gland in Neural Control of Cell Proliferation in Healthy and Malignant Tissue.- 23.1 Introduction.- 23.2 The Role of the Autonomic Nervous System in the Control of Normal and Neoplastic Crypt Cell Proliferation in the Gut.- 23.3 Efferent Neural Connections Between the Pineal Gland and the Autonomic Nervous System.- 23.4 The Enteric Nervous System and Its Possible Role in Neural Control of Crypt Cell Proliferation in the Normal Gut. Is It Suitably Located?.- 23.5 Neural Control of Normal Cell Proliferation in Organs Other Than the Gastrointestinal System.- 23.6 The Precise Role of the Pineal Gland in the Normal Mechanism of Control of Proliferation in the Gastrointestinal Tract.- 23.7 The Role of the Pineal Gland in Induction or Promotion of Malignancy: How Important is It?.- 23.8 Further Consideration of the Role of Melatonin in the Control of Normal Crypt Cell Proliferation in the Gut.- 23.9 The Possible Role of the Pineal as a Modulator of Neuroendocrine Activity in Controlling Tumor Growth (Rather Than a Direct Effect Via the Autonomic Nervous System or Changes in the Level of Melatonin Secretion).- 23.10 The Relationship Between Pinealectomy and Melatonin Levels in the Body.- 23.11 Are Any Other Possible Antitumor Factors Produced by the Pineal Gland Besides Melatonin, and Could These Be Involved in the Physiological Control of Malignancy?.- 23.12 Relationship of Pinealectomy and Its Effects on the Intestinal Crypts with Similar Effects on the Crypts Associated with Limbic Lesions.- 23.13 Is it Possible That the Pineal Gland Acts Directly on the Crypts Via the Limbic System and the Autonomic Nervous System?.- 23.14 Does the Pineal Gland Act on the Crypts Via the Limbic System Indirectly by Affecting the General Level of Excitability of the Brain, i. e. Not a Specific Effect on the Limbic System?.- 23.15 Conclusions.- References.- D. Molecular Mechanisms of Action.- 24 Reactive Oxygen Species, DNA Damage, and Carcinogenesis: Intervention with Melatonin.- 24.1 Introduction.- 24.2 Endogenous Oxidative Damage to DNA.- 24.3 Reactive Oxygen Species and DNA Damage.- 24.4 Lipid Peroxidation and DNA Damage.- 24.5 Melatonin as a Free Radical Scavenger.- 24.6 Melatonin as an Antioxidant.- 24.7 Concluding Remarks.- References.- 25 Could the Antiproliferative Effect of Melatonin Be Exerted Via the Interaction of Melatonin with Calmodulin and Protein Kinase C?.- 25.1 Introduction.- 25.2 Calmodulin Involvement in Cell Proliferation: Effects of Melatonin.- 25.3 Protein Kinase C Involvement in Cell Proliferation: Effects of Melatonin.- 25.4 Concluding Remarks.- References.- Section V: Oncotherapeutic Potential of Melatonin.- 26 Efficacy of Melatonin in the Immunotherapy of Cancer Using Interleukin-2.- 26.1 Introduction.- 26.2 Materials and Methods.- 26.3 Results.- 26.4 Discussion.- References.- 27 Melatonin Cancer Therapy.- 27.1 Introduction.- 27.2 Undisputed Biological Effects of Melatonin in Human Beings.- 27.3 Melatonin Affects Sleep and Body Temperature.- 27.4 Light, Melatonin and the Manipulation of Circadian Orientation.- 27.5 The Pineal, Melatonin, and Cancer.- 27.6 Circadian Cytokinetic Rhythms.- 27.7 Melatonin in Human Cancer Therapy.- 27.8 Does Melatonin Benefit Human Beings with Cancer?.- 27.9 Lissoni’s Broad Phase II Trials.- 27.10 Lissoni’s Disease-Specific Randomized Controlled Clinical Trials of Melatonin.- 27.11 Lissoni’s Randomized Controlled Trials of Melatonin Plus Interleukin-2 vs Interleukin-2 Alone.- 27.12 Melatonin Trials of Other Investigators.- 27.13 Minimal Clinical Trial Design for the Productive Study of Melatonin.- 27.14 A Useful Melatonin Study Design.- 27.15 Objective, Physiologic Measurement of Fatigue Needed.- 27.16 Chronobiology and Drug Development.- References.- Section VI: Electromagnetic Fields and Cancer: The Possible Role of Melatonin.- 28 Circadian Disruption and Breast Cancer.- 28.1 Background.- 28.2 Light and Melatonin.- 28.3 Electric and Magnetic Fields and Melatonin.- 28.4 Breast Cancer in Blind Women.- 28.5 Conclusion.- References.- 29 Breast Cancer and Use of Electric Power: Experimental Studies on the Melatonin Hypothesis.- 29.1 Introduction.- 29.2 The Melatonin Hypothesis.- 29.3 Effect of ELF MFs on Melatonin Levels.- 29.4 Effect of ELF MFs on Breast Tissue Proliferation.- 29.5 Effect of ELF MFs on Mammary Carcinogenesis.- 29.6 Effect of ELF MFs on Immune Responses to Tumor Formation.- 29.7 Magnetic Field Exposure and Breast Cancer: Conclusions.- References.- 30 Magnetic Field Exposure and Pineal Melatonin Production (Mini-Review).- 30.1 Introduction.- 30.2 Circadian Rhythm of Melatonin Secretion.- 30.3 The Response of the Pineal Gland to Electromagnetic Fields: Role of Duration and Intensity of Exposure.- 30.4 Effect of Magnetic Field Exposure on Humans.- 30.5 Comments.- References.- 31 Nocturnal Hormone Profiles in Healthy Humans Under the Influence of Pulsed High-Frequency Electromagnetic Fields.- 31.1 Introduction.- 31.2 Materials and Methods.- 31.2.1 Subjects.- 31.2.2 Experimental Procedure.- 31.2.3 Protocol.- 31.2.4 Nocturnal Hormone Profiles.- 31.2.5 Data Analysis.- 31.3 Results.- 31.4 Discussion.- References.- 32 Weak High-Frequency (Radiofrequency, Microwave) Electromagnetic Fields: Epidemiological Evidence of Their Impact on Cancer Development and Reproductive Outcome.- 32.1 Introduction.- 32.2 Studies.- 32.2.1 Cancer Studies.- 32.2.2 Studies on Reproduction.- 32.3 Conclusions.- 32.3.1 Cancer Studies.- 32.3.2 Studies on Reproduction.- References.