ISBN: 3-540-64051-7
TITLE: The Pineal Gland and Cancer
AUTHOR: Bartsch, C.; Bartsch, H.; Blask, D.E.; Cardinali, D.P.; Hrushesky, W.J.M.; Mecke, Dieter (Eds.)
TOC:

Section I: Significance of the Pineal Gland and Its Hormone Melatonin 1 
1 Some Historical Remarks Concerning Research 
on the Pineal Gland and Cancer 
Vera Lapin 3 
References 4 
2 Biology of the Pineal Gland and Melatonin in Humans 
Lutz Vollrath 5 
2.1 Introduction 5 
2.2 The Pineal Gland in Animal Species 5 
2.2.1 Structural Aspects, Innervation, and Pinealocyte Receptors 6 
2.2.2 Melatonin (MEL) Synthesis and the Regulation of Its Day/Night Rhythm 9 
2.2.3 The Influence of Light and Darkness on MEL Formation 11 
2.2.4 The Function of MEL in Non-Human Mammals 12 
2.2.5 Influence of Magnetic and Electromagnetic Fields 
on the Pineal Gland 12 
2.3 The Human Pineal Gland and MEL 13 
2.3.1 General Aspects 13 
2.3.2 Release and Fate of MEL 14 
2.3.3 Interindividual Variation of MEL Secretion 15 
2.3.4 Day/Night Rhythm of MEL Formation in Humans 16 
2.3.5 Influence of Light and Dark on MEL Secretion 18 
2.3.6 Seasonal Differences in MEL Secretion 19 
2.3.7 MEL Secretion in Old Age and Pineal Calcification 20 
2.3.8 Various Factors Influencing MEL Secretion 21 
2.3.9 MEL and Seasonal Affective Disorder 22 
2.3.10 Electromagnetic and Magnetic Fields 23 
2.3.11 Function of MEL in Humans 24 
2.4 Conclusions 28 
References 29 
3 The Role of Melatonin in the Neuroendocrine System: 
Multiplicity of Sites and Mechanisms of Action 
Daniel P. Cardinali, Rodolfo A. Cutrera, Luis I. Brusco, Ana I. Esquifino 50 
3.1 Melatonin Is a Universal Time-Related Signal 50 
3.2 Sites of Melatonin Action Are Multiple 51 
3.3 Melatonin Promotes GABAergic Responses in SCN and the Brain 52 
3.4 Melatonin Acts on Cells Through cAMP- 
and Non-cAMP-Signal Transduction Pathways 54 
3.5 Melatonin Interacts with Cytoskeletal Proteins 55 
3.6 Melatonin Exerts Antioxidant Effects 56 
3.7 Melatonin Restores Amplitude of Circadian Rhythm 
in Chronic Inflammation or Aging 58 
3.8 Concluding Remarks 61 
References 61 
4 The Pineal Gland and Chronobiologic History: 
Mind and Spirit as Feedsidewards in Time Structures for Prehabilitation 
Franz Halberg, Germaine Cornlissen,Ario Conti, Georges J.M. Maestroni, 
Cristina Maggioni, Federico Perfetto, Roberto Salti, Roberto Tarquini, 
George S. Katinas, Othild Schwartzkopff 66 
4.1 Introduction 67 
4.2 Render Measurable What as Yet Is Not: Emotion, Mind, and Spirit 70 
4.3 Let Us Learn That We Do Not Know Even What We Should Know 72 
4.4 Tarquini and Pineal Gland History 74 
4.5 AnatomicalClinical Associations 75 
4.6 The Homeostatic Melatonin Era 76 
4.7 Sampling and Assessing Chronomes 77 
4.8 Subtle Human Melatonin Rhythms 79 
4.9 Pineal Gland and Adrenal Cortex, Feedsidewards 85 
4.10 Circaseptans 87 
4.11 The Need for Dense Sampling Before the Ruling Out of Rhythms 
and Presence of Melatonin 89 
4.12 A Controversy Resolved 91 
4.13 Summary 95 
References 100 
Appendix 104 
5 Melatonin Involvement in Cancer: Methodological Considerations 
Germaine Cornlissen, Franz Halberg, Federico Perfetto, 
Roberto Tarquini, Cristina Maggioni, Lennart Wetterberg 117 
5.1 Introduction 118 
5.2 Chronoradiotherapy 125 
5.3 Historical Perspective 125 
5.4 Chronochemotherapy 126 
5.5 Need for Marker Rhythmometry 126 
5.6 Chronorisk 128 
5.7 Rhythm Scrambling 130 
5.8 Lessons from Studies on Pituitary Grafts 
With and Without a Hypothalamus 130 
5.9 Methodological Considerations 131 
5.9.1 Specificity 131 
5.9.2 Risk Versus Disease 132 
5.9.3 Melatonin as an Oncostatic Drug: Importance of Timing 137 
5.9.4 Coordination Via Feedsidewards: Importance of Circaseptans 139 
5.9.5 Environmental Effects from Near and Far 142 
5.10 Concluding Remarks 142 
References 143 
Section II: 
Effect of Tumor Growth on the Production and Secretion of Pineal Melatonin 151 
6 Analysis of Melatonin in Patients with Cancer 
of the Reproductive System 
Christian Bartsch, Hella Bartsch, Dieter Mecke 153 
6.1 Introduction 154 
6.2 Methodological Considerations and Problems Encountered 
in Estimating the Function of the Pineal Gland in Cancer Patients 154 
6.2.1 Analytical Methods 154 
6.2.2 Parameters Interfering with the Estimation 
of Pineal Function in Patients 156 
6.3 Studies on Patients with Breast Cancer 158 
6.4 Studies on Patients with Gynecological Cancers 165 
6.4.1 Endometrial Cancer 165 
6.4.2 Ovarian Cancer 167 
6.5 Studies on Patients with Prostate Cancer 168 
References 171 
7 Melatonin in Patients with Cancer of Extra-Reproductive Location 
Tatiana V. Kvetnaia, Igor M. Kvetnoy, Hella Bartsch, Christian Bartsch, 
Dieter Mecke 177 
7.1 Introduction 177 
7.2 Patients and Methods 179 
7.3 Results 180 
7.3.1 Nocturnal Urinary aMT6s Excretion in Cancer Patients 180 
7.3.2 Correlations of Nocturnal Urinary aMT6s Excretion 
with Immunocytochemical Parameters 
Measured in Gastrointestinal and Lung Cancer 182 
7.3.3 Correlations Among Intratumoral Parameters 
in Gastrointestinal Cancers 182 
7.4 Discussion 183 
7.4.1 Melatonin Secretion in Human Cancer Patients 183 
7.4.2 Correlation Between MT Production 
and Proliferative Activity in Tumor Cells 189 
7.4.3 Correlation Among Tumoral Parameters 189 
7.5 Conclusion 190 
References 191 
8 The Modulation of Melatonin in Tumor-Bearing Animals: 
Underlying Mechanisms and Possible Significance for Prognosis 
Hella Bartsch, Christian Bartsch, Dieter Mecke 197 
8.1 Introduction 198 
8.2 Studies with Chemically-Induced Mammary Cancers 198 
8.2.1 Acute Effects of DMBA-Administration on Circulating Melatonin: 
Evidence for an Induction of the Hepatic Degradation of the Hormone 199 
8.2.2 The Effects of DMBA-Induced Mammary Tumor Growth 
on Circulating Melatonin and the Pineal Melatonin Biosynthetic Pathway 200 
8.3 Studies with Serial Transplants Derived 
from DMBA-Induced Mammary Cancers 202 
8.3.1 Early Passage: Localized Carcinosarcoma 202 
8.3.2 Late Passages: Metastasizing Sarcoma 203 
8.4 Studies with Chemically Induced Colon Cancers 205 
8.5 Conclusions and Considerations 205 
References 206 
9 The Pineal Gland, Melatonin, and Neoplastic Growth: 
Morphological Approach 
Michal Karasek 210 
9.1 Introduction 210 
9.2 Morphological Studies of Tumors Following Melatonin Treatment 
and Pinealectomy 211 
9.3 Pineal Morphology in Tumor-Bearing Animals 212 
9.4 Pineal Morphology in Human Malignancy 213 
References 216 
Section III: Effects of Melatonin and of Unidentified Pineal Products on Tumor Growth 219 
10 In Vitro Effects of Melatonin on Tumor Cells 
Samuel Cos, Emilio J. Snchez-Barcel 221 
10.1 Introduction 221 
10.2 Effects of Melatonin on Breast Cancer Cells 222 
10.2.1 Effects of Melatonin on Proliferation of Breast Cancer Cells In Vitro 222 
10.2.2 Effects of Melatonin on the Metastatic Behavior of Breast Cancer Cells 225 
10.2.3 Influence of Melatonin on Active Cell Death of Mammary Cancer Cells 227 
10.2.4 Mechanisms of the Oncostatic Action of Melatonin In Vitro 227 
10.3 Effect of Melatonin on Melanoma Cells 230 
10.4 Effect of Melatonin on Cancer Cells from Female Reproductive Organs 232 
10.5 Effect of Melatonin on Other Neoplasms 233 
10.6 Conclusions 235 
References 235 
11 Melatonin and Colon Carcinogenesis 
Vladimir N. Anisimov 240 
11.1 Introduction 240 
11.2 Effect of Melatonin on Colon Carcinoma Development 241 
11.2.1 Inhibitory Effect of Melatonin on 1,2-Dimethylhydrazine-Induced 
Colon Carcinogenesis in Rats 241 
11.2.2 Effect of Melatonin on Colon Tumor Growth In Vitro and In Vivo 243 
11.3 Early Stages of 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis 
As Targets for the Effect of Melatonin 243 
11.3.1 Effect of Melatonin on the Genotoxic Action of 1,2-Dimethylhydrazine 244 
11.3.2 Effect of a Single 1,2-Dimethylhydrazine Administration 
on Free Radical Processes in Rats 246 
11.3.3 Effect of Melatonin on Free Radical Processes in Rats 246 
11.3.4 Carbohydrate and Lipid Metabolism in Rats Exposed 
to a Single Dose of 1,2-Dimethylhydrazine 246 
11.3.5 Effect of 1,2-Dimethylhydrazine on the Neuroendocrine System 
of Rats 247 
11.4 Effect of Melatonin on Late Stages of 1,2-Dimethylhydrazine-Induced 
Colon Carcinogenesis 248 
11.4.1 Free Radical Processes in Rats with Colon Tumors Induced 
by 1,2-Dimethylhydrazine: Effect of Melatonin 248 
11.4.2 Effect of Melatonin on Proliferative Activity 
and Apoptosis in Colon Mucosa and Colon Tumors Induced 
by 1,2-Dimethylhydrazine in Rats 248 
11.4.3 Pineal Function in Rats with Colon Tumors Induced 
by 1,2-Dimethylhydrazine 250 
11.4.4 Melatonin-Containing Cells in the Intestinal Mucosa of Rats 
with 1,2-Dimethylhydrazine-Induced Colon Tumors: 
Effect of Exogenous Melatonin 252 
11.4.5 Disturbances in Carbohydrate and Lipid Metabolism 
During Carcinogenesis Induced by 1,2-Dimethylhydrazine in Rats 252 
11.4.6 Effect of Melatonin on Carbohydrate and Lipid Metabolism in Rats 
with Colon Tumors Induced by 1,2-Dimethylhydrazine 253 
11.4.7 Possible Effect of Melatonin on the Immune System 
in Rats Exposed to 1,2-Dimethylhydrazine 253 
11.5 Conclusion 254 
References 255 
12 Role of Extrapineal Melatonin and Related APUD Series Peptides 
in Malignancy 
Igor M. Kvetnoy, Tatiana V. Kvetnaia,Vadim V.Yuzhakov 259 
12.1 Introduction 259 
12.2 Extrapineal Melatonin: Cellular Localization, Role, 
and Significance Within the Diffuse Neuroendocrine System 261 
12.3 Extrapineal MT and APUD Series Peptides: 
Possible Participation in Endogenous Mechanisms of Tumor Growth 263 
12.4 Extrapineal Melatonin and Tumor Radiosensitivity: 
New Approaches for Modification of Antitumor Therapy 267 
12.5 General Conclusion and Future Perspectives 270 
References 271 
13 A Survey of the Evidence That Melatonin and Unidentified Pineal 
Substances Affect Neoplastic Growth 
Ietskina Ebels, Bryant Benson 275 
13.1 Introduction 276 
13.2 The Role of the Pineal Hormone Melatonin 277 
13.2.1 The Effects of Melatonin in Relation to Malignant Growth 277 
13.2.2 The Effects of Melatonin in Relation to the Immune System and Stress 280 
13.3 Effects of Yet Unknown Pineal Substances on Malignant Cells in Culture 281 
13.3.1 Extracts of Ovine Pineal Glands 281 
13.3.2 Extracts of Rat Pineals 282 
13.3.3 Studies on an Unidentified Bovine Pineal Substance 
Which Inhibits MCF-7 Cell Growth in Vitro 283 
13.4 Possible Presence of Kynurenines and Kynurenamines 
in Pineal Extracts 288 
13.5 The Possible Significance of a Bovine Pineal Gland-Derived Decapeptide 
for the Growth of Malignant Cells in Vivo 288 
13.6 Summary 289 
References 290 
14 Experimental Studies of the Pineal Gland Preparation Epithalamin 
Vladimir Kh. Khavinson,V.G. Morozov,Vladimir N. Anisimov 294 
14.1 Introduction 294 
14.2 Epithalamin  a Low Molecular Weight Peptide Preparation 295 
14.3 Effect of Epithalamin on the Life Span of Mice, Rats, 
and Drosophila melanogaster 296 
14.4 The Influence of Epithalamin on the Function of the Nervous, Endocrine, 
and Immune Systems of Young and Old Rats 299 
14.5 The Effect of Epithalamin on Spontaneous Tumor Development 
in Rats and Mice 302 
References 303 
Section IV: Mechanisms of Action of Melatonin on Tumor Cells 307 
A. Actions Via the Endocrine System 309 
15 An Overview of the Neuroendocrine Regulation 
of Experimental Tumor Growth by Melatonin and Its Analogues 
and the Therapeutic Use of Melatonin in Oncology 
David E. Blask 309 
15.1 Introduction 309 
15.2 Effects of Melatonin and Its Analogues on Experimental Cancer Growth 310 
15.2.1 Melatonin and Breast Cancer 311 
15.2.2 Melatonin and Melanoma 317 
15.2.3 Melatonin and Sarcoma 318 
15.2.4 Melatonin and Other Tumors 320 
15.3 Melatonin Binding in Neoplastic Tissues 322 
15.3.1 Mouse Melanoma 322 
15.3.2 Hamster Melanoma 323 
15.3.3 Human Melanoma 323 
15.3.4 Murine Mammary Cancer 323 
15.3.5 Human Breast Cancer 324 
15.3.6 Human Benign Prostatic Hyperplasia 325 
15.3.7 Other Immortalized Cell Lines 325 
15.4 Potential Melatonin Signal Transduction Mechanisms 
in Neoplastic Cells 326 
15.4.1 Cyclic AMP and G Proteins 326 
15.4.2 Phosphoinositide Metabolism 326 
15.4.3 Nonmelatonin Receptor Expression 327 
15.4.4 Transcriptional Regulation 327 
15.4.5 Genomic Interactions 328 
15.4.6 Calcium/Calmodulin (Ca^{2+}/CaM) and the Cytoskeleton 328 
15.4.7 Redox Mechanisms: Glutathione and Nitric Oxide 329 
15.4.8 Tumor Linoleic Acid Uptake and Metabolism 331 
15.5 Melatonin in the Chemoendocrine Therapy of Human Malignancies 332 
15.6 Conclusions 335 
References 335 
16 Modulation of the Estrogen Response Pathway 
in Human Breast Cancer Cells by Melatonin 
Steven M. Hill, Todd Kiefer, Stephenie Teplitzky, Louaine L. Spriggs, 
Prahlad Ram 343 
16.1 Introduction 343 
16.2 Melatonin and Breast Cancer 344 
16.3 Melatonin Receptors 345 
16.3.1 Membrane-Associated, G Protein-Linked Melatonin Receptors 345 
16.3.2 Nuclear Melatonin Receptors 347 
16.4 Melatonin and the Estrogen Response Pathway 348 
16.4.1 Melatonin Modulation of ER Expression 348 
16.4.2 Melatonin Modulation of Estrogen-Regulated Genes 349 
16.4.3 Melatonin Modulation of ER Transactivation 350 
16.5 Conclusions 352 
References 355 
17 Benign and Tumor Prostate Cells as Melatonin Target Sites 
Nava Zisapel 359 
17.1 Effects of Melatonin on the Prostate Gland In Vivo 359 
17.2 Melatonin Action in Prostate Epithelial Cells In Vitro 360 
17.2.1 Benign Prostate Hypertrophy Cells 360 
17.2.2 Prostate Cancer Cells 362 
17.3 Melatonin Action in Prostate Epithelial Cells: 
Towards a Unifying Hypothesis 363 
References 363 
B. Actions Via the Immune System 365 
18 Neuroimmunomodulation Via the Autonomic Nervous System 
Konrad Schauenstein, Ingo Rinner, Peter Felsner, 
Albert Wlfler, Helga S. Haas, J. Ross Stevenson, Werner Korsatko, 
Peter M. Liebmann 365 
18.1 Introduction 365 
18.2 Adrenergic In Vivo Effects on Immune Functions 366 
18.3 Cholinergic Immunomodulation 367 
18.4 Conclusions 368 
References 369 
19 Melatonin and Immune Functions 
Peter M. Liebmann, Albert Wlfler, Konrad Schauenstein 371 
19.1 Evidence of an Immunoregulatory Role of Melatonin (MEL) 371 
19.2 Protective Effects of MEL on alpha_2-Adrenergic Immunosuppression 
in Rats 372 
19.3 CD4^+ Lymphocytes and Monocytes/Macrophages 
as Targets of MEL Activity 373 
19.4 Possible Mechanisms of Action of MEL on Immune Cells 374 
19.4.1 MEL Membrane Receptors on Immune Cells 375 
19.4.2 MEL as a Ligand for the Nuclear Receptors RZR-alpha and RZR-beta 376 
19.4.3 MEL as a Calmodulin Antagonist 377 
19.4.4 MEL as Antioxidant 378 
19.5 Conclusion 379 
References 379 
20 Melatonin and the Immune System: 
Therapeutic Potential in Cancer,Viral Diseases, 
and Immunodeficiency States 
Georges J.M. Maestroni 384 
20.1 Neuroimmune Interactions with the Environment 384 
20.2 Melatonin and the Immune-Hematopoietic System 385 
20.2.1 Functional Effects 385 
20.2.2 Cytokines Which Mediate the Effect of Melatonin 386 
20.2.3 Melatonin Receptors 387 
20.2.4 Clinical Trials 388 
20.2.5 Mechanism of Action 388 
20.3 Conclusion 389 
References 391 
21 Melatonin Rhythms in Mice: 
Role in Autoimmune and Lymphoproliferative Diseases 
Ario Conti, Georges J.M. Maestroni 395 
21.1 Introduction 396 
21.2 Melatonin Endogenous Rhythm in Mice 397 
21.3 The Role of Pineal Gland and Melatonin in Autoimmune 
and Lymphoproliferative Diseases 398 
21.3.1 Autoimmune Diabetes 398 
21.3.2 Collagen-Induced Arthritis 400 
21.3.3 Induced T Cell Leukemia 402 
21.4 Conclusions 404 
References 406 
22 Mechanisms Involved in the Immunomodulatory Effects of Melatonin 
on the Human Immune System 
Juan M. Guerrero, Sofia Garcia-Maurio, David Pozo, 
Antonio Garcia-Pergaeda, Antonio Carrillo-Vico, Patrocinio Molinero, 
Carmen Osuna, Juan R. Calvo 408 
22.1 Introduction 408 
22.2 Effects of Melatonin on the Immune System 409 
22.3 Mechanisms of Action of Melatonin: The Membrane Receptor 410 
22.4 Nuclear Receptors for Melatonin in the Immune System 411 
22.5 The Physiological Role of Membrane Receptors 
Versus Nuclear Receptors 412 
References 414 
C. Actions Via Neural Pathways 417 
23 The Role of the Pineal Gland in Neural Control of Cell Proliferation 
in Healthy and Malignant Tissue 
Brian D. Callaghan 417 
23.1 Introduction 418 
23.2 The Role of the Autonomic Nervous System in the Control 
of Normal and Neoplastic Crypt Cell Proliferation in the Gut 418 
23.3 Efferent Neural Connections Between the Pineal Gland 
and the Autonomic Nervous System 420 
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? 421 
23.5 Neural Control of Normal Cell Proliferation in Organs 
Other Than the Gastrointestinal System 422 
23.6 The Precise Role of the Pineal Gland in the Normal Mechanism 
of Control of Proliferation in the Gastrointestinal Tract 422 
23.7 The Role of the Pineal Gland in Induction or Promotion of Malignancy: 
How Im portant is It? 423 
23.8 Further Consideration of the Role of Melatonin in the Control 
of Normal Crypt Cell Proliferation in the Gut 426 
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) 427 
23.10 The Relationship Between Pinealectomy and Melatonin Levels 
in the Body 428 
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? 429 
23.12 Relationship of Pinealectomy and Its Effects on the Intestinal Crypts 
with Similar Effects on the Crypts Associated with Limbic Lesions 430 
23.13 Is it Possible That the Pineal Gland Acts Directly on the Crypts 
Via the Limbic System and the Autonomic Nervous System? 430 
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? 431 
23.15 Conclusions 432 
References 434 
D. Molecular Mechanisms of Action 442 
24 Reactive Oxygen Species, DNA Damage, and Carcinogenesis: 
Intervention with Melatonin 
Russel J. Reiter 442 
24.1 Introduction 442 
24.2 Endogenous Oxidative Damage to DNA 443 
24.3 Reactive Oxygen Species and DNA Damage 444 
24.4 Lipid Peroxidation and DNA Damage 445 
24.5 Melatonin as a Free Radical Scavenger 447 
24.6 Melatonin as an Antioxidant 448 
24.7 Concluding Remarks 450 
References 451 
25 Could the Antiproliferative Effect of Melatonin Be Exerted 
Via the Interaction of Melatonin 
with Calmodulin and Protein Kinase C? 
Fernando Antn-Tay, Gloria Bentez-King 456 
25.1 Introduction 456 
25.2 Calmodulin Involvement in Cell Proliferation: Effects of Melatonin 457 
25.3 Protein Kinase C Involvement in Cell Proliferation: 
Effects of Melatonin 458 
25.4 Concluding Remarks 460 
References 460 
Section V: Oncotherapeutic Potential of Melatonin 463 
26 Efficacy of Melatonin in the Immunotherapy 
of Cancer Using Interleukin-2 
Paolo Lissoni 465 
26.1 Introduction 466 
26.2 Materials and Methods 467 
26.3 Results 468 
26.4 Discussion 472 
References 474 
27 Melatonin Cancer Therapy 
William J.M. Hrushesky 476 
27.1 Introduction 477 
27.2 Undisputed Biological Effects of Melatonin in Human Beings 477 
27.3 Melatonin Affects Sleep and Body Temperature 479 
27.4 Light, Melatonin and the Manipulation of Circadian Orientation 481 
27.5 The Pineal, Melatonin, and Cancer 482 
27.6 Circadian Cytokinetic Rhythms 485 
27.7 Melatonin in Human Cancer Therapy 495 
27.8 Does Melatonin Benefit Human Beings with Cancer? 496 
27.9 Lissoni's Broad Phase II Trials 497 
27.10 Lissoni's Disease-Specific Randomized 
Controlled Clinical Trials of Melatonin 497 
27.11 Lissoni's Randomized Controlled Trials 
of Melatonin Plus Interleukin-2 vs Interleukin-2 Alone 498 
27.12 Melatonin Trials of Other Investigators 498 
27.13 Minimal Clinical Trial Design for the Productive Study of Melatonin 499 
27.14 A Useful Melatonin Study Design 500 
27.15 Objective, Physiologic Measurement of Fatigue Needed 500 
27.16 Chronobiology and Drug Development 503 
References 504 
Section VI: Electromagnetic Fields and Cancer: The Possible Role of Melatonin 509 
28 Circadian Disruption and Breast Cancer 
Richard G. Stevens 511 
28.1 Background 511 
28.2 Light and Melatonin 513 
28.3 Electric and Magnetic Fields and Melatonin 514 
28.4 Breast Cancer in Blind Women 514 
28.5 Conclusion 515 
References 515 
29 Breast Cancer and Use of Electric Power: 
Experimental Studies on the Melatonin Hypothesis 
Wolfgang Lscher 518 
29.1 Introduction 518 
29.2 The Melatonin Hypothesis 519 
29.3 Effect of ELF MFs on Melatonin Levels 520 
29.4 Effect of ELF MFs on Breast Tissue Proliferation 521 
29.5 Effect of ELF MFs on Mammary Carcinogenesis 521 
29.6 Effect of ELF MFs on Immune Responses to Tumor Formation 527 
29.7 Magnetic Field Exposure and Breast Cancer: Conclusions 528 
References 530 
30 Magnetic Field Exposure and Pineal Melatonin Production (Mini-Review) 
Brahim Selmaoui, Yvan Touitou 534 
30.1 Introduction 534 
30.2 Circadian Rhythm of Melatonin Secretion 535 
30.3 The Response of the Pineal Gland to Electromagnetic Fields: 
Role of Duration and Intensity of Exposure 535 
30.4 Effect of Magnetic Field Exposure on Humans 536 
30.5 Comments 538 
References 539 
31 Nocturnal Hormone Profiles in Healthy Humans Under the Influence 
of Pulsed High-Frequency Electromagnetic Fields 
Klaus Mann, Peter Wagner, Christoph Hiemke, Clarissa Frank, 
Joachim Rschke 541 
31.1 Introduction 541 
31.2 Materials and Methods 542 
31.2.1 Subjects 542 
31.2.2 Experimental Procedure 543 
31.2.3 Protocol 543 
31.2.4 Nocturnal Hormone Profiles 543 
31.2.5 Data Analysis 544 
31.3 Results 544 
31.4 Discussion 547 
References 549 
32 Weak High-Frequency (Radiofrequency, Microwave) 
Electromagnetic Fields: Epidemiological Evidence 
of Their Impact on Cancer Development and Reproductive Outcome 
Detlev Jung, Dirk-Matthias Rose, Katja Radon 551 
32.1 Introduction 551 
32.2 Studies 552 
32.2.1 Cancer Studies 552 
32.2.2 Studies on Reproduction 559 
32.3 Conclusions 562 
32.3.1 Cancer Studies 562 
32.3.2 Studies on Reproduction 563 
References 563 
Subject Index 567 
END
