NEL, Melatonin: Clinical Significance and Therapeutic Application

R.J. Reiter, D.X. Tan & M. Allegra:
Melatonin: reducing molecular pathology and dysfunction due to "free radical and associated reactants
2002; 23 (suppl 1):3-8 pii:NEL230702R01 PMID:

Submitted: January 11, 2002 Accepted: January 14, 2002

Key words:
melatonin; oxidative stress; free radicals; antioxidant

Abstract
Endogenously produced metabolites of ground state oxygen are highly reactive and destructive to intracellular and extracellular molecules. The resulting damage, referred to as oxidative stress, leads to molecular and cellular dysfunction. The destruction of essential macromolecules by oxygen-based reactants is the basis of some diseases and is believed to be involved in the processes of aging. Free radical scavengers and antioxidants neutralize and/or metabolically remove reactive species from cells before they carry out their destructive activities. Melatonin is a highly ubiquitous direct free radical scavenger and indirect antioxidant. This brief report summarizes the interactions of melatonin with reactive species and identifies the resulting products. The paper also defines the melatonin antioxidant cascade wherein not only melatonin but at least one of the products, i.e., N1-acetyl-N2-formyl-5-methoxykynuramine, formed as a result of melatonin scavenging hydrogen peroxide is also a potent scavenger. The review summarizes the data which shows that melatonin is not only a pharmacologically useful free radical scavenger but that it functions in this capacity at physiological concentrations as well. Finally, this report identifies high oxidative stress situations in humans where melatonin has proven effective in reducing the severity of the disease state. In the last decade there have been hundreds of publications documenting melatonin's protective actions against a vast array of conditions, e.g., ischemia/reperfusion injury, toxin exposure, lipopolysaccharide exposure, etc., where free radical damage is a component of the condition.

Introduction
Intracellular hostilities are not uncommonly propagated by free radicals and associated reactive species. A number of reactants are generated as a consequence of the one, two and three electron reduction of molecular oxygen (O2) (Fig.1). Free radicals are molecules that have an unpair valence electron; this makes these molecules highly reactive and they often damage neighboring molecules by abstracting an electron from them. Besides the free radicals, there are other intermediates that do not possess an unpaired electron in their outer orbital, but that are, nevertheless, also highly reactive (Fig.1). Not all damaging reactants are derived from oxygen; some are nitrogen or chloride-based.
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D.P. Cardinali, L.I. Brusco, S.P. Lloret & A.M. Furio:
Melatonin in sleep disorders and jet-lag
2002; 23 (suppl 1):9-13 pii:NEL230702R02 PMID:

Abstract
In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency. This is particularly marked in Alzheimer's disease (AD) patients. Melatonin is effective to reduce significantly benzodiazepine use. In addition, melatonin administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from delayed sleep phase syndrome or jet lag. Urinary levels of 6-sulphatoxymelatonin decrease with age and in chronic diseases like AD or coronary heart disease. The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect).

Exogenous melatonin induces sleep in healthy subjects
The promoting effect of melatonin on sleep and sedation has been known since long. Such effect of melatonin is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect). Initial studies addressing the effect of melatonin on sleep made use of the i.v. or the intranasal route [1-3] or administered very large doses of the methoxyindole by the oral route [1, 4]. From these early studies it was concluded that melatonin reduces sleep latency and induces sleepiness and fatigue.
More recently, the effect of lower doses of melatonin were examined. These studies included young normal volunteers and patients with insomnia of different origins including Alzheimer's disease patients exhibiting sundowning syndrome [see 5]. In most instances melatonin significantly improved subjective and/or objective sleep parameters.
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M. Karasek, R.J. Reiter:
Melatonin and aging
2002; 23 (suppl 1):14-16 pii:NEL230702R03 PMID:

Abstract
Although many theories relating the pineal secretory product melatonin to aging have been put forward, the role of this agent in the aging process is not clear. However, there are several reasons to postulate a role for melatonin in this process. Melatonin levels fall gradually over the life-span. Melatonin is a potent free radical scavenger. Melatonin deficiency is related to suppressed immunocompetence. In at least one animal model melatonin supplementation increased life-span although several other studies have failed. The aging process is multifactorial, and no single element seems to be of basic importance. It seems, however, that although melatonin can not be univocally recognized as a substance delaying aging, some of its actions may be beneficial for the process of aging. However, the precise role of melatonin in the aging process remains to be determined.

Introduction
Although many theories relating the pineal secretory product melatonin to aging have been put forward, the role of this agent in the aging process is not clear. There are several reasons to postulate a role for melatonin in this process. First, melatonin participates in many vital life processes, and its secretion falls gradually over the life-span. Second, diminished melatonin secretion in advanced age may be related to deterioration of many circadian rhythms, as a consequence of a reduced function of suprachiasmatic nuclei. Third, recently discovered role of melatonin in scavengering of free radicals, and the proposed link between oxidative stress and aging itself as well as age-related diseases (such as neoplastic disease, Alzheimer and Parkinson diseases) suggest a role for melatonin in these processes. Fourth, melatonin acts as endogenous sleep-inducing agent, and its reduced concentrations may result in lowered sleep efficacy very often associated with advancing age. Finally, melatonin exhibits immunoenhancing properties, and suppressed immunocompetence has been implicated in the acceleration of aging processes.
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Key words:
melatonin; Alzheimer's disease; sleep disorders; cognitive impairment; aging

Abstract
About 45% of Alzheimer's disease (AD) patients have disruptions in their sleep and sundowning agitation. Since melatonin secretion is greatly inhibited in AD patients we have used melatonin to treat sleep disorders in AD patients since 1995. In a first study [21] we reported, in 7 out of 10 dementia patients treated with melatonin (3 mg p.o. at bed time), a decreased sundowning. In a second study [22] we examined 14 AD patients who received 9 mg melatonin daily for 22 to 35 months, observing a significant improvement of sleep quality with stabilization of behavioral and cognitive parameters. In a third study [23] we reported two monozygotic twins with AD and similar cognitive impairment, one of them receiving 6 mg melatonin at bedtime daily for 3 years. Melatonin treatment improved sleep quality and suppressed sundowning. We now report the effect of melatonin (4-month-long treatment with 6 mg/day) in 45 AD patients with sleep disturbances. Melatonin improved sleep and suppressed sundowning, an effect seen regardless of the concomitant medication employed to treat cognitive or behavioral signs of AD. Melatonin treatment seems to constitute a selection therapy to ameliorate sundowning and to slow evolution of cognitive impairment in AD patients.

Sleep disorders are common in Alzheimer's disease
The prevalence of Alzheimer's disease (AD) is rapidly increasing as a growing number of people are living to old age. Sleep disturbances are common, and highly disruptive, symptoms associated with AD. Approximately 4.5-5 million Argentines (13-15% of the national population) are 65 years or more. Approximately 450 000 Argentines are currently afflicted with AD and this number is expected to increase 3-4-fold over the next 50 years.
Crosssectional studies report that about 40% of AD patients have disruptions in their sleep [1, 2]. When sleep disturbances do occur, they constitute a significant physical and psychological stress for the caregiver and are frequently related to patient institutionalization. For these reasons, optimization in management of sleep disturbances is a treatment priority for AD patients.

M. Pawlikowski, K. Winczyk & M. Karasek:
Oncostatic action of melatonin: facts and question marks
2002; 23 (suppl 1):24-29 pii:NEL230702R05 PMID:

Abstract
The paper presents the data concerning the in vivo effects of melatonin on experimentally-induced tumors in animals and the in vitro effects on animal and human tumor cells.
The majority of experimental tumors responded to the melatonin treatment with growth inhibition. However, some negative or opposite results (i.e. stimulation of tumor instead of inhibition) were also reported. Some of the negative results can be attributed to the improper timing of melatonin administration. Melatonin was also shown to inhibit the growth of several animal and human tumor cell lines in vitro. On the basis of these experiments, a hypothesis of the oncostatic action of melatonin was put forward. The mechanism of the postulated action is complex and probably includes: 1) modulation of the endocrine system; 2) modulation of the immune system; 3) the direct oncostatic action of melatonin on tumor cells. The latter includes the recently discovered anti-oxidative action which probably plays an important role in the countering the DNA damage during the radiation challenge or the exposure to chemical carcinogens. It also includes the antiproliferative and pro-apoptotic effects exerted via melatonin receptors expressed by tumor cells. The involvement of the membrane melatonin receptors is mainly assumed. However, the recent data from our and other laboratories suggest also the involvement of RZR/ROR receptors (the putative melatonin nuclear receptors) in both melatonin-induced proliferation inhibition and apoptosis.

Introduction
The possible role of the pineal hormone, melatonin in combating cancer is very fascinating, but at the same time very controversial field of biomedical research. Since the discovery of melatonin numerous experiments investigating its effect on various experimentally-induced animal tumors in vivo and on both animal and human tumor cells in vitro have been performed. In the present paper we attempt to summarize these experiments and to discuss the mechanism of postulated oncostatic action of melatonin.
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C. Bartsch, H. Bartsch & M. Karasek:
Melatonin in clinical oncology
2002; 23 (suppl 1):30-38 pii:NEL230702R06 PMID:

Abstract
The aim of this article is provide a survey of the current knowledge relating to the analysis of melatonin and its administration to cancer patients. On the basis of this compilation of data it can be discussed under which conditions melatonin may be used for diagnostic and/or therapeutic purposes in clinical oncology.
Melatonin is depressed in patients with cancers of different origins during the phase of primary tumour growth whereas a normal or sometimes elevated pineal melatonin secretory activity is found during early stages of tumour development or when recidivations arise. The clinical studies of Lissoni show that melatonin, particularly if combined with interleukin-2, is able to favourably influence the course of advanced malignant disease leading to a prolonged survival as well as to an improved quality of life. These findings require to be verified by independent and controlled replication studies. If they can be confirmed it should be attempted to administer melatonin to patients with earlier stages of cancer parallel to standard oncological treatment regimens. In such trials it should be tested whether a substitutional therapy in patients with endogenously depressed melatonin may favourably affect the course of the disease both in quantitative (inhibitory effect on tumour growth and spread) and qualitative terms (improved performance status).

Introduction
In the 1970s it was reported that removal of the pineal gland or hypothalamic lesions stimulate the development and growth of solid malignant tumours in experimental animals [1, 2]. These findings indicated an involvement of the autonomic nervous system as well as of the pineal gland in malignancy. Subsequent studies attempted to clarify the possible mechanisms involved by testing the therapeutic effect of the pineal hormone melatonin on tumour-bearing animals as well as to analyse the levels of circulating melatonin in such animals. It was found that melatonin inhibits relatively well-differentiated malignant cancers such as DMBA-induced mammary tumours if administered in the late afternoon [3, 4]. Under such conditions melatonin is able to antagonize to a good extent the tumour-stimulatory effect of surgical or physiological pinealectomy due to constant light via neuroendocrine pathways involving prolactin and to a lesser extent also estradiol [5]. If such tumours become less differentiated during serial passaging losing their epithelial cell elements melatonin becomes less and less effective to influence such tumours [6]. Under in vitro conditions melatonin inhibits only a limited number of cell-lines, e.g. certain sub-clones of the mammary cell-line MCF-7, at physiological concentrations [7]. Many cell lines are, however, refractory to melatonin [8] and human primary cell cultures can even be stimulated by the pineal hormone [9]. To estimate the clinical potential of melatonin a survey is given regarding the results of both diagnostic and therapeutic studies in cancer patients.
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M. Karbownik:
Potential Anticarcinogenic action of melatonin and other antioxidants "mediated by antioxidative mechanisms
2002; 23 (suppl 1):39-44 pii:NEL230702R07 PMID:

Key words:
melatonin; protection; antioxidants; oxidative stress; carcinogens; DNA; membranes cancer initiation

Abstract
The complex process of carcinogenesis is, to a large extent, due to oxidative stress. Numerous indicators of oxidative damage are enhanced in the result of the action of carcinogens. Several antioxidants protect, with different efficacy, against oxidative abuse, exerted by carcinogens. Recently, melatonin (N-acetyl-5-methoxytryptamine) and some other indoleamines have gained particular meaning in the defense against oxidative stress and, consequently, carcinogenesis. Some antioxidants, like ascorbic acid, play a bivalent role in the antioxidative defense, revealing, under specific conditions, prooxidative effects. Among known antioxidants, melatonin is particularly frequently applied in experimental models of anticarcinogenic action. In the numerous studies, examining several parameters of oxidative damage and using several in vitro and in vivo models, this indoleamine has been shown to protect DNA and cellular membranes from the oxidative abuse caused by carcinogens. When either preventing or decreasing the oxidative damage to macromolecules, melatonin also protects against the initiation of cancer. The protection provided by melatonin and some other antioxidants against cellular damage, due to carcinogens, make them potential therapeutic supplements in the conditions of increased cancer risk.

There is a balance between the production and detoxification of reactive oxygen species (ROS) under physiological conditions [1, 2]. Any internal or external pathological factor, carcinogens included, may disrupt this balance, leading to conditions reffered to as oxidative stress; indeed, oxidative stress plays a significant role in the pathogenesis of cancer [3]. Oxidative stress participates in all the steps of carcinogenesis; at the first step, an initiation, free radical damage different molecules - DNA, lipids, and protein, leading directly or indirectly to mutations and, consequently, to cancer initiation [4].
The products of oxidative damage to DNA, lipid, and protein constitute markers of oxidative damage [5] but, at the same time, they may contribute per se to DNA damage and, in consequence, to cancer development [6-9]. For instance, 8-oxo-2'-deoxyguanosine (8oxodGuo), a product of DNA damage, is highly mutagenic [6, 7]. Numerous byproducts of lipid peroxidation damage DNA via different mechanisms [7, 8]. The oxidative damage to proteins may result in changes of enzyme activities and of some properties of membranes, like permeability, fluidity, signaling pathway, etc. [9].
Both endogenous and exogenous antioxidants can prevent the formation of early metabolites of the damage to macromolecules and, in this way, protect against cancer.

1.2. Potential mechanisms of the anticarcinogenic action of melatonin and of other antioxidants
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K. Skwarlo-Sonta:
Melatonin in immunity: comparative aspects
2002; 23 (suppl 1):61-66 pii:NEL230702R08 PMID:

Key words:
pineal gland; melatonin; immunity; chickens; mammals; thymic hormones; bursin; opioids

Abstract
Pineal gland, by the diurnal rhythm of synthesis and release of its principal hormone, melatonin (MEL), is involved in reciprocal relationships between neuroendocrine and immune systems, responsible for keeping internal homeostasis in vertebrate animals. In this paper the experimental data, indicating that both strategic (developmental, thus antigen independent) and emergency (evoked by antigenic activation of the mature immune system) levels of interactions between pineal gland and immune system, operate in mammals and birds, are reviewed. The cells and organs of immune system using membrane receptors as well as nuclear orphan receptors perceive MEL message. Effects exerted by MEL on immune parameters are different, and depend on several factors, including dose and way of MEL application, species, sex, age of animal, its immune system maturation, way of immune system activation, and parameter examined, as well as the season, circadian rhythm of both immunity and pineal gland function, stressful conditions, accompanying experimental procedure, etc. In turn, lymphoid organ-derived hormones and cytokines, soluble factors secreted by activated immune cells act as messages understood by the pineal gland, closing the regulatory loop of the bi-directional functional connections between both systems.

Introduction
Maintaining of homeostasis within the vertebrate' body is possible due to a strict cooperation between the neuroendocrine and immune systems. Both systems take important information from other sources (external environment and antigens, internal milieu, cognitive and non-cognitive stimuli, physical and psychical stress), and communicate intensively. In the healthy organism, there is a profound modulation of immune reactivity by neurotransmitters and hormones and conversely, immune cells-derived soluble mediators, cytokines, have an effect on neuroendocrine function. It means that the communication between neuroendocrine and immune systems includes the use of common signal and recognition molecules [1].
In the last two decades, the role of melatonin (MEL), the main neurohormone synthesized and released by the pineal gland, as a neuro-modulator has been examined extensively [2] and its participation in the immunomodulation has been accepted [3]. Due to its particular ability to transduce an external information on light, not perceived by both neuro- and endocrine systems, into a biochemical message understood by the whole body, pineal gland may be considered as a separate part of the homeostasis keeping system (Fig. 1). This message, consisting of the daily rhythm of MEL synthesis and release, is thereafter transmitted to the immune system using several intermediate mechanisms. These mechanisms will be discussed in the present paper. Moreover, the experimental data indicating that the pineal gland itself is able to receive the information from immune system will be presented as well.
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A. Lewinski & M. Karbownik:
Melatonin and the thyroid gland
2002; 23 (suppl 1):73-78 pii:NEL230702R09 PMID:

Key words:
melatonin; pineal gland; thyroid hormones; thyroid gland;
growth processes; cell proliferation; secretion

Abstract
This review briefly summarizes the published data on relationships observed between melatonin - the main pineal hormone, and the thyroid gland. The prevailing part of the survey is devoted to thyroid growth processes and function. A large experimental evidence exists suggesting the inhibitory action of melatonin on thyroid growth and function; this effect has been revealed by using different experimental models: by chronic and short-term melatonin administration in vivo, by light restriction, which is known to increase the activity of the pineal gland, by pinealectomy, etc., as well as by employing the in vitro conditions. Thus, much information has been accumulated, indicating - in experimental conditions - a mutual relationship between the pineal gland and the thyroid. The confirmation of these relations in clinical studies in humans meets numerous difficulties, resulting - among others - from the fact that, nowadays, human beings, as well as certain animal species, used in experimental studies, have been living far away from their natural and original habitat. It makes almost impossible to compare the results obtained in particular studies performed in different species, on the pineal-thyroid interrelationship.

Introduction
Melatonin (N-acetyl-5-methoxytryptamine) - the main secretory product of the pineal gland - displays several functions in living organisms. It is known for its role in seasonal reproductive physiology, circadian rhythmicity and sleep processes and for its ability to reduce the "jet lag" symptoms in humans [1]. Additionally, melatonin has been shown to modulate immune functions, growth processes and cancerogenesis, and oxidative processes [2-6]. The existing relationship between the pineal and the thyroid gland has been evidenced in result of numerous experimental studies. Several questions, however, still arise, namely:

2) are there any intermediate substances or factors involved in this regulation?;

3) is there a local (autocrine?) regulation of thyroid hormone secretion by melatonin in the thyroid gland?;

4) does melatonin participate in the control of thyroxine (T4) monodeiodination reaction, leading to triiodothyronine (T3) formation in peripheral tissues?;

5) are there any cells in the body capable to produce both thyroid hormones and melatonin?; etc.
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E. Sewerynek:
Melatonin and the cardiovascular system
2002; 23 (suppl 1):79-83 pii:NEL230702R10 PMID:

Key words:
melatonin; cardiovascular system; hypertension; hypercholesterolemia

Abstract
Melatonin concentrations in serum, as well as urinary levels of its main metabolite, 6sulphatoxymelatonin, decrease with age. In the course of aging, the frequency of heart diseases, both acute and chronic, systematically increases. The evidence from the last 10 years suggests that melatonin influences the cardiovascular system. The presence of vascular melatoninergic receptors/binding sites has been demonstrated; these receptors are functionally linked with vasoconstrictor or vasodilatory effects of melatonin. Melatonin can contribute in cardioprotection of the rat heart, following myocardial ischemia. It has been shown that patients with coronary heart disease have a low melatonin production rate, especially those with higher risk of cardiac infarction and/or sudden death. There are clinical data reporting some alterations of melatonin in human stroke and coronary heart disease. The suprachiasmatic nucleus and, possibly, the melatoninergic system may also modulate cardiovascular rhythmicity. Hypercholesterolemia and hypertension are the other age-related symptoms. People with high levels of LDL-cholesterol have low levels of melatonin. It has been shown that melatonin suppresses the formation of cholesterol by 38% and reduces LDL accumulation by 42%. A 10-20% reduction of cholesterol concentration in women using the B-oval pill has been observed. It is a very important because, even a 1015% reduction in blood cholesterol concentration has bee shown to result in a 20 to 30% decrease in the risk of coronary heart disease. People with hypertension have lower melatonin levels than those with normal blood pressure. The administration of the hormone in question declines blood pressure to normal range. It has been observed that melatonin, even in a dose 1 mg, reduced blood pressure and decreased catecholamine level after 90 min in human subjects. Melatonin may reduce blood pressure via the following mechanisms:

It is well known that melatonin concentrations in serum, as well as urinary levels of its main metabolite, 6sulphatoxymelatonin, decrease in elderly subjects [1]. In the course of aging, the incidence of heart diseases, both acute and chronic, systematically increases. The evidence from the last 10 years suggests that melatonin influences the cardiovascular system. Similarly to other organs and systems, the cardiovascular system exhibits diurnal and seasonal rhythms, including the heart rate, cardiac output, and blood pressure [2]. The suprachiasmatic nucleus and, possibly, the melatoninergic system can modulate the cardiovascular rhythm.
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M. Karasek & A. Lerchl:
Melatonin and magnetic fields
2002; 23 (suppl 1):84-87 pii:NEL230702R11 PMID:

Abstract
There is public health concern raised by epidemiological studies indicating that extremely low frequency electric and magnetic fields generated by electric power distribution systems in the environment may be hazardous. Possible carcinogenic effects of magnetic field in combination with suggested oncostatic action of melatonin lead to the hypothesis that the primary effects of electric and magnetic fields exposure is a reduction of melatonin synthesis which, in turn, may promote cancer growth.
In this review the data on the influence of magnetic fields on melatonin synthesis, both in the animals and humans, are briefly presented and discussed.

Introduction
Extremely low frequency electric (ELF-EF) and magnetic fields (ELF-MF), e.g. generated by high-voltage transmission lines and household appliances, are present worldwide and receive increasing attention because of their potential consequences for human health [1-3], especially associated with increased risk for cancer and childhood leukemia [2]. Additionally some attention has also been paid to other possible health hazards, such as interference with cardiac pacemakers [4], Alzheimer's disease [5], and adverse pregnancy outcome [6]. Working Group organized by National Institute of Environmental Health Services concluded in the report published in 1998, on the basis of almost 900 publications, that "ELF-EMF are possibly carcinogenic to humans". This conclusion is based on limited evidence that residential exposure to ELF-MF is carcinogenic to children it terms of childhood leukemia, and occupational exposure to ELF-MF is carcinogenic to humans in terms of chronic lymphocytic leukemia [4]. It has been also concluded that there is inadequate evidence for an association between occupational exposure to EFL-MF and risk for other cancer [4]. Moreover, the same report states: "None of the evidence for adverse health effects seen after exposure to ELF EMF achieved a degree of evidence exceeding ‘inadequate' (for humans) or ‘weak" (for experimental animals)" [3]. In humans it concerns adverse birth outcomes, reproductive effects, Alzheimer's disease, amyotrophic lateral sclerosis, suicide or depression, cardiovascular disease [3].
Possible carcinogenic effects of EMF in combination with suggested oncostatic action of melatonin [see 7, 8] lead to the hypothesis that the primary effects of EMF exposure is a reduction of melatonin synthesis which, in turn, may promote cancer growth [9].
In this review the data on the influence of EMF on melatonin synthesis, both in the animals and humans, are briefly presented and discussed.
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I.M. Kvetnoy:
Extrapineal melatonin in pathology: new perspectives for diagnosis, "prognosis, and treatment of illness
2002; 23 (suppl 1):92-96 pii:NEL230702R12 PMID:

Abstract
During the last decade, attention was concentrated on melatonin - one of the hormones of the diffuse neuroendocrine system, which has been considered only as a hormone of the pineal gland, for many years. Currently, melatonin has been identified not only in the pineal gland, but also in extrapineal tissues - retina, harderian gland, gut mucosa, cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, ovary, carotid body, placenta and endometrium as well as in non-neuroendocrine cells like mast cells, natural killer cells, eosinophilic leukocytes, platelets and endothelial cells. The above list of the cells storing melatonin indicates that melatonin has a unique position among the hormones of the diffuse neuroendocrine system, which is present in practically all organ systems. Functionally, melatonin-producing cells are certain to be part and parcel of the diffuse neuroendocrine system as a universal system of response, control and organism protection. Taking into account the large number of melatonin-producing cells in many organs, the wide spectrum of biological activities of melatonin and especially its main property as a universal regulator of biological rhythms, it should be possible to consider extrapineal melatonin as a key paracrine signal molecule for the local coordination of intercellular relationships. Analysis of our long-term clinical investigations shows the direct participation and active role of extrapineal melatonin in the pathogenesis of tumor growth and many other non-tumor pathologies such as gastric ulcer, immune diseases, neurodegenerative processes, radiation disorders, etc. The modification of antitumor and other specific therapy by the activation or inhibition of extrapineal melatonin activity could be useful for the improvement of the treatment of illness.

Introduction
About 30 years ago Pearse first suggested that a specialized, highly organized cell system should exist in organisms, whose main feature was the ability of component cells to produce peptide hormones and biogenic amines. The concept was based on an extensive series of experiments on distinguishing endocrine cells in different organs, identifying endocrine cell-generated products and making a thorough cytochemical and ultrastructural analysis of these cells [1]. Different types of cells widely dispersed throughout the organism have a common ability of absorbing monoamine precursors (5-hydroxytryptophan and L-dihydroxyphenylalanine) and decarboxylating them, thus producing biogenic amines. That ability accounts for the term APUD, an abbreviation of "Amine Precursor Uptake and Decarboxylation" used by Pearse to designate the cell series [2]. Presently, the APUD series includes over 60 types of cells located in gut, pancreas, urogenital tract, airway epithelium, pineal gland, thyroid gland, adrenals, adenohypophysis and hypothalamus, carotid body, skin, sympathetic ganglia, thymus, placenta and other organs [3-5]. Meanwhile ... ...

NEUROENDOCRINOLOGY LETTERS (NEL)
including Psychoneuroimmunology, Neuropsychopharmacology,
Reproductive Medicine, Chronobiology and Human Ethology
ISSN 0172–780X

NEUROENDOCRINOLOGY LETTERS:
A peer-reviewed transdisciplinary Journal covering neuroendocrinology, psychoneuroimmunology and chronobiology. A peer-reviewed transdisciplinary Journal. RAPID publication of papers from basic and clinical research, review articles and state-of the-art.
E-mail: editor@nel.edu

NEUROENDOCRINOLOGY LETTERS (NEL)
including Psychoneuroimmunology, Neuropsychopharmacology,
Reproductive Medicine, Chronobiology and Human Ethology. ISSN 0172–780X

SUPPLEMENT 1, 2002
Ordering info HERE
(per article $35.00)

ABSTRACTS
REVIEWS
1 Reiter et al | 2 Cardinali et al | 3 Karasek & Reiter
4 Cardinali et al | 5 Pawlikowski et al | 6 Bartsch et al
7 Karbownik | 8 Skwarlo-Sonta | 9 Lewinski & Karbownik
10 Sewerynek | 11 Karasek & Lerchl | 12 Kvetnoy

NEUROENDOCRINOLOGY LETTERS (NEL) including Psychoneuroimmunology, Neuropsychopharmacology, Reproductive Medicine, Chronobiology and Human Ethology. ISSN 0172–780X

SUPPLEMENT 1, 2002 Ordering info HERE (per article $35.00)

ABSTRACTS REVIEWS 1 Reiter et al | 2 Cardinali et al | 3 Karasek & Reiter 4 Cardinali et al | 5 Pawlikowski et al | 6 Bartsch et al 7 Karbownik | 8 Skwarlo-Sonta | 9 Lewinski & Karbownik 10 Sewerynek | 11 Karasek & Lerchl | 12 Kvetnoy

NEUROENDOCRINOLOGY LETTERS (NEL)
including Psychoneuroimmunology, Neuropsychopharmacology,
Reproductive Medicine, Chronobiology and Human Ethology. ISSN 0172–780X

SUPPLEMENT 1, 2002
Ordering info HERE
(per article $35.00)

ABSTRACTS
REVIEWS
1 Reiter et al | 2 Cardinali et al | 3 Karasek & Reiter
4 Cardinali et al | 5 Pawlikowski et al | 6 Bartsch et al
7 Karbownik | 8 Skwarlo-Sonta | 9 Lewinski & Karbownik
10 Sewerynek | 11 Karasek & Lerchl | 12 Kvetnoy