Michael Cohen

Bio: Michael Cohen is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Pineal gland & Melatonin. The author has an hindex of 6, co-authored 8 publications receiving 835 citations.

Melatonin inhibition and pinealectomy enhancement of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the rat.

Abstract: The effects of the pineal hormone, melatonin, and of pinealectomy on the incidence of mammary adenocarcinoma in Sprague-Dawley rats treated with 7,12-dimethylbenz(alpha)-anthracene (DMBA) were investigated. Melatonin (2.5 mg/kg), begun on the same day as DMBA (5 mg) treatment and given daily in the afternoon for 90 days, significantly reduced the incidence of mammary tumors from 79% (control) to 20% (treated) (p less than 0.002). Rats pinealectomized at 20 days of age and treated with 7 mg of DMBA at 50 days of age had a higher incidence of tumors (88%) compared to control animals (22%). Fifteen mg of DMBA, which resulted in a higher incidence of tumors, reduced the difference between pinealectomized and control animals. Melatonin only partially reversed the effects of pinealectomy, reducing the incidence from 87% (pinealectomy alone) to 63% (pinealectomy plus melatonin); however, the tumor incidence was still lower (27%) in nonpinealectomized, melatonin-treated animals. Assessment of plasma prolactin, luteinizing hormone, follicle-stimulating hormone, estradiol, and cortisol in DMBA-treated tumor-free and tumor-bearing animals revealed a significantly lower plasma prolactin concentration [27 +/- 5 (S.E.) ng/ml] in melatonin-treated animals as compared to vehicle-treated animals [65 +/- 8 ng/ml]. The concentration of plasma prolactin was less in melatonin-treated, pinealectomized rats (55 +/- 10 ng/ml) as compared to vehicle-treated, pinealectomized animals (101 +/- 13 ng/ml). Other hormones were not affected by melatonin treatment. These data support the hypothesis that melatonin inhibits the development of DMBA-induced mammary tumors in the rat while removal of the pineal gland stimulates development of such tumors. Additionally, these experiments provide evidence that these effects may be mediated by a suppression of plasma prolactin levels.

Evidence for a cytoplasmic melatonin receptor

Abstract: MELATONIN, a secretion of the pineal gland, has profound inhibitory effects on the development and maturation of gonadal organs in mammals1. Pinealectomy of the rat or hamster results in premature enlargement of the uterus and ovary2,3 in females and gonadal organs in males4,5, while melatonin administration reverses the effects of pinealectomy and suppresses gonadal growth and maturation in these species1. The physiological site and mechanism of action are uncertain. The hormone seems to act both in the central nervous system and at peripheral sites; previous studies have demonstrated inhibition of luteinising hormone (LH) and follicle stimulating hormone (FSH) secretion by the pituitary5,6 as well as inhibition of oestrogen and progesterone synthesis by ovarian tissue slices7,8. Since other hormones are known to exert their effects through binding to receptor proteins in target organs, we have examined melatonin binding in hamster and rat tissues and human ovaries, and here report evidence for the presence of a specific melatonin receptor in the supernatant fraction of several organs.

Antineoplastic Drugs: Clinical Pharmacology and Therapeutic Use

Abstract: The treatment of malignant disease has undergone an evolution over the past decade with the development of many new agents and combinations of agents useful in antineoplastic therapy. Such agents are somewhat unique from other classes of drugs in having a very narrow therapeutic index. Furthermore, as many of these agents only exert their effects during certain phases of the cell cycle, their action is schedule-dependent. Thus, a thorough understanding of the pharmacology of these agents and of potential drug interactions is imperative for their safe and effective use by the oncologist or cancer therapist. This review will deal with the clinical pharmacology of some of the more commonly used antineoplastic agents with emphasis on selected newer agents of proven therapeutic efficacy.

Pineal Melatonin: Cell Biology of Its Synthesis and of Its Physiological Interactions*

Abstract: I Introduction UNTIL 35 yr ago, most scientists did not take research on the pineal gland seriously The decade beginning in 1956, however, provided several discoveries that laid the foundation for what has become a very active area of investigation These important early observations included the findings that, 1), the physiological activity of the pineal is influenced by the photoperiodic environment (1–5); 2), the gland contains a substance, N-acetyl-5-methoxytryptamine or melatonin, which has obvious endocrine capabilities (6, 7); 3), the function of the reproductive system in photoperiodically dependent rodents is inextricably linked to the physiology of the pineal gland (5, 8, 9); 4), the sympathetic innervation to the pineal is required for the gland to maintain its biosynthetic and endocrine activities (10, 11); and 5), the pineal gland can be rapidly removed from rodents with minimal damage to adjacent neural structures using a specially designed trephine (12) Since the mid 1960s, research on t

Melatonin in humans.

Abstract: Three centuries ago, the French philosopher Rene Descartes described the pineal gland as “the seat of the soul,” but it was not until the late 1950s that melatonin, the principal substance secreted by the pineal gland, was identified.1 There is now evidence that melatonin may have a role in the biologic regulation of circadian rhythms, sleep, mood, and perhaps reproduction, tumor growth, and aging (Table 1). However, uncertainties and doubts still surround the role of melatonin in human physiology and pathophysiology. This review summarizes current knowledge about melatonin in humans and its clinical implications. Physiology and Pharmacology In humans, the . . .

Rotating Night Shifts and Risk of Breast Cancer in Women Participating in the Nurses' Health Study

Abstract: Background: Melatonin shows poten-tial oncostatic action,and light expo-sure during night suppresses melatoninproduction. There is little information,however,about the direct effect ofnight work on the risk of cancer. Weinvestigated the effect of night work inbreast cancer. Methods: We examinedthe relationship between breast cancerand working on rotating night shiftsduring 10 years of follow-up in 78562women from the Nurses’ Health Study.Information was ascertained in 1988about the total number of years duringwhich the nurses had worked rotatingnight shifts with at least three nightsper month. From June 1988 throughMay 1998,we documented 2441 inci-dent breast cancer cases. Logistic re-gression models were used to calculaterelative risks (RRs) and 95% confi-dence intervals (CIs),adjusted for con-founding variables and breast cancerrisk factors. All statistical tests weretwo-sided. Results: We observed a mod-erate increase in breast cancer riskamong the women who worked 1–14years or 15–29 years on rotating nightshifts (multivariate adjusted RR = 1.08[95% CI = 0.99 to 1.18] and RR = 1.08[95% CI = 0.90 to 1.30],respectively).The risk was further increased amongwomen who worked 30 or more yearson the night shift (RR = 1.36; 95% CI =1.04 to 1.78). The test for trend was sta-tistically significant ( P = .02).Conclu-sions: Women who work on rotatingnight shifts with at least three nightsper month,in addition to days and eve-nings in that month,appear to have amoderately increased risk of breastcancer after extended periods of work-ing rotating night shifts. [J Natl CancerInst 2001;93:1563–8]The suprachiasmatic nucleus in the hy-pothalamus, one of the most importantphysiologic determinants of alertness andperformance, drives a circadian pace-maker in mammals, with an intrinsic pe-riod averaging 24 hours. Light is the pri-mary stimulus to disrupt and reset thispacemaker, which is expressed in chang-ing melatonin rhythms. Light exposure atnight may, therefore, be related to a vari-ety of behavioral changes and associatedhealth problems not yet well explored.Studies (1)have suggested an increasedrisk of coronary heart disease among ro-tating night shift workers, not fully ex-plained by an increased prevalence ofcoronary risk factors. Others have linkednight work to an increased breast cancerrisk among women (2).Melatonin, the “hormone of the dark-ness,” has only recently gained substantialattention from the scientific communitywith regard to its potential oncostatic ac-tions and its possible effect on breast can-cer risk (3–10).Melatonin serum levels inhumans decrease when people are ex-posed to light at night (11).Suppressedserum melatonin levels might enhance tu-mor development (12).Observationalstudies (2,13–15)are compatible with aneffect of melatonin on breast cancer risk,reporting meaningful increases in breastcancer risk among postmenopausal womenexposed to shiftwork. Recently, a tumor-promoting effect of light exposure wasdemonstrated on chemically induced tu-mors in rodents (16).To date, melatoninhas been shown to be oncostatic for a va-riety of tumor cells in experimental car-cinogenesis (17–26).The evidence of arelation between melatonin and oncogen-esis in humans is conflicting (27),butthe majority of reports indicate protectiveaction (28).Several mechanisms have been hy-pothesized to explain an association be-tween melatonin and breast cancer. Cohenet al. (29)proposed that loss of pinealfunction and the resulting decreased mel-atonin serum levels may increase repro-ductive hormone levels and, in particular,estradiol levels, thereby increasing thegrowth and proliferation of hormone-sensitive cells in the breast. More recentresearch focuses on potential mechanismsthrough which melatonin is directly onco-static. Melatonin is believed to have anti-mitotic activity by affecting directly hor-mone-dependent proliferation throughinteraction with nuclear receptors (4).An-other explanation is that melatonin in-creases the expression of the tumor sup-pressor gene p53 (3).Cells lacking p53have been shown to be genetically un-stable and thus more prone to tumors (30).Breast cancer is the most common can-cer among women in the United States.To date, the relationship between nightwork and breast cancer risk has not beenevaluated in prospective cohort studies. Acausal link between the two would be ofpublic health importance, because smallchanges in shift patterns may create a sub-stantial decrease of disease burden amongwomen.In this report, we evaluate the relation-ship between night work, as a surrogatefor light exposure at night, and breastcancer risk in a large prospective cohortof premenopausal and postmenopausalwomen. Our analysis is based on 10 yearsof follow-up in 78562 women participat-ing in the Nurses’ Health Study.

Clinical pharmacology of 5-fluorouracil.

Abstract: 5-Fluorouracil, first introduced as a rationally synthesised anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metabolic pathways as uracil. Although several potential sites of antitumour activity have been identified, the precise mechanism of action and the extent to which each of these sites contributes to tumour or host cell toxicity remains unclear. Several assay methods are available to quantify 5-fluorouracil in serum, plasma and other biological fluids. Unfortunately, there is no evidence that plasma drug concentrations can predict antitumour effect or host cell toxicity. The recent development of clinically useful pharmacodynamic assays provides an attractive alternative to plasma drug concentrations, since these assays allow the detection of active metabolites of 5-fluorouracil in biopsied tumour or normal tissue. 5-Fluorouracil is poorly absorbed after oral administration, with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). Recently, studies have demonstrated the pharmacokinetic rationale and clinical feasibility of hepatic arterial infusion and intraperitoneal administration of 5-fluorouracil. In addition, 5-fluorouracil continues to be used in topical preparations for the treatment of malignant skin cancers. Following parenteral administration of 5-fluorouracil, there is rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes. The rapid elimination is primarily due to swift catabolism of 5-fluorouracil in the liver. As with all drugs, caution should be used in administering 5-fluorouracil in various pathophysiological states. In general, however, there are no set recommendations for dose adjustment in the presence of renal or hepatic dysfunction. Drug interactions continue to be described with other antineoplastic drugs, as well as with other classes of agents.

Extrapineal melatonin: sources, regulation, and potential functions.

Abstract: Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.