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Journal Article

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

01 Nov 1981-Cancer Research (Cancer Res)-Vol. 41, pp 4432-4436
TL;DR: 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 is supported.
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.
Citations
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Journal ArticleDOI
TL;DR: This review summarizes current knowledge about melatonin in humans and its clinical implications and concludes that there is evidence that melatonin may have a role in the biologic regulation of circadian rhythms, sleep, mood, and perhaps reproduction, tumor growth, and aging.
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 . . .

1,446 citations

Journal ArticleDOI
TL;DR: It is suggested that working a rotating night shift at least three nights per month for 15 or more years may increase the risk of colorectal cancer in women.
Abstract: Exposure to light at night suppresses the physiologic production of melatonin, a hormone that has antiproliferative effects on intestinal cancers. Although observational studies have associated night-shift work with an increased risk of breast cancer, the effect of night-shift work on the risk of other cancers is not known. We prospectively examined the relationship between working rotating night shifts and the risk of colorectal cancers among female participants in the Nurses' Health Study. We documented 602 incident cases of colorectal cancer among 78 586 women who were followed up from 1988 through 1998. Compared with women who never worked rotating night shifts, women who worked 1-14 years or 15 years or more on rotating night shifts had multivariate relative risks of colorectal cancer of 1.00 (95% confidence interval [CI] = 0.84 to 1.19) and 1.35 (95% CI = 1.03 to 1.77), respectively (P(trend) =.04). These data suggest that working a rotating night shift at least three nights per month for 15 or more years may increase the risk of colorectal cancer in women.

748 citations

Journal ArticleDOI
TL;DR: This review addresses the complicated web of potential behavioral and physiological consequences resulting from exposure to light at night, as well as the large‐scale medical and ecological implications that may result.
Abstract: Organisms must adapt to the temporal characteristics of their surroundings to successfully survive and reproduce. Variation in the daily light cycle, for example, acts through endocrine and neurobiological mechanisms to control several downstream physiological and behavioral processes. Interruptions in normal circadian light cycles and the resulting disruption of normal melatonin rhythms cause widespread disruptive effects involving multiple body systems, the results of which can have serious medical consequences for individuals, as well as large-scale ecological implications for populations. With the invention of electrical lights about a century ago, the temporal organization of the environment has been drastically altered for many species, including humans. In addition to the incidental exposure to light at night through light pollution, humans also engage in increasing amounts of shift-work, resulting in repeated and often long-term circadian disruption. The increasing prevalence of exposure to light at night has significant social, ecological, behavioral, and health consequences that are only now becoming apparent. This review addresses the complicated web of potential behavioral and physiological consequences resulting from exposure to light at night, as well as the large-scale medical and ecological implications that may result.

678 citations


Cites background from "Melatonin inhibition and pinealecto..."

  • ...In addition, DMBAinduced mammary tumors grew more slowly in rats treated with melatonin when compared with control rats that did not receive melatonin ([73], reviewed in [74])....

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Journal ArticleDOI
TL;DR: The aim of this review is to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis, which reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism.
Abstract: Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.

672 citations


Cites background from "Melatonin inhibition and pinealecto..."

  • ...The anticarcinogenic effect of MEL is best described in vivo and in vitro on the estrogenresponsive mammary tumors (Tamarkin et al., 1981; Blask and Hill, 1986; Hill and Blask, 1988; Scott et al., 2001; Teplitzky et al., 2001; Kiefer et al., 2002)....

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Journal Article
TL;DR: The carcinogen-induced rat mammary carcinoma model is today the standard laboratory animal model in the study of human breast cancer and has a number of features that make it particularly attractive to the experimental oncologist, e.g., tumor induction ease and reliability.
Abstract: The carcinogen-induced rat mammary carcinoma model, developed a quarter of a century ago by Dr. Charles Brenton Huggins, is today the standard laboratory animal model in the study of human breast cancer. This model has a number of features that make it particularly attractive to the experimental oncologist, e.g., tumor induction ease and reliability, organ site specificity, tumors of ductal origin, tumors of predominantly carcinomatous histopathological characteristics, tumors of varying growth factor and/or hormone responsiveness, and the potential to examine tumor initiation and promotion processes. Since the development of this model, an extensive literature describing the biological behavior and responsiveness of these tumors has been provided. The purpose of this communication is to condense, summarize, and integrate this vast literature into a single review with the intent on facilitating information acquisition and conceptualism by both the new and the established experimental oncologist. In addition, and equally important, this communication is a tribute to Dr. Huggins, whose pioneering efforts in the development of this model and whose scientific contributions and dedication to the oncological sciences in general have made an important and lasting impact on us all.

517 citations

References
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Journal ArticleDOI
TL;DR: By the usual criteria in endocrinology, the pineal now fulfills all the qualifications of an organ of internal secretion.
Abstract: ONLY A LITTLE over a decade ago, any discussion of the function of the pineal gland included qualifying adjectives such as alleged, supposed, and putative. In the same vein, since it connoted a hormonal function, rather than referring to the pineal as a gland, the phrase pineal organ was usually employed to describe this portion of the epithalamus. However, this is no longer the case, at least in mammals. By the usual criteria in endocrinology, the pineal now fulfills all the qualifications of an organ of internal secretion. Several major discoveries revolutionized ideas concerning the function of the pineal gland. Certainly, as noted frequently in other reviews, the isolation and identification of N-acetyl-5-methoxytryptamine (melatonin), a pineal hormone, from bovine pineal tissue by Lerner et al. (1, 2) provided a strong impetus for subsequent investigations on this sometimes exasperating organ. At least as important as this discovery, however, were the observations that light and darkness govern both ...

1,229 citations


"Melatonin inhibition and pinealecto..." refers background in this paper

  • ...The pituitary hormone affected most rapidly by melatonin treatment is prolactin, which is markedly suppressed in the circulation (14, 16)....

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  • ...In the Syrian hamster, the pineal gland and its hormone melatonin induce gonadal collapse (7, 14, 16, 17, 19, 21, 22)....

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  • ...Earlier studies indicate that, contrary to inhibiting prolactin secretion, melatonin administration actually causes an increase in circulating prolactin (14)....

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Journal Article
TL;DR: If prolactin can be shown to influence human breast epithelium in a manner similar to its effect on rodent mammary tissue, then prophylactic and/of chemotherapeutic control of human breast tumorigenesis may be feasible by appropriate drug-mediated Prolactin suppression.
Abstract: It is unequivocal that prolactin is an influential hormone in murine mammary tumorigenesis The Berenblum hypothesis (7), a well-known theoretical model of tumorigenesis that depicts this oncogenic process as a two-step mechanism, ie, initiation and promotion, is a conceptual scheme in which the action of prolactin in mammary tumorigenesis may be understood According to this conceptual model, prolactin would participate in both the initiation and promotion steps of mammary tumorigenesis, In the initiation phase, variations in prolactin secretion appear to influence the metabolism of the mammary epithelium, so that the epithelium would be either more receptive to or refractory to an initiating agent (eg, chemical carcinogen, physical carcinogens, oncogenic viruses, ets) ie, a permissive action In the promotion phase, prolactin may act as either a promoter or an antipromoter of the "transformed" mammary epithelium In promotion, the hormone may either directly or indirectly (via the ovary) stimulate mitotic activity of the "transformed" epithelium In antipromotion the hormone, in the presence of requisite hormones (eg, glucocorticoids), may synergistically induce differentiation (eg, lactation) in the "transformed" epithelium A tumor would result in the former (promotion) but not in the latter (antipromotion) case Whether or not prolactin is significantly influential in human breast tumorigenesis remains to be determined This is an extremely important area of research which is justifiably receiving increased attention For if prolactin can be shown to influence human breast epithelium in a manner similar to its effect on rodent mammary tissue, then prophylactic and/of chemotherapeutic control of human breast tumorigenesis may be feasible by appropriate drug-mediated prolactin suppression

489 citations

Journal ArticleDOI
18 Jun 1965-Science
TL;DR: Data emphasize the importance of the pineal gland in the regulation of photoperiodic influences on the gonads in hamsters exposed to light-dark cycles.
Abstract: Exposure of male hamsters to cycles of 1 hour of light and 23 hours of darkness causes atrophy of the gonads. Pinealectomy prevents this atrophy, but has no effect on animals exposed to light-dark cycles of 16 : 8. Likewise, removal of both eyes induces gonad atrophy which is prevented by pinealectomy. These data emphasize the importance of the pineal gland in the regulation of photoperiodic influences on the gonads.

427 citations


"Melatonin inhibition and pinealecto..." refers background in this paper

  • ...In the Syrian hamster, the pineal gland and its hormone melatonin induce gonadal collapse (7, 14, 16, 17, 19, 21, 22)....

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Journal ArticleDOI
TL;DR: It is indicated that chronic daily injections of melatonin can depress reproductive function in hamsters and that the effectiveness of the injections is dependent upon the time of day at which they are administered.
Abstract: Hamsters were maintained on a long photoperiod (14L:10D) and were injected once daily with melatonin (10-25 mug) or sesame oil. Males which received melatonin during the afternoon (e.g., 6.5-13.75 h after lights-on) showed regressed testes and decreased levels of serum LH and FSH after several weeks of treatment. Injections of the oil vehicle or injections of melatonin given in the morning (3 h after lights-on) had no detectable effect on testicular size or on serum gonadotropins. Females which received melatonin during the afternoon became acyclic after several weeks of treatment and showed a diurnal pattern of LH secretion. The acyclic females required 4-6 weeks to resume estrous cyclicity following termination of the melatonin injections. The effects of melatonin on gonadal function and on serum gonadotropin concentrations in both sexes were similar to the previously observed effects of prolonged exposure to short photoperiods. These results indicate that chronic daily injections of melatonin can depress reproductive function in hamsters and that the effectiveness of the injections is dependent upon the time of day at which they are administered.

419 citations

Journal ArticleDOI
TL;DR: Removal of the pineal organ from small rodents may be rapidly accomplished by immobilizing the skull in a head mounting device and by cutting and removing a circular disc of bone overlying the Pineal area with the use of a dental machine and a specially designed circle cutter.
Abstract: Removal of the pineal organ from small rodents may be rapidly accomplished by (1) immobilizing the skull in a head mounting device and (2) by cutting and removing a circular disc of bone overlying the pineal area with the use of a dental machine and a specially designed circle cutter.

309 citations


"Melatonin inhibition and pinealecto..." refers methods in this paper

  • ...Pinealectomies were performed at 20 days of age accord ing to the procedure of Hoffman and Reiter (6)....

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