Preventive and curative effect of melatonin on mammary carcinogenesis induced by dimethylbenz[a]anthracene in the female Sprague–Dawley rat

INTRODUCTION: It has been well documented that the pineal hormone, melatonin, which plays a major role in the control of reproduction in mammals, also plays a role in the incidence and growth of breast and mammary cancer. The curative effect of melatonin on the growth of dimethylbenz [a]anthracene-induced (DMBA-induced) mammary adenocarcinoma (ADK) has been previously well documented in the female Sprague–Dawley rat. However, the preventive effect of melatonin in limiting the frequency of cancer initiation has not been well documented. METHODS: The aim of this study was to compare the potency of melatonin to limit the frequency of mammary cancer initiation with its potency to inhibit tumor progression once initiation, at 55 days of age, was achieved. The present study compared the effect of preventive treatment with melatonin (10 mg/kg daily) administered for only 15 days before the administration of DMBA with the effect of long-term (6-month) curative treatment with the same dose of melatonin starting the day after DMBA administration. The rats were followed up for a year after the administration of the DMBA. RESULTS: The results clearly showed almost identical preventive and curative effects of melatonin on the growth of DMBA-induced mammary ADK. Many hypotheses have been proposed to explain the inhibitory effects of melatonin. However, the mechanisms responsible for its strong preventive effect are still a matter of debate. At least, it can be envisaged that the artificial amplification of the intensity of the circadian rhythm of melatonin could markedly reduce the DNA damage provoked by DMBA and therefore the frequency of cancer initiation. CONCLUSION: In view of the present results, obtained in the female Sprague–Dawley rat, it can be envisaged that the long-term inhibition of mammary ADK promotion by a brief, preventive treatment with melatonin could also reduce the risk of breast cancer induced in women by unidentified environmental factors

Tamoxifen Stimulates Melatonin Secretion After Exposure to a Mammary Carcinogen, the Dimethyl Benz(a)Anthracene, in Sprague Dawley Female Rat

International audienceA single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of the tumors is preceded, during the la-tency phase, by a series of neuroendocrine disturbances, including attenuation of the preovulatory Luteinizing Hormone surge and Gonadotropin-Releasing Hormone release and amplification of the preovulatory 17-Estradiol (E2) surge. Also, E2 treatment leads to a complete blunting of the Isoproterenol-induced stimulation of Melatonin secretion.In this study, we examined the hypothesis that Tamoxifen, an antagonist of E2, would stimulate the Isoproterenol-induced Mela-tonin (MT) secretion from the pineal gland, during the latency phase. Sprague-Dawley rats, 55-60 days of age, received, on the Estrous day of the Estrous cycle, a single dose of 15 mg DMBA delivered by intragastric intubation. In order to avoid possible interactions with endogenous steroids or mammary tumor-derived compounds, they were ovariectomized 5 days later and, one month later, sacrificed by decapitation at 10 a.m. Then, pineal glands were removed and placed in perifusion chambers containing Hanks 199 medium. The medium was satured with O 2 /CO 2 (95 %/5 %) and its pH was 7.4. Ten independent chambers were immersed in a water bath at 37°C. Each pineal gland received medium (flow rate : 0.16 ml/min) through a system of input lines. The fractions were collected every 10 min, and immediately frozen at –20°C until Melatonin RIA. Experiments were repeated to obtain up to five experimental points for each treatment. Tamoxifen (10-9 to 10-7 M) was applied during the entire perifusion period (7 hours). Isoproterenol (10-6 M) was applied for 20 min after 3 hours in perifusion. Melatonin concentrations and Areas Under the Curves were compared using two-factor ANOVA as well as parametric or nonparametric two-sample methods after testing sample normality. In vehicle treated rats, Tamoxifen treatment, at the concentration of 10-9 M, leads to a non significant amplification of the Isoproterenol-induced stimulation of Melatonin secretion. In DMBA-treated rats, Tamoxifen treatment leads,starting from 10-9 M to a dose-dependent increase (up to 400% increase) of the Isoproterenol-induced stimulation of Melatonin. The results suggest that in addition to the well documented beneficial effects of Tamoxifen at the mammary gland level, this E2 antagonist may also have, after DMBA treatment, an additional beneficial effect at the pineal gland level throughout the stimulation of Melatonin, which exerts an inhibitory action on the induction and on the growth of breast cancers

Implication du système mélatoninergique dans la carcinogénèse mammaire induite par le 7,12-Diméthylbenz(a)anthracène(DMBA)chez la ratte de souche Sprague-Dawley

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF