The effect of constant illumination on the development of spontaneous tumors in female CBA mice was investigated. Fifty female CBA mice starting from the age of 2 months were kept under standard light/dark regimen (12 hr light: 12hr dark; LD) and 50 CBA mice of similar age were kept under constant illumination (24 hr a day, 2,500 Lux, LL). Exposure to the LL regimen decreased food consumption but did not influence body weight, significantly accelerated age-related disturbances in estrous function, and was followed by a significant increase in spontaneous tumor incidence in female CBA mice. Tumor incidence as well as the number of total or malignant tumors was significantly increased in the LL group compared to the LD group (p < 0.001). The incidence of lung adenocarcinomas, leukemias and hepatocarcinomas was 7/50; 6/50 and 4/50 in the LL group and 1/50; 0/50 and 0/50 in the LD group. Mice from the LL groups had shorter life spans then those from the LD group. The data demonstrate, for the first time, that exposure to constant illumination was followed by increases in the incidence of spontaneous lung carcinoma, leukemias and hepatocarcinoma in female CBA mice. Alternation of the day and night circadian cycle is an important regulator of a wide variety of physiological rhythms in organisms. Light exposure at night has been found to be related to a number of serious behavioral and health problems including cancer. In rodents, light-at-night leads to disruption of the ovulatory cycle followed by hyperplastic processes and tumor development in mammary gland, ovaries and uteri. 1,2 A tumor-promoting effect of exposure to the LL regimen was shown on chemical carcinogenesis in the mammary gland of rats. [3][4][5][6] Prolonged light exposure suppresses the night peak of melatonin, the 'hormone of the night.' 7,8 Melatonin is the principal hormone of the pineal gland, the small neuroendocrine gland connected with the brain that mediates information on light from the retina to the organism. 7,8 A significant increase in the risk of breast and colorectal cancers was shown in women who frequently did not sleep during the period of the night, about 1:30 a.m., when melatonin levels are typically the highest. 9 -12 The 'Melatonin hypothesis' suggests reduced pineal melatonin production might increase human breast cancer risk because lower melatonin output would lead to an increase in female sex hormones and stimulate proliferation of breast tissue. 13 Data on the enhancing effect of constant illuminations on spontaneous endometrial carcinogenesis in BDII/Han rats 14 agree with this suggestion. There are data on the promoting effect of the LL regimen on hepatocarcinogenesis induced by N-nitrosodimethylamine (DENA) in rats 15 and on the development of neurogenic and kidney tumors in progeny of rats exposed to N-nitrosomethylurea in utero. 16 We report, for the first time, that exposure to constant illumination increased the incidence of spontaneous lung carcinoma, leukemias and hepatocarcinoma in female CBA mice. MATERIAL AND ME...

The effect of various regimens of treatment with melatonin on the development of mammary tumors in HER2/neu transgenic mice was investigated. Female HER-2/neu mice starting from the age of 2 months were kept under standard light/dark regimen and as given melatonin with tap water (20 mg/l) during the night time 5 times monthly (interrupted treatments) or constantly to natural death. Intact mice served as controls. Treatment with melatonin slowed down age-related disturbances in estrous function most in the group exposed to interrupted treatment with the hormone. Constant treatment with melatonin decreased incidence and size of mammary adenocarcinomas, and incidence of lung metastases, compared to controls. The number of mice bearing 4 and more tumors was reduced in the group with constant melatonin treatment. Interrupted treatment with melatonin promote mammary carcinogenesis in HER-2/neu transgenic mice. The data demonstrate the regimen-dependent inhibitory effect of melatonin on the development of spontaneous mammary tumors in HER-2/neu mice but not on overall survival with implication about the likely cause of the effect. Polycystic kidney disease is common in this transgenic line. Adverse effect of melatonin on the life span in our study may be unique to the transgenic model used and may not be relevant to the suppressive effect of melatonin in delay of mammary cancer. © 2002 Wiley-Liss, Inc. Key words: melatonin; HER-2/neu, transgenic mice; mammary cancerBreast cancer is one of the most common cancers and is a leading cause of mortality in women. 1,2 The HER-2/neu oncogene encodes a 185 kDa (p 185) receptor protein that belongs to the epidermal growth factor receptor family involved in organogenesis and epithelial differentiation. 3 Amplification and mutation of HER-2/neu plays a pathogenetic role in several malignancies, including carcinoma of the breast, ovary and uterus. 4,5 Overexpression of ErbB-2/HER-2/neu occurs in 15-40% of human breast cancers. 6 Its appearance is correlated with poor prognosis and is therefore an important target for physiologic investigation and therapeutic intervention. 5 It was shown that treatment with pineal indole hormone melatonin inhibits the development of carcinogeninduced or transplanted tumors in the mammary gland, uterine cervix and colon in various animal models. [7][8][9][10] It is worthy of note that in the majority of in vivo studies only 1 dose and regimen of treatment with melatonin has been investigated; however in vitro studies have shown the dose-dependent effect of the hormone on tumor growth. 9,10 At present, several mechanisms for the effect of melatonin on mammary cancer tumorigenesis have been proposed: an endocrine hypothesis, 9,10 based on the effects of melatonin on pituitary or sex hormones controlling mammary gland development, and a direct action on tumor cells through melatonin-mediated antiproliferative, antioxidant or immunoenhancing effects. 10 Recently by using the HER-2/neu transgenic mice as a model of mammary carcinogenesis, we showed an inh...

No abstract

Female FVB/N HER-2/neu transgenic mice from the age of 2 months were subcutaneously injected with saline, the peptide Epitalonா (Ala-Glu-Asp-Gly) or with the peptide Vilonா (Lys-Glu) in a single dose of 1 g/mouse for 5 consecutive days every month. Epitalon treatment reduced the cumulative number and the maximum size of tumors (p < 0.05). Furthermore, the number of mice bearing 1 mammary tumor was increased, whereas the number of mice bearing 2 or more mammary tumors was reduced in Epitalon-treated in comparison to saline-treated animals (p < 0.05). The size but not the number of lung metastases was reduced in Epitalontreated compared to saline-treated mice (p < 0.05). The treatment with Vilon produced significant negative effects when compared to the control group, with an increased incidence of mammary cancer development (p < 0.05), a shorter mean latent period of tumors (p < 0.05) and an increased cumulative number of tumors (p < 0.05). A 3.7-fold reduction in the expression of HER-2/neu mRNA was found in mammary tumors from HER-2/neu transgenic mice treated with Epitalon compared to control animals. The expression of mRNA for HER-2/neu was also partially reduced in Vilon-treated mice, but it remained significantly higher in Vilon-than in Epitalon-treated animals (1.9-fold increase). The data demonstrate the inhibitory effect of Epitalon in the development of spontaneous mammary tumors in HER-2/ neu mice, suggesting that a downregulation of HER-2/neu gene expression in mammary adenocarcinoma may be responsible, at least in part, for the antitumor effect of the peptide. © 2002 Wiley-Liss, Inc. Key words: peptide; HER-2/neu; transgenic mice; mammary cancerBreast cancer is one of the most common cancers and is a leading cause of mortality in women. 1,2 The HER-2/neu oncogene encodes a 185 kDa (p 185) receptor protein belonging to the epidermal growth factor receptor family involved in organogenesis and epithelial differentiation. 3 Amplification and mutation of HER-2/neu plays a pathogenetic role in several malignancies, including carcinoma of the breast, ovary and uterus. 4,5 Overexpression of ErbB-2/HER-2/neu occurs in 15-40% of human breast cancers. 6 Its appearance correlates with poor prognosis, and it is, therefore, an important target for physiologic investigation and therapeutic intervention. 5 It has been shown that treatment with the pineal indole hormone melatonin inhibits the development of mammary gland tumorigenesis both in vitro and in vivo. [7][8][9][10] It was also shown that the polypeptide pineal preparation Epithalamin inhibits both the growth of transplantable mammary tumors and the development of spontaneous mammary tumors in female C3H/Sn and SHR mice and mammary carcinogenesis induced by 7,12-dimethylbenzanthracene mammary tumors or by total-body X-ray irradiation in female rats. 11-13 Clinical use of Epithalamin was shown to be effective for the treatment of ovarian disturbances and of some types of cancer, breast cancer included. 14 However, the in vivo use of Epithalamin has been rathe...

No abstract