[Effect of light deprivation on homeostasis, life span and development of spontaneous tumors in HER-2/neu transgenic mice]. / Vliianie svetovoi deprivatsii n pokazateli gomeostaza, prodolzhitel'nost' zhizni i razvitei spontannykh opukholei u transgennykh myshei HER-2/neu.

Twenty five female HER-2/neu transgenic mice (FVB/N), aged 2 months, were surgically deprived of lighting; 30 intact transgenic mice, kept under standard conditions, were in control. Light deprivation was followed by inhibited intake of feed, decreased body mass and delayed age-associated estral disorders, as compared with control. Mean survival rate among experimental mice was higher by 13.5% than in control (p 0.001). Mean life span among the last surviving 10% of the experimental mice was longer than in control by 21.5% while maximum life span--by 21%. Although the number of tumor bearers under 7 months in the study group was twice that in control (p<0.05), they had almost equalized by the end of the experiment. The number of multiple malignancies and the size of tumor and metastases to the lung increased too.

Mammary tumors in HER-2/NEU mice are characterized by low content of estrogen receptors-alpha and absence of progesterone receptors.

Transgenic mice carrying erbB2(HER-2)neu gene are characterized by high incidence of mammary adenocarcinoma. The content of estrogen receptor was no more than 10 fmol/mg protein in 8 of 14 studied tumors, while the content of progesterone receptors was even lower in all 14 studied tumors. Based on these data, we distinguish two subtypes of HER-2/neu-adenocarcinomas in mice: ER+,PR- and ER-,PR-, which can be used for the development of new approaches to the treatment of receptor-negative mammary gland tumors.

Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice.

Female transgenic FVB/N mice carrying the breast cancer gene HER-2/neu received epithalon (Ala-Glu-Asp-Gly) in a dose of 1 mg subcutaneously 5 times a week to from the 2nd month of life to death. Epithalon prolonged the average and maximum lifetimes of mice by 13.5 (p<0.05) and 13.9%, respectively. The peptide prolonged the average lifetime of animals without neoplasms (by 34.2%, p<0.05). Epithalon decelerated the development of age-related disturbances in reproductive activity and suppressed the formation of neoplasms. The peptide decreased the incidence of breast adenocarcinomas, lungs metastases (by 1.6 times, p<0.05), and multiple tumors (by 2 times). Epithalon 3.7-fold increased the number of mice without breast tumors (p<0.05), while the number of animals with 6 or more breast tumors decreased by 3 times (p<0.05). Epithalon prolonged the lifetime of mice with breast tumors by 1.4 times (p<0.05). These results indicate that Epithalon possesses geroprotective activity and inhibits breast carcinogenesis in transgenic mice, which is probably related to suppression of HER-2/neu expression.

Epithalon inhibits tumor growth and expression of HER-2/neu oncogene in breast tumors in transgenic mice characterized by accelerated aging.

Female transgenic FVB mice carrying breast cancer gene HER-2/neu were monthly injected with Vilon or Epithalon (1 microgram subcutaneously for 5 consecutive days) starting from the 2nd month of life. Epithalon markedly inhibited neoplasm development: the maximum size of breast adenocarcinomas was 33% lower than in the control (p < 0.05). The intensity of HER-2/neu mRNA expression in breast tumors of Epithalon-treated mice was 3.7 times lower than in control animals. These results indicate that Epithalon inhibits breast tumor development in transgenic mice, which is probably related to suppression of HER-2/neu expression.

[Effect of Epitalon and Vilon treatment on mammary carcinogenesis in transgenic erbB-2/NEU mice]. / Vliianie épitalona i vilona na prodolzhitel'nost' zhizni i razvitie opukholei molochnoi zhelezy u samok transgennykh mishei erB-2/neu.

Female transgenic FVB mice transfected with the mammary erbB-2/neu oncogene were injected 0.1 ml 0.9% solution of sodium chloride (control), 1 meg Vilon peptide (Lys-Glu) or Epitalon peptide (Ala-Glu-Asp-Glu), s.c., 5 days in succession once a month, beginning from the age of 2 months. The characteristics of mammary tumor induction in the control and experimental groups did not differ until the age of 9 months. Later on, Epitalon-treated mice revealed distinct inhibition of carcinogenesis. One tumor per animal was detected in 7% (control), 4% (Vilon) and 16% (Epitalon) (p < 0.05). Two or more tumors per animal were in 75%, 95% and 56%, respectively (p < 0.05). Largest diameter of mammary adenocarcinoma in the Epitalon group was smaller than in controls by 33% (p < 0.05). Although the number of mice with metastases to the lung in all three groups was practically identical, their incidence in the Vilon group was 2.6 times higher than in Epitalon-treated animals (p < 0.05). Largest diameter of metastasis in the Epitalon group was the smallest, too. Our data point to inhibition of mammary carcinogenesis by Epitalon in transgenic erbB-2/neu mice.

[The use of mutagenic and transgenic mice for the study of aging mechanisms and age pathology]. / Ispol'zovanie mutantnykh i transgennykh myshei dlia izucheniia mekhanizmov stareniia i vozrastnoi patologii.

Increased interest is emerging for using mouse models to assess the genetics of aging and age-related diseases, cancer including. Despite this demand, relatively little information is available on relations between aging and spontaneous tumor development in transgenic and null mutant mice. Analysis of various transgenic and knockout rodent models which characterized by shortening or extension of the life span gives an unique possibility to evaluate the role of involved in aging genes in mechanisms of carcinogenesis. Only few models represent examples of life span extension. Ames dwarf mutant mice, p66-/- knocked out mice, aMUPA and MGMT, transgenic mice live longer than wild-type strains. The incidence of spontaneous tumors in these mice was usually similar to those in controls, whereas the latent period of tumor development was increased. Practically all models of accelerated aging show the increased tumor incidence and shortening of tumor latency. This phenomenon has been observed both in animals which display phenotype more resemble to the natural aging and in animals showed only partial features of normal aging process. These observations are in agreement with the data on the positive correlation between tumor incidence and the rate of its age-related increase, and the aging rate in a population.

The effect of light regimen and melatonin on the development of spontaneous mammary tumors in HER-2/neu transgenic mice is related to a downregulation of HER-2/neu gene expression.

OBJECTIVES AND DESIGN: The effect and the mechanism of light regimen and melatonin on the development of mammary tumors in HER2/neu transgenic mice were investigated. Female HER-2/neu mice starting from the age of 2 months were kept under standard light/dark regimen (LD) or constant light illumination (LL) and a part of each group was given melatonin (20 mg/l) during the night time. RESULTS: The exposure to LL failed to change the incidence of spontaneous mammary adenocarcinoma development, the size of mammary tumors, as well as the incidence and size of lung metastases. However, the number of tumors per mouse was significantly increased in the LL group as compared to the LD group. The number of mice bearing 4 and more tumors was higher in the LL group than in the LD group, whereas the number of mice bearing 1 to 3 tumors was lower in the LL group in comparison with the LD group. Melatonin decreased the incidence and size of mammary adenocarcinomas, and the incidence of lung metastases in the LD group but not in the LL group. The mean number of tumors per mouse was not changed by melatonin treatment in both light regimens. The number of mice bearing 4 and more tumors was reduced by melatonin more significantly in the LL group than in LD group. Melatonin treatment resulted in a 2.5-fold reduction in the expression of HER-2/neu mRNA in mammary tumors from HER-2 /neu transgenic mice. CONCLUSION: The data demonstrate the influence of the LD light regiment and melatonin treatment in the development of spontaneous mammary tumors in HER-2/neu mice suggesting a melatonin-dependent modulation of HER-2/neu gene expression in mammary adenocarcinoma.