Hemangiosarcoma in mice administered pregabalin: analysis of genotoxicity, tumor incidence, and tumor genetics.
نویسندگان
چکیده
Pregabalin, (S)-3-(aminomethyl)-5-methylhexanoic acid, binds with high affinity to the α(2)δ subunit of voltage-gated calcium channels and exerts analgesic, anxiolytic, and antiseizure activities. Two-year carcinogenicity studies were completed in B6C3F1 and CD-1 mice and two separate studies in Wistar rats. Doses in mice were 200, 1000, and 5000 mg/kg/day, with systemic exposures (AUC(0-24 h)) up to 31 times the mean exposure in humans, given the maximum recommended clinical dose. In rats, doses were 50, 150, and 450 mg/kg/day in males and 100, 300, and 900 mg/kg/day in females; systemic exposures up to 24 times were achieved in clinical trials. In both strains of mice, pregabalin treatment was associated with an increased incidence of hemangiosarcoma primarily in liver, spleen, and bone marrow. The incidence of hemangiosarcoma was higher in B6C3F1 mice than in CD-1 mice, consistent with its spontaneous incidence. Pregabalin did not increase the incidence of any other tumor type in rats and was not genotoxic, based on an extensive battery of in vivo and in vitro tests in bacterial and mammalian systems. Thus, pregabalin is a single-species, single tumor-type, nongenotoxic mouse carcinogen. Hemangiosarcomas occurring in mice treated with pregabalin were genotypically distinct from hemangiosarcomas induced by genotoxic carcinogens in humans with respect to ras and p53 mutation patterns and were similar to spontaneous tumors. Furthermore, there was a strong association between pregabalin treatment and bone marrow changes in these studies in mice, suggesting a possible link between the effects observed in bone marrow and the increase in tumor incidence in pregabalin-treated mice.
منابع مشابه
Investigating the anti-tumoral effect of curcumin on the mice in which Ehrlich ascites and solid tumor is created
Objective(s): In this study, the effects of different doses of curcumin application on Ehrlich ascites tumor (EAT) created in the mice of BALB/c type were investigated.Materials and Methods: Curcumin extracts can have hindering effect on tumor volume, vascular density, EAT cells around the tissues, and can support apoptosis. EAT cells (1x106) received from stock animals were injected intraperit...
متن کاملArteether Exerts Antitumor Activity and Reduces CD4+CD25+FOXP3+ T-reg Cells in Vivo
Background: Chemo-immunotherapy is one of the new achievements for treatment of cancer, by which the success of anti-cancer therapy can be increased. In vitro studies have been shown that Arteether (ARE) induces apoptosis in tumor cells, but not in normal cells. Objective: To investigate the cytotoxic and immunomodulatory properties of Arteether in-vivo and in-vitro. Methods: In this study, we ...
متن کاملThe effect of exercise training on the level of tissue IL-6 and vascular endothelial growth factor in breast cancer bearing mice
Objective(s): The goal of this study was assessing the prophylactic effect of exercise and its role as an adjuvant therapy on level of cytokines involved in angiogenesis in estrogen-dependent breast cancer. Materials and Methods: Forty female BALB/c mice were randomly assigned to exercise-tumor-exercise (ETE), exercise-tumor-rest (ETR), rest-tumor-exercise (RTE) and rest-tumor-rest (RTR) groups...
متن کاملAnticancer Activity of Indigofera aspalathoides and Wedelia calendulaceae in Swiss Albino Mice
The methanolic extracts of Indigofera aspalathoides (MEIA) and Wedelia calendulaceae (MEWC) were evaluated for their anticancer activity against Ehrlich Ascites Carcinoma (EAC) in Swiss albino mice. On day 1, the extract of Indigofera aspalathoides at a dose of 250 and 500 mg/kg body weight and the extract of Wedelia calendulaceae at a dose of 250 and 500 mg/kg body weight were administered ora...
متن کاملLong Acting Propranolol and HSP-70 Rich Tumor Lysate Reduce Tumor Growth and Enhance Immune Response against Fibrosarcoma in Balb/c Mice
Background: Noradrenaline (NA), the principal neurotransmitter released from sympathetic nerve terminals, influences T-cell maturation, not only directly in developing T cells, but also indirectly, by acting on the thymic nonlymphoid cells. In vitro and in vivo studies have demonstrated the anti-proliferative, anti-migratory, antiangiogenic and cytotoxic properties of propranolol, β-AR blocker,...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Toxicological sciences : an official journal of the Society of Toxicology
دوره 128 1 شماره
صفحات -
تاریخ انتشار 2012