Abstract 4933: Six-month oral toxicity study of endoxifen in rats

Abstract

Abstract The tamoxifen metabolite, endoxifen (N-desmethyl-4-hydroxytamoxifen), is being developed for oral and local topical administration for prevention and therapy of breast cancer. As part of this development, the toxicity of oral endoxifen was evaluated in a chronic (six-month) study in rats. Groups of 25 female CD rats received daily oral (gavage) exposure to endoxifen at doses of 0 (vehicle control), 5, or 50 mg/kg/day for six months. In vivo assessments included survival; clinical and physical signs of toxicity; body weight; food consumption; ophthalmology; and clinical pathology (clinical chemistry, hematology, coagulation). Fifteen rats per group were euthanized and necropsied after six months of endoxifen exposure; remaining rats in each group were euthanized and necropsied after a four-week recovery period. All gross lesions and approximately 45 tissues per animal were evaluated microscopically. In addition, bone marrow smears collected from rats euthanized for the six month necropsy were evaluated for DNA damage (micronucleus assessment). Daily oral administration of endoxifen at 5 or 50 mg/kg/day for six months induced no treatment-related mortality, clinical evidence of toxicity, or effects on ophthalmology. Endoxifen was not genotoxic, as it had no effect on the incidence of bone marrow micronuclei. Both dose levels of endoxifen induced similar suppressions of body weight gain; food consumption was also significantly decreased in both endoxifen-treated groups. Both dose levels of endoxifen induced gross and microscopic changes in hormone-sensitive tissues. Gross pathology was identified at necropsy in the ovary (cysts) and uterus (small) in both endoxifen groups; mean relative ovarian weight was increased and mean relative uterine weight was decreased in endoxifen groups. Microscopic findings were identified in the ovaries (corpora lutea depletion, cysts), uterus (atrophy, endometrial hyperplasia), cervix (mucinous hypertrophy), mammary gland (hyperplasia), and pituitary gland (vacuolation). These changes are consistent with the activity of endoxifen as an endocrine disruptor, and suggest effects on the hypothalamic-pituitary-gonadal axis. After six months of daily oral administration, both dose levels of endoxifen induced significant reductions in body weight gain and food consumption; alterations in the weights of hormone-sensitive organs; and gross and microscopic effects, primarily in hormone-sensitive tissues. Most of the effects of endoxifen observed in this study can be ascribed to its potent antiestrogenic activity, and are interpreted as signs of its pharmacologic action. However, the gross and microscopic changes seen at both dose levels of endoxifen used in this study demonstrate that a No Observed (Adverse) Effect Level (NO[A]EL) for daily oral administration of endoxifen to female rats for six months could not be determined. [Supported by HHSN261201500024I from the NCI, DHHS.] Citation Format: Thomas L. Horn, William D. Johnson, Carol J. Detrisac, Patrick T. Curry, Elizabeth R. Glaze, David L. McCormick. Six-month oral toxicity study of endoxifen in rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4933.