title: Repeat dose study of the novel proapoptotic chemotherapeutic agent alpha-tocopheryloxy acetic acid in mice.
abstract: Alpha-tocopheryloxy acetic acid (α-TEA) is an ether derivative of vitamin E and has been shown to suppress tumor growth in various murine and human xenograft tumor models, including melanoma, breast, lung, prostate, and ovarian cancers. The purpose of this study was to assess its safety and pharmacokinetics after repeat dosing in a preclinical murine model. Male and female mice received α-TEA doses of 100, 300, or 1500 mg/kg/day by daily oral gavage for 28 days. α-TEA serum levels were determined weekly by high-performance liquid chromatography with mass spectrometric detection. After 28 days of dosing, complete blood counts were taken, blood chemistry was analyzed, and histology was performed. Pharmacokinetic parameters were determined after single dosing. There was no mortality, and we found no clinical signs of toxicity in any of the α-TEA doses tested. Histopathological evaluation of major organs (heart, lung, kidney, liver, spleen, jejunum, ileum, and cecum) revealed no significant α-TEA treatment-related lesions. Blood counts revealed low-grade anemia but no other significant differences between treatment and control groups. Blood chemistry revealed moderate liver toxicity that was dose dependent and was absent in the lowest dose group. There were no significant sex-specific differences in the toxicity profile. The half-life of orally administered α-TEA was determined to be 52 h. This is the first report comprehensively evaluating the toxicity profile of this novel anticancer drug and will facilitate the design of clinical trials to evaluate the safety and antitumor efficacy of α-TEA in patients with cancer.
authors.affiliation: Laboratory of Tumor Immunology and Therapeutics, Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, Oregon 97213, USA. tobias.hahn@providence.org
authors.forename: Tobias
authors.initials: T
authors.lastname: Hahn
authors.forename: Emmanuel T
authors.initials: ET
authors.lastname: Akporiaye
mesh_terms: D000740:Anemia / Q000139:chemically induced; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury; D004353:Drug Evaluation, Preclinical; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D024505:Tocopherols / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; C488288:2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid; D024505:Tocopherols