Alpha-Tocopheryl succinate: Toxicity and lack of anti-tumour activity in immuno-competent mice

Food and Chemical Toxicology . 2007 Aug 29; [Epub ahead of print] [Link]

Ireland DJ, Kissick HT, Beilharz MW.

Microbiology and Immunology (M502), School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, 6009 Perth, Western Australia, Australia.


Alpha-tocopheryl succinate (α-TOS), an analogue of vitamin E (VitE), inhibits peritoneal human malignant mesoethelioma xenograft development in immuno-compromised mice via the induction of apoptosis of tumour cells [Tomasetti, M., Gellert, N., Procopio, A., Neuzil, J., 2004. A vitamin E analogue suppresses malignant mesothelioma in a preclinical model: a future drug against a fatal neoplastic disease? Int. J. Cancer 109, 641–642]. We tested the effect of systemic α-TOS treatment in our immuno-competent and syngeneic murine mesothelioma model. VitE analogues such as α-TOS have been developed for clinical use as supplements mainly for the treatment of VitE deficiency and are considered safe and non-toxic when taken orally. In our murine model of mesothelioma α-TOS was not only ineffective at inhibiting established tumour development at the published doses, but resulted in severe side effects characterized by both behavioural changes, intra-peritoneal abnormalities and the destruction of T cells. Toxicity of α-TOS has not been reported to date perhaps due to a lack of studies conducted in fully immuno-competent hosts. Our results suggest that the translation of animal studies to clinical treatment with α-TOS requires careful consideration.

Keywords: Mesothelioma; Animal model; Vitamin E; Toxicity; Anti-cancer therapy

Abbreviations: α-TOS, alpha-tocopheryl succinate; VitE, vitamin E; DMSO, dimethyl sulphoxide; TNF, tumour necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; FGFR1, fibroblast growth factor receptor-1; SEM, standard error of the mean; FACS, fluorescence activated cell sorting; s.c., subcutaneous; i.p., intra-peritoneal; ROS, reactive oxygen species; MM, malignant mesothelioma