Hee-Yeon Cho1, Steve Swenson1, Thu Zan Thein1, Weijun Wang1, Neloni R Wijeratne2, Nagore I Marín-Ramos1, Jonathan E Katz2, Florence M Hofman1,3, Axel H Schönthal4, Thomas C Chen1,3. 1. Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 2. Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, California, USA. 3. Department of Pathology Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 4. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Abstract
BACKGROUND: NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent temozolomide (TMZ). It is undergoing preclinical development as a therapeutic for brain-localized malignancies. The aim of this study was to characterize metabolism and pharmacokinetic (PK) properties of NEO212 in preclinical models. METHODS: We used mass spectrometry (MS) and modified high-performance liquid chromatography to identify and quantitate NEO212 and its metabolites in cultured glioblastoma cells, in mouse plasma, brain, and excreta after oral gavage. RESULTS: Our methods allowed identification and quantitation of NEO212, POH, TMZ, as well as primary metabolites 5-aminoimidazole-4-carboxamide (AIC) and perillic acid (PA). Intracellular concentrations of TMZ were greater after treatment of U251TR cells with NEO212 than after treatment with TMZ. The half-life of NEO212 in mouse plasma was 94 min. In mice harboring syngeneic GL261 brain tumors, the amount of NEO212 was greater in the tumor-bearing hemisphere than in the contralateral normal hemisphere. The brain:plasma ratio of NEO212 was greater than that of TMZ. Excretion of unaltered NEO212 was through feces, whereas its AIC metabolite was excreted via urine. CONCLUSIONS: NEO212 preferentially concentrates in brain tumor tissue over normal brain tissue, and compared to TMZ has a higher brain:plasma ratio, altogether revealing favorable features to encourage its further development as a brain-targeted therapeutic. Its breakdown into well-characterized, long-lived metabolites, in particular AIC and PA, will provide useful equivalents for PK studies during further drug development and clinical trials with NEO212.
BACKGROUND: NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent temozolomide (TMZ). It is undergoing preclinical development as a therapeutic for brain-localized malignancies. The aim of this study was to characterize metabolism and pharmacokinetic (PK) properties of NEO212 in preclinical models. METHODS: We used mass spectrometry (MS) and modified high-performance liquid chromatography to identify and quantitate NEO212 and its metabolites in cultured glioblastoma cells, in mouse plasma, brain, and excreta after oral gavage. RESULTS: Our methods allowed identification and quantitation of NEO212, POH, TMZ, as well as primary metabolites 5-aminoimidazole-4-carboxamide (AIC) and perillic acid (PA). Intracellular concentrations of TMZ were greater after treatment of U251TR cells with NEO212 than after treatment with TMZ. The half-life of NEO212 in mouse plasma was 94 min. In mice harboring syngeneic GL261 brain tumors, the amount of NEO212 was greater in the tumor-bearing hemisphere than in the contralateral normal hemisphere. The brain:plasma ratio of NEO212 was greater than that of TMZ. Excretion of unaltered NEO212 was through feces, whereas its AIC metabolite was excreted via urine. CONCLUSIONS: NEO212 preferentially concentrates in brain tumor tissue over normal brain tissue, and compared to TMZ has a higher brain:plasma ratio, altogether revealing favorable features to encourage its further development as a brain-targeted therapeutic. Its breakdown into well-characterized, long-lived metabolites, in particular AIC and PA, will provide useful equivalents for PK studies during further drug development and clinical trials with NEO212.
Authors: Hee-Yeon Cho; Weijun Wang; Niyati Jhaveri; Shering Torres; Joshua Tseng; Michelle N Leong; David Jungpa Lee; Amir Goldkorn; Tong Xu; Nicos A Petasis; Stan G Louie; Axel H Schönthal; Florence M Hofman; Thomas C Chen Journal: Mol Cancer Ther Date: 2012-08-28 Impact factor: 6.261
Authors: Thomas C Chen; Hee-Yeon Cho; Weijun Wang; Jenny Nguyen; Niyati Jhaveri; Rachel Rosenstein-Sisson; Florence M Hofman; Axel H Schönthal Journal: Cancer Lett Date: 2014-12-15 Impact factor: 8.679
Authors: Hee-Yeon Cho; Thu Zan Thein; Weijun Wang; Stephen D Swenson; Rochelle A Fayngor; Mengting Ou; Nagore I Marín-Ramos; Axel H Schönthal; Florence M Hofman; Thomas C Chen Journal: Mol Cancer Ther Date: 2019-01-15 Impact factor: 6.261
Authors: Hee-Yeon Cho; Weijun Wang; Niyati Jhaveri; David Jungpa Lee; Natasha Sharma; Louis Dubeau; Axel H Schönthal; Florence M Hofman; Thomas C Chen Journal: Mol Cancer Ther Date: 2014-07-03 Impact factor: 6.261
Authors: Roger Stupp; Monika E Hegi; Warren P Mason; Martin J van den Bent; Martin J B Taphoorn; Robert C Janzer; Samuel K Ludwin; Anouk Allgeier; Barbara Fisher; Karl Belanger; Peter Hau; Alba A Brandes; Johanna Gijtenbeek; Christine Marosi; Charles J Vecht; Karima Mokhtari; Pieter Wesseling; Salvador Villa; Elizabeth Eisenhauer; Thierry Gorlia; Michael Weller; Denis Lacombe; J Gregory Cairncross; René-Olivier Mirimanoff Journal: Lancet Oncol Date: 2009-03-09 Impact factor: 41.316