Vitamin E phosphate (VEP) nucleoside prodrugs are designed to bypass two mechanisms\nof tumor resistance to therapeutic nucleosides: nucleoside transport and kinase downregulation.\nCertain isoforms of vitamin E (VE) have shown activity against solid and hematologic tumors and\nresult in chemosensitization. Because gemcitabine is one of the most common chemotherapeutics for\nthe treatment of cancer, it was used to demonstrate the constructs utility. Four different VE isoforms\nwere conjugated with gemcitabine at the 5 position. Two of these were Ã?´-tocopherol-monophosphate\n(MP) gemcitabine (NUC050) and Ã?´-tocotrienol-MP gemcitabine (NUC052). NUC050 was shown to be\nable to deliver gemcitabine-MP intracellularly by a nucleoside transport independent mechanism.\nIts half-life administered IV in mice was 3.9 h. In a mouse xenograft model of non-small cell lung\ncancer (NSCLC) NCI-H460, NUC050 at a dose of 40 mg/kg IV qwk Ã?â?? 4 resulted in significant\ninhibition to tumor growth on days 11ââ?¬â??31 (p < 0.05) compared to saline control (SC). Median survival\nwas 33 days (NUC050) vs. 25.5 days (SC) ((hazard ratio) HR = 0.24, p = 0.017). Further, NUC050\nsignificantly inhibited tumor growth compared to historic data with gemcitabine at 135 mg/kg IV\nq5d Ã?â?? 3 on days 14ââ?¬â??41 (p < 0.05). NUC052 was administered at a dose of 40 mg/kg IV qwk Ã?â?? 2\nfollowed by 50 mg/kg qwk Ã?â?? 2. NUC052 resulted in inhibition to tumor growth on days 14ââ?¬â??27\n(p < 0.05) and median survival was 34 days (HR = 0.27, p = 0.033). NUC050 and NUC052 have been\nshown to be safe and effective in a mouse xenograft of NSCLC.
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