Abstract
Vitamin E phosphate (VEP) nucleoside prodrugs are designed to bypass two mechanisms of tumor resistance to therapeutic nucleosides: nucleoside transport and kinase downregulation. Certain isoforms of vitamin E (VE) have shown activity against solid and hematologic tumors and result in chemosensitization. Because gemcitabine is one of the most common chemotherapeutics for the treatment of cancer, it was used to demonstrate the constructs utility. Four different VE isoforms were conjugated with gemcitabine at the 5′ position. Two of these were δ-tocopherol-monophosphate (MP) gemcitabine (NUC050) and δ-tocotrienol-MP gemcitabine (NUC052). NUC050 was shown to be able to deliver gemcitabine-MP intracellularly by a nucleoside transport independent mechanism. Its half-life administered IV in mice was 3.9 h. In a mouse xenograft model of non-small cell lung cancer (NSCLC) NCI-H460, NUC050 at a dose of 40 mg/kg IV qwk × 4 resulted in significant inhibition to tumor growth on days 11–31 (p < 0.05) compared to saline control (SC). Median survival was 33 days (NUC050) vs. 25.5 days (SC) ((hazard ratio) HR = 0.24, p = 0.017). Further, NUC050 significantly inhibited tumor growth compared to historic data with gemcitabine at 135 mg/kg IV q5d × 3 on days 14–41 (p < 0.05). NUC052 was administered at a dose of 40 mg/kg IV qwk × 2 followed by 50 mg/kg qwk × 2. NUC052 resulted in inhibition to tumor growth on days 14–27 (p < 0.05) and median survival was 34 days (HR = 0.27, p = 0.033). NUC050 and NUC052 have been shown to be safe and effective in a mouse xenograft of NSCLC.
Highlights
IntroductionThere have been a number of attempts to develop prodrugs of gemcitabine with modifications at the 5’ position of the sugar to address some of the shortcomings of its pharmacology and activity
Nucleosides can suffer from short half-lives as a result of deamination [1,2]
There have been a number of attempts to develop prodrugs of gemcitabine with modifications at the 5’ position of the sugar to address some of the shortcomings of its pharmacology and activity
Summary
There have been a number of attempts to develop prodrugs of gemcitabine with modifications at the 5’ position of the sugar to address some of the shortcomings of its pharmacology and activity These approaches have attempted to first and foremost prevent deamination by cytidine deaminase (CDA), the enzyme responsible for gemcitabine’s short half-life [5,6,7,8]. Less commonly, such approaches have attempted to bypass gemcitabine’s requirement for an intact nucleoside transport system for intracellular penetration [5,6,8] and deoxycytidine kinase (dCK) for phosphorylation to gemcitabine-monophosphate (MP) [7,8], the rate limiting step on the way to formation of the therapeutically active diphosphate (DP) and triphosphate (TP). Where such has been published, these constructs have tended to have a relatively short half-life [5,8]
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