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Activity of Vitamin E Phosphate (VEP) Prodrugs of Gemcitabine in a Xenograft Model of NSCLC (NCI-H460)
1  Epigenetics Pharma, Mercer Island, WA, USA

Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

VEP nucleosides bypass two mechanisms of tumor resistance: nucleoside transport and kinase downregulation.  Isoforms of VE have shown activity against solid and hematologic tumors.  Gemcitabine was conjugated at the 5’ position to either δ-tocopherol-MP (NUC050) or δ-tocotrienol-MP (NUC052).

NUC050 has been demonstrated to deliver gemcitabine-MP intracellularly.  Its half-life IV in mice is 3.9 compared to 0.28 hours for gemcitabine (European J Cancer. 2016. 61(Suppl. 1):S119).

When tumors in nude mice reached 32 to 75 mg mm3 (day 4) treatment was initiated with gemcitabine (120 mg/kg IP q3dx9), NUC050 or NUC052 (both 40 mg/kg qwkx4) and compared to saline control (SC).

Gemcitabine inhibited tumor growth but was not tolerated.  NUC050 resulted in inhibition to tumor growth on days 11-31 (p<0.05), with a nadir of -73% compared to SC.  Median survival was 25.5 days (SC) vs 33 days (NUC050) ((hazard ratio) HR=0.24, p=0.017).  NUC052 had the dose increased to 50 mg/kg after 2 doses.  NUC052 resulted in inhibition to tumor growth on days 14-27 (p<0.05), with a nadir of -45%, 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 NSCLC xenograft.  Studies have been initiated in a pancreatic cancer xenograft.