A prodrug form of gemcitabine
NUC-1031 is a prodrug form of the anticancer nucleoside analog gemcitabine .1,2 NUC-1031 is more lipophilic than gemcitabine and enters cells through passive diffusion.1 It inhibits the growth of L1210, CEM, MP-2, and BxPC-3 cancer cells in vitro (IC50 = 35, 30, 60, and 40 nM, respectively).2 NUC-1031 (0.076 mmol/kg) reduces tumor growth in Mia-PaCa-2 and BxPC-3 mouse xenograft models, which are partially responsive and resistant to gemcitabine, respectively.3
1.Thornton, P.J., Kadri, H., Miccoli, A., et al.Nucleoside phosphate and phosphonate prodrug clinical candidatesJ. Med. Chem.59(23)10400-10410(2016) 2.Slusarczyk, M., Lopez, M.H., Balzarini, J., et al.Application of ProTide technology to gemcitabine: A successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical developmentJ. Med. Chem.57(4)1531-1542(2014) 3.McGuigan, C., Habib, N.A., Wasan, H.S., et al.A phosphoramidate ProTide (NUC-1031) and acquired and intrinsic resistance to gemcitabineJ. Clin. Oncol.29(15_suppl)e13540(2016)
Cell experiment: | NUC-1031(5.0 mg) is dissolved in DMSO (0.050 mL) and D2O (0.15 mL). After recording the control 31P NMR at 37 °C, a previously defrosted human, rat, or dog serum (0.30 mL) is added to the sample, which is next submitted to the 31P NMR experiments at 37°C. The spectra are recorded every 30 min over 13 h. 31P NMR recorded data are processed and analyzed with the Bruker Topspin 2.1 program[1]. |
Animal experiment: | Balb/c nude mice are female, six to eight week old, with the weight of 20 ± 2 g. They are intraperitoneally given NUC-1031 (i.p 0.228 mmol/kg, 132.3 mg/kg, 2×/WK) or vehicle for 2 weeks. NUC-1031 is dissolved in 40% Captisol solution. (40% Captisol is prepared by dissolving 20mg of Captisol with pure water, and made the final volume 50 mL. The solvent is filtered with 0.22 μm filter). Mice are monitored daily for body weight change and clinical symptoms for 2 weeks[1]. |
参考文献: [1]. Slusarczyk M, et al. Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development. J Med Chem. 2014 Feb 27;57(4):1531-42. | |
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