Gemcitabine is a pyrimidine nucleoside analogue commonly used for the treatment of solid tumors. Acelarin is a gemcitabine ProTide with cytotoxic activity against a range of cancer cell lines in vitro, including L1210 (IC50=0.035±0.02μM), CEM (IC50=0.1±0.03μM), MP-2 (IC50=0.44±0.06μM), and BxPC-3 (IC50=0.15±0.04μM). The colorimetric MTT assay showed that acelarin was more cytotoxic than gemcitabine and its activity was not significantly affected by deoxycytidine. In a nude mouse xenograft model of MiaPaCa-2 human pancreatic cancer cells, acelarin at a dose of 0.076mmol/kg achieved significantly greater reduction in tumor volume than gemcitabine on Day 7 after the first administration of the compounds[2].
作用机制
Acelarin is a gemcitabine ProTide that bears a phosphoramidate moiety on the 5’-carbon of the ribose. It has been shown to resist cytidine deaminase-mediated degradation. Acelarin bypasses deoxycytidine kinase-mediated monophosphorylation and does not rely on the nucleoside transporter human equilibrative nucleoside transporter-1 to exert the anticancer effect.[2]
Acelarin 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A2780 cells
600 nM (IC50)
2 h
To assess the kinetics of NUC-1031 cellular uptake and activation by analyzing intracellular levels of the active metabolite dFdCTP and its incorporation into DNA. Results showed that dFdCTP peaked at 48 hours post-treatment (350 nmol/10^6 cells).
Transl Oncol. 2024 Dec;50:102114
HuCCT1 cells
1 μM (IC50)
24 h
To assess the kinetics of NUC-1031 cellular uptake and activation by analyzing intracellular levels of the active metabolite dFdCTP and its incorporation into DNA. Results showed that dFdCTP peaked at 24 hours post-treatment (220 nmol/10^6 cells) and remained detectable up to 96 hours.
Transl Oncol. 2024 Dec;50:102114
A2780 ovarian cancer cells
5 nM to 500 nM
2 h
To evaluate the cytotoxic differences between NUC-1031 and gemcitabine on A2780 cells. Results showed that the cytotoxic effects of NUC-1031 were more prolonged than those of gemcitabine.
Sci Rep. 2019 May 21;9(1):7643
MiaPaCa2 pancreatic cancer cells
5 nM to 250 nM
4 days
To evaluate the cytotoxic differences between NUC-1031 and gemcitabine on MiaPaCa2 cells. Results showed that NUC-1031 retained cytotoxicity in the presence of deoxycytidine (dCyd), while gemcitabine was completely inactive.
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