Sapacitabine,the prodrug of CNDAC,is a nucleoside analog with a unique action mechanism of inducing DNA strand breaks

• Published in: Ai zheng 2012-08, Vol.31 (8), p.373-380
• Main Authors: Liu, Xiao-Jun, Nowak, Billie, Wang, Ya-Qing, Plunkett, William
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacology; Arabinonucleosides - pharmacology; CHO Cells; Cricetinae; Cricetulus; Cytarabine - analogs & derivatives; Cytarabine - pharmacology; Cytosine - analogs & derivatives; Cytosine - pharmacology; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; DNA Breaks, Double-Stranded - drug effects; DNA Repair - drug effects; DNA-Binding Proteins - deficiency; DNA双链断裂; DNA链断裂; Gemcitabine; Homologous Recombination - genetics; Inhibitory Concentration 50; Original; Prodrugs; 修复机制; 前药; 核苷类似物; 核苷酸切除修复; 活性代谢产物; 阿糖胞苷
• ISSN: 1000-467X; 1944-446X
• DOI: 10.5732/cjc.012.10077

Sapacitabine is an orally bioavailable prodrug of the nucleoside analog 2’-C-cyano-2’-deoxy-1-β-D-arabino-pentofuranosylcytosine（CNDAC）.Both the prodrug and active metabolite are in clinical trials for hematologic malignancies and/or solid tumors.CNDAC has a unique mechanism of action：after incorporation into DNA,it induces single-strand breaks（SSBs） that are converted into double-strand breaks（DSBs） when cells go through a second S phase.In our previous studies,we demonstrated that CNDAC-induced SSBs can be repaired by the transcription-coupled nucleotide excision repair pathway,whereas lethal DSBs are mainly repaired through homologous recombination.In the current work,we used clonogenic assays to compare the DNA damage repair mechanism of CNDAC with two other deoxycytidine analogs：cytarabine,which is used in hematologic malignacies,and gemcitabine,which shows activity in solid tumors.Deficiency in two Rad51 paralogs,Rad51D and XRCC3,greatly sensitized cells to CNDAC,but not to cytarabine or gemcitabine,indicating that homologous recombination is not a major mechanism for repairing damage caused by the latter two analogs.This study further suggests clinical activity and application of sapacitabine that is distinct from that of cytarabine or gemcitabine.