TY - JOUR
T1 - Sapacitabine, the prodrug of CNDAC, is a nucleoside analog with a unique action mechanism of inducing DNA strand breaks
AU - Liu, Xiao Jun
AU - Nowak, Billie
AU - Wang, Ya Qing
AU - Plunkett, William
PY - 2012/6/26
Y1 - 2012/6/26
N2 - Sapacitabine is an orally bioavailable prodrug of the nucleoside analog 2'-C-cyano2'-d-eoxy1 D arabinop entofuranosylcytosine (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 singlest rand breaks (SSBs) that are converted into doublestrand breaks (DSBs) when cells go through a second S phase. In our previous studies, we demonstrated that CNDAC in duced SSBs can be repaired by the transcription oupled 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.
AB - Sapacitabine is an orally bioavailable prodrug of the nucleoside analog 2'-C-cyano2'-d-eoxy1 D arabinop entofuranosylcytosine (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 singlest rand breaks (SSBs) that are converted into doublestrand breaks (DSBs) when cells go through a second S phase. In our previous studies, we demonstrated that CNDAC in duced SSBs can be repaired by the transcription oupled 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.
KW - CNDAC
KW - Cytarabine
KW - Gemcitabine
KW - Homologous recombination
KW - Sapacitabine
UR - http://www.scopus.com/inward/record.url?scp=84865222487&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865222487&partnerID=8YFLogxK
U2 - 10.5732/cjc.012.10077
DO - 10.5732/cjc.012.10077
M3 - Article
C2 - 22739266
AN - SCOPUS:84865222487
SN - 1000-467X
VL - 31
SP - 373
EP - 380
JO - Chinese Journal of Cancer
JF - Chinese Journal of Cancer
IS - 8
ER -