TY - JOUR
T1 - Sapacitabine for cancer
AU - Liu, Xiaojun
AU - Kantarjian, Hagop
AU - Plunkett, William
N1 - Funding Information:
Investigations from the authors’ laboratories were supported by Grants CA28596, CA81534 and CA100532 from the National Cancer Institute, Department of Health and Human Services. The authors state no conflict of interest and have received no payment in preparation of this manuscript.
PY - 2012/4
Y1 - 2012/4
N2 - Introduction: Sapacitabine is an orally bioavailable nucleoside analog prodrug that is in clinical trials for hematologic malignancies and solid tumors. The active metabolite of sapacitabine, CNDAC (2′-C-cyano-2′- deoxy-1-β-d-arabino-pentofuranosylcytosine), exhibits the unique mechanism of action of causing single-strand breaks (SSBs) after incorporation into DNA, which are converted into double-strand breaks (DSBs) when cells enter a second S-phase. CNDAC-induced DSBs are predominantly repaired through homologous recombination (HR). Cells deficient in HR components are greatly sensitized to CNDAC. Therefore, sapacitabine could be specifically effective against tumors that are deficient in this repair pathway. Areas covered: This review summarizes results from supporting evidence for the mechanisms of action of sapacitabine, its preclinical activities and the current results of clinical trials in a variety of cancers. The novel action mechanism of sapacitabine is discussed, with a view to validate it as a chemotherapeutic drug targeting malignancies with defects in HR. Expert opinion: Knowledge of CNDAC mechanism identifies tumors that may be sensitized to sapacitabine, thus enabling a personalized treatment strategy. It also creates the opportunity to overcome resistance to current front-line therapies and identify synergistic interactions with known anticancer drugs. The results of such investigations may provide rationales for the design of sapacitabine-based clinical trials.
AB - Introduction: Sapacitabine is an orally bioavailable nucleoside analog prodrug that is in clinical trials for hematologic malignancies and solid tumors. The active metabolite of sapacitabine, CNDAC (2′-C-cyano-2′- deoxy-1-β-d-arabino-pentofuranosylcytosine), exhibits the unique mechanism of action of causing single-strand breaks (SSBs) after incorporation into DNA, which are converted into double-strand breaks (DSBs) when cells enter a second S-phase. CNDAC-induced DSBs are predominantly repaired through homologous recombination (HR). Cells deficient in HR components are greatly sensitized to CNDAC. Therefore, sapacitabine could be specifically effective against tumors that are deficient in this repair pathway. Areas covered: This review summarizes results from supporting evidence for the mechanisms of action of sapacitabine, its preclinical activities and the current results of clinical trials in a variety of cancers. The novel action mechanism of sapacitabine is discussed, with a view to validate it as a chemotherapeutic drug targeting malignancies with defects in HR. Expert opinion: Knowledge of CNDAC mechanism identifies tumors that may be sensitized to sapacitabine, thus enabling a personalized treatment strategy. It also creates the opportunity to overcome resistance to current front-line therapies and identify synergistic interactions with known anticancer drugs. The results of such investigations may provide rationales for the design of sapacitabine-based clinical trials.
KW - ATM
KW - BRCA2
KW - CNDAC
KW - Homologous recombination
KW - Leukemia and lymphoma
KW - Nucleotide excision repair
KW - Rad51
KW - Sapacitabine
KW - Solid tumor
KW - Xrcc3
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U2 - 10.1517/13543784.2012.660249
DO - 10.1517/13543784.2012.660249
M3 - Article
C2 - 22329458
AN - SCOPUS:84863250250
SN - 1354-3784
VL - 21
SP - 541
EP - 555
JO - Expert Opinion on Investigational Drugs
JF - Expert Opinion on Investigational Drugs
IS - 4
ER -