The University of Texas M.D. Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX, USA.
Expert Opin Investig Drugs. 2012 Apr;21(4):541-55. doi: 10.1517/13543784.2012.660249. Epub 2012 Feb 14.
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.
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.
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.
沙柏西他滨是一种口服生物可利用的核苷类似物前药，正在临床试验中用于血液系统恶性肿瘤和实体瘤。沙柏西他滨的活性代谢物 CNDAC（2'-C-氰基-2'-脱氧-1-β-D-阿拉伯戊呋喃糖基胞嘧啶）在掺入 DNA 后具有独特的作用机制，会导致单链断裂（SSB），当细胞进入第二个 S 期时，这些单链断裂会转化为双链断裂（DSB）。CNDAC 诱导的 DSB 主要通过同源重组（HR）修复。HR 成分缺失的细胞对 CNDAC 非常敏感。因此，沙柏西他滨可能对缺乏这种修复途径的肿瘤具有特异性疗效。
本综述总结了支持沙柏西他滨作用机制、临床前活性以及各种癌症临床试验当前结果的证据，讨论了沙柏西他滨的新型作用机制，以期将其验证为一种针对 HR 缺陷的恶性肿瘤的化疗药物。
了解 CNDAC 的作用机制可以识别可能对沙柏西他滨敏感的肿瘤，从而实现个性化的治疗策略。它还为克服对当前一线治疗的耐药性以及确定与已知抗癌药物的协同作用提供了机会。这些研究的结果可能为基于沙柏西他滨的临床试验设计提供依据。
