Griffiths E A, Choy G, Redkar S, Taverna P, Azab M, Karpf A R
Roswell Park Cancer Institute, Elm & Carlton Sts., Buffalo, New York 14263, USA.
Astex Pharmaceuticals, 4140 Dublin Blvd., Dublin, California 94582, USA.
Drugs Future. 2013 Aug;38(8):535-543.
SGI-110 is a second-generation hypomethylating prodrug whose active metabolite is the well-characterized drug decitabine. This novel compound is an oligonucleotide consisting of decitabine linked through a phosphodiester bond to the endogenous nucleoside deoxyguanosine. The dinucleotide configuration provides protection from drug clearance by deamination, while maintaining at least equivalent effects on gene-specific and global hypomethylation both in vitro and in animal model systems. This agent is currently being tested in phase I and II clinical trials in humans and has been demonstrated to be safe and well tolerated as a single agent, with evidence of promising activity in heavily pretreated (including currently FDA approved hypomethylating drugs) myelodysplastic syndrome and acute myeloid leukemia patients. Ongoing trials are also open in platinum-resistant ovarian cancer and hepatocellular carcinoma.
SGI-110是一种第二代低甲基化前体药物，其活性代谢产物是已被充分研究的药物地西他滨。这种新型化合物是一种寡核苷酸，由通过磷酸二酯键与内源性核苷脱氧鸟苷相连的地西他滨组成。二核苷酸结构可防止药物通过脱氨作用清除，同时在体外和动物模型系统中对基因特异性和整体低甲基化保持至少同等的效果。该药物目前正在进行人体I期和II期临床试验，已证明作为单一药物是安全且耐受性良好的，有证据表明在经过大量预处理（包括目前FDA批准的低甲基化药物）的骨髓增生异常综合征和急性髓系白血病患者中具有有前景的活性。正在进行的试验也在铂耐药卵巢癌和肝细胞癌中开展。
