科研之友
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摘要
AEG-35156 is a fully phosphorothioated second-generation 19-mer mixed-bockbone antisense oligonucleotide (ASO) consisting of on 11-nucleotide DNA core flanked at the 3' and 5' ends by four 2'-O-methyl RNA residues. The ASO was rationally designed to target the X-linked inhibitor of apoptosis protein (XIAP). XIAP which is a member of the family of IAPs, has been shown to hove an increasingly complex role in cancer Although considerable evidence now supports XIAP as a validated target in anticancer drug design, the efficacy of antisense as a therapeutic approach remains to be proven clinically, especially in the treatment of cancer Preclinically, AEG-35156 exhibits high potency and selectivity for its target and exerts brood-spectrum antitumor activity against a panel of human cancer xenografts. It also combines synergistically with conventional cytotoxic drugs to induce long-term tumor regression. The ASO entered its first phase I clinical trial in cancer patients in 2004, where it was administered as either a 7- or 3-day continuous infusion an a 21-day treatment cycle. Several other phase I/II trials hove also been initiated exploring different administration schedules and the effect of combination with chemotherapy in more focused disease groups. Pharmacodynamic and biomarker studies played an important role in these clinical trials. Evidence has now accrued in cancer patients for target knockdown in surrogate tissues, leading to the induction of apoptosis, and clinical responses hove been reported.
- 出版日期2009-6
