DNA Therapeutics, Evry, France.
Mol Ther Nucleic Acids. 2012 Jul 31;1(7):e33. doi: 10.1038/mtna.2012.27.
Increased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistances. coDbait is a 32-base pair (bp) double-stranded DNA molecule with a cholesterol moiety covalently attached to its 5'-end to facilitate its cellular uptake. We report here the preclinical pharmacokinetic and toxicology studies of subcutaneous coDbait administration in rodents and monkeys. Maximum plasma concentration occurred between 2 to 4 hours in rats and at 4 hours in monkeys. Increase in mean AUC0-24h was linear with dose reaching 0.5 mg·h/ml for the highest dose injected (32 mg) for both rats and monkeys. No sex-related differences in maximum concentration (Cmax) nor AUC0-24h were observed. We extrapolated these pharmacokinetic results to humans as the subcutaneous route has been selected for evaluation in clinical trials. Tri-weekly administration of coDbait (from 8 to 32 mg per dose) for 4 weeks was overall well tolerated in rats and monkeys as no morbidity/mortality nor changes in clinical chemistry and histopathology parameters considered to be adverse effects have been observed.
癌细胞中 DNA 修复活性的增加是其对当前放射和化学疗法产生耐药性的主要机制之一。分子 coDbait 是一类新型药物的首个候选药物，这类药物的作用靶点是双链 DNA 断裂修复途径，旨在克服这些耐药性。coDbait 是一种带有胆固醇部分的 32 个碱基对（bp）双链 DNA 分子，其 5' 端通过共价键连接，以促进其细胞摄取。我们在此报告了皮下给予 coDbait 在啮齿动物和猴子中的临床前药代动力学和毒理学研究。在大鼠中，最大血浆浓度出现在 2 至 4 小时之间，而在猴子中则出现在 4 小时。在大鼠和猴子中，AUC0-24h 的增加与剂量呈线性关系，最高剂量（32mg）的 AUC0-24h 达到 0.5mg·h/ml。未观察到最大浓度（Cmax）或 AUC0-24h 与性别有关的差异。我们将这些药代动力学结果外推到人类，因为皮下给药途径已被选择用于临床试验评估。在大鼠和猴子中，每周三次给予 coDbait（每次剂量为 8 至 32mg），连续 4 周，总体耐受性良好，未观察到发病率/死亡率或临床化学和组织病理学参数的变化，这些参数被认为是不良反应。
