Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA.
Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, University of Texas M.D. Anderson Cancer Center, Bastrop, Texas, 78602, USA.
Pharm Res. 2017 Jun;34(6):1224-1232. doi: 10.1007/s11095-017-2139-x. Epub 2017 Mar 28.
This study was designed to test the short-term toxicity of DHA-dFdC in a mouse model and its efficacy in a mouse model of leukemia at or below its repeat-dose maximum tolerated dose (RD-MTD).
A repeat-dose dose-ranging toxicity study was designed to determine the tolerability of DHA-dFdC when administered to DBA/2 mice by intravenous (i.v.) injection on a repeat-dose schedule (i.e. injections on days 0, 3, 7, 10, and 13). In order to determine the effect of a lethal dose of DHA-dFdC, mice were injected i.v. with three doses of DHA-dFdC at 100 mg/kg on days 0, 3, and 5 (i.e. a lethal-RD). The body weight of mice was recorded two or three times a week. At the end of the study, major organs (i.e. heart, liver, spleen, kidneys, lung, and pancreas) of mice that received the lethal-RD or RD-MTD were weighed, and blood samples were collected for analyses. Finally, DHA-dFdC was i.v. injected into DBA/2 mice with syngeneic L1210 mouse leukemia cells to evaluate its efficacy at or below RD-MTD.
The RD-MTD of DHA-dFdC is 50 mg/kg. At 100 mg/kg, a lethal-RD, DHA-dFdC decreases the weights of mouse spleen and liver and significantly affected certain blood parameters (i.e. white blood cells, lymphocytes, eosinophils, and neutrophil segmented). At or below its RD-MTD, DHA-dFdC significantly prolonged the survival of L1210 leukemia-bearing mice.
DHA-dFdC has dose-dependent toxicity, affecting mainly spleen at a lethal-RD. At or below its RD-MTD, DHA-dFdC is effective against leukemia in a mouse model.
本研究旨在测试 DHA-dFdC 在小鼠模型中的短期毒性及其在低于重复剂量最大耐受剂量（RD-MTD）的白血病小鼠模型中的疗效。
设计了一项重复剂量剂量范围毒性研究，以确定 DHA-dFdC 在以重复剂量方案（即 0、3、7、10 和 13 天注射）通过静脉（i.v.）注射给予 DBA/2 小鼠时的耐受性。为了确定致死剂量 DHA-dFdC 的作用，小鼠在第 0、3 和 5 天（即致死-RD）静脉注射三剂 100mg/kg 的 DHA-dFdC。每周记录两次或三次小鼠体重。研究结束时，称重接受致死-RD 或 RD-MTD 的小鼠的主要器官（即心脏、肝脏、脾脏、肾脏、肺和胰腺），并采集血液样本进行分析。最后，将 DHA-dFdC 静脉注射到具有同基因 L1210 小鼠白血病细胞的 DBA/2 小鼠中，以评估其在 RD-MTD 或以下时的疗效。
DHA-dFdC 的 RD-MTD 为 50mg/kg。在 100mg/kg 时，致死-RD 时，DHA-dFdC 降低了小鼠脾脏和肝脏的重量，并显著影响了某些血液参数（即白细胞、淋巴细胞、嗜酸性粒细胞和中性粒细胞分叶）。在 RD-MTD 或以下时，DHA-dFdC 显著延长了携带 L1210 白血病的小鼠的存活时间。
DHA-dFdC 具有剂量依赖性毒性，在致死-RD 时主要影响脾脏。在 RD-MTD 或以下时，DHA-dFdC 对白血病小鼠模型有效。
