A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma
A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma
复制标题
DOI：
10.1002/cmdc.201900324
复制
发表时间：
2019-07-04
期刊：
影响因子：
3.4
通讯作者：
Obika, Satoshi
中科院分区：
文献类型：
--
作者：
Matsushita, Katsunori;Okuda, Takumi;Obika, Satoshi
使用抗癌化疗药物的主要问题是宿主毒性。患者因不良反应需要中断或改变化疗。在这项研究中，我们旨在减少吉西他滨 (GEM) 治疗胰腺导管腺癌的不良事件，并重点关注正常细胞与癌细胞中过氧化氢水平的差异。我们设计并合成了一种新型硼酸酯笼式前药，该前药可被癌细胞中发现的高浓度 H2O2 激活，释放 GEM。 H2O2 可激活的 GEM (A-GEM) 对 H2O2 比其他活性氧 (ROS) 具有更高的选择性，并且具有与体外 H2O2 浓度相对应的细胞毒性作用。免疫缺陷小鼠的异种移植模型表明，体内给药时A-GEM的效果不逊色于GEM。特别是，与 GEM 治疗后相比，A-GEM 治疗后的骨髓抑制显着降低。
The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate-ester-caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2-activatable GEM (A-GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A-GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A-GEM treatment compared with that following GEM treatment.