Novel DNA cross-linking agents and combination strategies for tumor-specific activation

项目概要/摘要 癌细胞由于其异常生长而处于增加的基础氧化应激状态。作为 结果，与正常细胞相比，癌细胞的活性氧（ROS）水平升高 细胞这一特征已被用于开发一类ROS活化的前药， 在ROS存在下变得具有细胞毒性。ROS活化的前药作为 癌症的单一疗法面临许多挑战，包括肿瘤异质性， 前药活化、靶向药物递送困难、缺乏治疗持久性等。 迫切需要一种策略来增强ROS活化的前药的功效和选择性 to a wide宽variety品种of cancer癌症.本课题组研制的H2 O2活化的DNA烷基化试剂 在氧化应激下对癌细胞而不是正常细胞表现出选择性毒性， 这表明它们与扩增的试剂或癌症疗法组合的潜在用途 尤其是癌细胞中的ROS水平。据报道，促氧化剂如维生素C可以作为抗氧化剂。 有效的促氧化剂，在癌细胞中特异性诱导H2 O2，同时保护正常细胞 这是由于较高的过氧化氢酶表达，其淬灭H2 O2。H2 O2的无毒特性- 活化的DNA交联剂在我们的实验室开发，与研究结果表明， vitC选择性地增强H2 O2在癌细胞中的积累，为以下研究提供了令人信服的理由： 以协同方式组合这两种治疗方式。总体假设 该项目的一个重要方面是，所选的促氧化剂与ROS活化的前药的组合可以 实现协同和持久的抗肿瘤作用，同时使不希望的副作用最小化。 具体而言，我们将开发新型ROS激活的抗癌前药， 特异性和药物样性质（目的1），并鉴定与 促氧化剂以改善ROS活化的前药的功效（目的2）。其意义 项目是通过ROS激活的前药和 促氧化剂代表了一种有效的癌症治疗策略。拟议的研究将确定 临床上可应用的ROS活化的前药，其与促氧化剂相容， 有效的、选择性的和持久的治疗益处。该项目的成功完成将 为重新利用ROS激活的DNA烷化剂用于癌症治疗铺平了道路。

Project summary/abstract Cancer cells are in a state of increased basal oxidative stress due to their aberrant growth. As a result, cancer cells have elevated levels of reactive oxygen species (ROS) compared to normal cells. This feature has been employed to develop a class of ROS-activated prodrugs that only become cytotoxic in the presence of ROS. The effectiveness of ROS-activated prodrugs as monotherapy for cancer faces many challenges, including tumor heterogeneity, insufficient prodrug activation, difficulty in targeted drug delivery, lack of therapeutic durability, etc. Novel strategies are urgently needed to augment the efficacy and selectivity of ROS-activated prodrugs to a wide variety of cancer. The H2O2-activated DNA alkylating agents developed by our group exhibit selective toxicity towards cancer cells under oxidative stress but not normal cells, suggesting their potential usage in combination with reagents or cancer therapies that amplify ROS level specially in cancer cells. It has been reported that prooxidants such as vitC can act as potent pro-oxidants to induce H2O2 specifically in cancer cells while normal cells are protected due to higher Catalase expression that quenches H2O2. The non-toxic feature of the H2O2- activated DNA cross-linking agents developed in our lab, together with the findings showing that vitC selectively intensify H2O2 accumulation in cancer cells, provides a compelling rationale for combining these two therapeutic modalities in a synergistic manner. The overarching hypothesis of this project is that the combination of selected pro-oxidants with ROS-activated prodrugs can achieve synergistic and durable antitumor effects while minimizing unwanted side-effects. Specifically, we will develop novel ROS-activated anticancer prodrugs with improved tumor specificity and drug like property (Aim 1), and identify ROS-activated prodrugs that synergize with pro-oxidants to improve the efficacy of ROS-activated prodrugs (Aim 2). The significance of this project is that targeting tumor redox through the combination of ROS-activated prodrugs and prooxidants represents an effective cancer treatment strategy. The proposed research will identify clinically applicable ROS-activated prodrugs that are compatible with prooxidant to confer efficacious, selective, and durable therapeutic benefits. Successful completion of the project will pave the way for repurposing ROS-activated DNA alkylating agents for cancer treatment.