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

项目概要/摘要 癌细胞由于异常生长而处于基础氧化应激增加的状态。作为一个 结果，与正常细胞相比，癌细胞的活性氧 (ROS) 水平升高 细胞。该功能已被用来开发一类 ROS 激活的前药，仅 在 ROS 存在下具有细胞毒性。 ROS 激活的前药的有效性 癌症单一疗法面临许多挑战，包括肿瘤异质性、不足 前药激活、靶向给药困难、缺乏治疗持久性等。 迫切需要策略来增强 ROS 激活前药的功效和选择性 到多种癌症。本课题组开发的H2O2活化DNA烷化剂 在氧化应激下对癌细胞表现出选择性毒性，但对正常细胞则不然， 表明它们与试剂或癌症疗法结合使用的潜在用途，以放大 ROS 水平特别是在癌细胞中。据报道，维生素C等促氧化剂可以起到 有效的促氧化剂可在癌细胞中特异性诱导 H2O2，同时保护正常细胞 由于较高的过氧化氢酶表达可淬灭 H2O2。 H2O2-的无毒特性 我们实验室开发的活化 DNA 交联剂，以及研究结果表明 vitC 选择性地增强癌细胞中 H2O2 的积累，为以下研究提供了令人信服的理由： 以协同方式结合这两种治疗方式。总体假设 该项目的重点在于，选定的促氧化剂与 ROS 激活的前药的组合可以 实现协同和持久的抗肿瘤作用，同时最大限度地减少不需要的副作用。 具体来说，我们将开发新型ROS激活的抗癌前药，以改善肿瘤 特异性和类药特性（目标 1），并鉴定与 ROS 激活的前药协同作用 促氧化剂可提高 ROS 激活的前药的功效（目标 2）。此举的意义 该项目的目标是通过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 临床上适用的 ROS 激活前药，与促氧化剂相容，可赋予 有效、选择性和持久的治疗效果。该项目的顺利完成将 为重新利用 ROS 激活的 DNA 烷化剂用于癌症治疗铺平道路。

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.