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

项目摘要/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。作为一名 结果，与正常相比，癌细胞中的活性氧(ROS)水平升高 细胞。这一特征已被用于开发一类ROS激活的前药，仅 在ROS存在的情况下变得具有细胞毒性。ROS激活的前体药物作为 癌症的单一治疗面临着许多挑战，包括肿瘤的异质性、不足 前药激活、靶向给药困难、治疗持久性不足等。 迫切需要战略来增强ROS激活的前体药物的有效性和选择性 与多种癌症有关。本课题组研制的过氧化氢活化DNA烷化剂 在氧化应激下对癌细胞表现出选择性毒性，但对正常细胞没有选择性毒性， 提示它们可能与放大的试剂或癌症疗法结合使用 ROS水平特别是在癌细胞中。据报道，像维生素C这样的促氧化剂可以起到 在正常细胞受到保护的情况下，有效的促氧化剂在癌细胞中特异性地诱导过氧化氢 由于过氧化氢酶表达较高，可猝灭过氧化氢。双氧水的无毒特性- 我们实验室开发的活性DNA交联剂，以及研究结果表明 VitC选择性地增强了癌细胞中的过氧化氢积聚，为 以协同的方式将这两种治疗方式结合起来。最重要的假设 该项目的主要目的是将选定的促氧化剂与ROS激活的前体药物相结合，可以 达到协同和持久的抗肿瘤效果，同时最大限度地减少有害的副作用。 具体地说，我们将开发具有改善肿瘤的新型ROS激活的抗癌前药 特异性和类药物特性(目标1)，并识别与之协同的ROS激活的前药 促氧化剂，以提高ROS激活的前体药物的疗效(目标2)。这件事的意义 项目是通过结合ROS激活的前药和联合靶向肿瘤氧化还原 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 临床适用的与促氧化剂相容的ROS激活前药以授予 有效、选择性和持久的治疗效果。该项目的成功完成将 为将ROS激活的DNA烷基化试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.