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

新型 DNA 交联剂和肿瘤特异性激活的组合策略

• 批准号: 10730787
• 负责人: Xiaohua Peng
• 金额: $ 46.2万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730787
• 关键词: Alkylating Agents; Ascorbic Acid; Biological; Breast Cancer Cell; Cell Death; Cells; Chemicals; Coupled; Cytoprotection; DNA; DNA Crosslinking Agent; DNA Damage; DNA Interstrand Crosslinking; Data; Development; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Effectiveness; Event; Exhibits; Face; Future; Growth; Human; Hydrogen Peroxide; In Vitro; Knowledge; Link; Malignant Neoplasms; Measures; Mechlorethamine; Mediating; Metabolic; Metabolism; Microsomes; Modality; Modeling; Mus; Normal Cell; Oncogene Activation; Oxidation-Reduction; Oxidative Stress; Pharmaceutical Preparations; Pre-Clinical Model; Prodrugs; Property; Reactive Oxygen Species; Reagent; Reporting; Research; Rodent; Testing; Therapeutic; Toxic effect; Toxicology; Tumor-Suppressor Gene Inactivation; Xenograft procedure; analog; anti-cancer; anticancer activity; antitumor effect; cancer cell; cancer therapy; catalase; clinical application; curative treatments; cytotoxic; improved; in vivo; mouse model; neoplastic cell; novel; novel strategies; side effect; synergism; targeted cancer therapy; therapy outcome; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor specificity

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.

项目摘要/摘要 由于其异常生长，癌细胞处于基础氧化应激的增加状态。作为 结果，与正常相比，癌细胞的活性氧（ROS）水平升高 细胞。此功能已被用来开发一类ROS激活的前药 在ROS存在下变细胞毒性。 ROS激活前药的有效性 癌症的单一疗法面临许多挑战，包括肿瘤异质性，不足 前药激活，靶向药物的难度，缺乏治疗耐用性等。 迫切需要策略来增强ROS激活前药的功效和选择性 多种癌症。由我们组开发的H2O2激活的DNA烷基化剂 在氧化应激下对癌细胞表现出选择性毒性，而不是正常细胞， 建议它们与试剂或癌症疗法相结合的潜在用途 ROS水平特别在癌细胞中。据报道，诸如VITC之类的促氧化剂可以充当 有效的促氧化剂可在癌细胞中特别诱导H2O2，而正常细胞受到保护 由于较高的过氧化氢酶表达淬灭H2O2。 H2O2-的无毒特征 激活的DNA交联剂在我们的实验室中开发，以及发现的发现表明 VITC有选择地加强H2O2在癌细胞中的积累，为 以协同的方式结合这两种治疗方式。总体假设 这个项目的是，选定的促氧化剂与ROS激活前药的结合可以 达到协同和耐用的抗肿瘤效应，同时最大程度地减少不需要的副作用。 具体而言，我们将开发具有改善肿瘤的新型ROS激活前药 特异性和毒品（例如财产）（AIM 1），并确定与ROS激活的前药 促氧化剂提高ROS激活前药的功效（AIM 2）。这一点的意义 项目是通过ROS激活前药和 培养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，与促氧化剂兼容 有效，选择性且耐用的治疗益处。成功完成项目将 为重新利用ROS激活的DNA烷基化剂进行癌症治疗铺平道路。