Mechanistic Comparison of Cisplatin with Synthetic DNA Repair-Shielding Anticance

顺铂与合成 DNA 修复屏蔽抗癌机制比较

• 批准号: 7142123
• 负责人: JOHN M ESSIGMANN
• 金额: $ 29.11万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142123
• 关键词: DNA damage; DNA repair; adduct; cis platinum compound; genetic promoter element; genetic recombination; oligonucleotides; ribosomal DNA; ribosomal RNA; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The goal of the proposed work is to translate our recent experimental findings on the mechanisms of antitumor responses to cisplatin into the development of novel compounds to treat cisplatin-resistant tumors. Earlier work on this grant discovered three novel prospective mechanisms of toxicity for cisplatin: (1) its DNA adducts attract proteins, some of which are expressed in cancer cells, that block DNA repair; (2) its DNA adducts "hijack" specific HMG-domain transcription factors away from their promoters, resulting in diminished expression of certain genes; and (3) mismatch repair proteins bind cisplatin adducts and sensitize cells to the drug. Based on the aforementioned discoveries, in the current grant period, we have developed several novel anticancer candidates with potentially novel mechanisms of action - mechanisms inspired by cisplatin. The lead candidate among these compounds, E27a, was designed to act by mechanisms that may be relevant for the treatment of cisplatin-resistant ovarian cancers. E27a is a bifunctional DNA damaging agent that can create damaged sites in DNA that have high affinity for the estrogen receptor. Principles incorporated into the design of E27a that were uncovered by our investigations of cisplatin include the ability of cisplatin DNA adducts to bind and sequester proteins important to tumor growth and survival. This proposal has two parallel objectives. One is to delineate further the molecular mechanisms responsible for the cytotoxic and antitumor effects of our new agent, E27a. The second is to compare its efficacy against ovarian cancers with that of cisplatin and related compounds that are in clinical use or are clinical candidates. The specific objectives of the proposed research are: (1) to synthesize molecular variants and radiolabeled analogs of platinum and E27a that are tools for structure-activity studies; (2) to perform comparative cytotoxicity studies against cisplatin and cisplatin homologues in sensitive and resistant ovarian cancer cells; (3) to determine the relationship between estrogen receptor expression and sensitivity of ovarian cancers to E27a and the resistance of those cancer cells to cisplatin; and (4) to compare the efficacy of E27a to that of cisplatin in animal models of human ovarian cancer. Using conventional and genetic animal models for ovarian cancer, and relevant cell lines, we plan to determine to what extent the molecules we have recently made work the mechanisms that we intended and to determine their relevance to cancer treatment. A combination of traditional (immunochemical, genetic) and recent (RNAi, accelerator mass spectrometry) methods will be used.

描述(申请人提供)：拟议工作的目标是将我们最近关于顺铂抗肿瘤反应机制的实验结果转化为开发治疗顺铂耐药肿瘤的新化合物。关于这笔赠款的早期工作发现了顺铂的三种新的预期毒性机制：(1)其DNA加合物吸引蛋白质，其中一些蛋白质在癌细胞中表达，从而阻止DNA修复；(2)其DNA加合物将特定的HMG结构域转录因子从其启动子“劫持”，导致某些基因的表达减少；以及(3)错配修复蛋白与顺铂加合物结合，并使细胞对药物敏感。基于上述发现，在当前的资助期间，我们开发了几个具有潜在新颖作用机制的新型抗癌候选药物--受顺铂启发的机制。这些化合物中的主要候选化合物E27a旨在通过可能与治疗顺铂耐药卵巢癌相关的机制发挥作用。E27a是一种双功能DNA损伤剂，可以在DNA中创建与雌激素受体具有高亲和力的损伤部位。我们对顺铂的研究发现，E27a设计中包含的原则包括顺铂DNA加合物结合和隔离对肿瘤生长和生存至关重要的蛋白质的能力。这项提议有两个平行的目标。一是进一步阐明我们的新药E27a的细胞毒性和抗肿瘤作用的分子机制。第二个是将其治疗卵巢癌的疗效与临床上使用的或临床候选的顺铂和相关化合物的疗效进行比较。拟议研究的具体目标是：(1)合成可用于构效关系研究的铂和E27a的分子变体和放射性标记类似物；(2)在敏感和耐药的卵巢癌细胞中进行针对顺铂和顺铂同系物的细胞毒性比较研究；(3)确定雌激素受体表达与卵巢癌对E27a的敏感性和这些癌细胞对顺铂的耐药性之间的关系；以及(4)在人卵巢癌的动物模型中比较E27a和顺铂的疗效。利用卵巢癌的传统和遗传动物模型，以及相关的细胞系，我们计划确定我们最近使分子在多大程度上发挥我们想要的机制，并确定它们与癌症治疗的相关性。将使用传统(免疫化学、遗传)和最近(RNAi、加速器质谱学)方法相结合的方法。