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: 7495925
• 负责人: JOHN M ESSIGMANN
• 金额: $ 5.32万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495925
• 关键词: Abbreviations; Affinity; Animal Model; Antitumor Response; Binding; Cancer cell line; Cell Death; Cell Line; Cell model; Cells; Cisplatin; Clinical; Collection; DNA Damage; DNA Repair; Development; Estrogen Receptors; Evaluation; Genes; Genetic; Goals; Grant; HMG Domain; Homologous Gene; Human; In Vitro; Investigation; Label; Lead; Literature; Malignant neoplasm of ovary; Methods; Mismatch Repair; Molecular; New Agents; Pharmaceutical Preparations; Platinum; Platinum Compounds; Protein Binding; Proteins; RNA Interference; Radiolabeled; Research; Resistance; Role; Site; Structure; Testing; Therapeutic; Toxic effect; Toxin; Transgenic Organisms; Translating; Variant; Work; accelerator mass spectrometry; adduct; analog; base; cancer cell; cancer therapy; chemical synthesis; clinically relevant; comparative; cytotoxic; cytotoxicity; design; in vivo; mouse model; novel; ovarian neoplasm; promoter; prospective; radiotracer; receptor expression; repaired; steroid analog; synthetic construct; tool; transcription factor; tumor; tumor growth; tumor xenograft

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 DMA adducts attract proteins, some of which are expressed in cancer cells, that block DMA repair; (2) its DMA 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 DMAdamaging agent that can create damaged sites in DMAthat 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 DMAadducts 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 radiolabled 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.

拟议工作的目标是将我们最新的实验结果转化为 顺铂的抗肿瘤效应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 DMA加合物吸引阻止DMA修复的蛋白质，其中一些蛋白质在癌细胞中表达；(2)其 DMA将特定的HMG结构域转录因子从它们的启动子“劫持”，导致 某些基因表达减弱；以及(3)错配修复蛋白结合顺铂加合物和 使细胞对药物敏感。根据上述发现，在当前的赠款期间，我们有 开发了几种具有潜在新作用机制的新型抗癌候选药物--机制 灵感来自顺铂。这些化合物中的主要候选化合物E27a被设计为通过 可能与治疗顺铂耐药卵巢癌相关的机制。E27a是一种 双功能DMAdamage代理，可在DMA中创建与 雌激素受体。我们的调查发现了E27a设计中包含的原则 顺铂包括顺铂DMA加合物结合和隔离对肿瘤重要的蛋白质的能力 成长和生存。这项提议有两个平行的目标。一是进一步描绘分子 我们的新药E27A的细胞毒性和抗肿瘤作用的机制。第二个是 其抗卵巢癌疗效与临床应用的顺铂及相关化合物的比较 使用或者是临床候选药物。拟议研究的具体目标是：(1)综合 铂和E27a的分子变体和放射性类似物，它们是结构-活性研究的工具； (2)对顺铂和顺铂同系物进行细胞毒性比较研究 (3)探讨雌激素受体表达与卵巢癌细胞耐药的关系。 卵巢癌对E27a的敏感性及癌细胞对顺铂的耐药性； 比较E27a和顺铂在人卵巢癌动物模型中的疗效。vbl.使用 卵巢癌的常规和遗传动物模型，以及相关的细胞系，我们计划确定 我们最近制造的分子在多大程度上发挥了我们想要的和确定的机制的作用 它们与癌症治疗的相关性。传统(免疫化学、遗传)和现代的组合 (RNAi，加速器质谱学)方法将被使用。