MECHANISTIC DEVELOPMENT OF PLATINUM BASED DRUGS

铂类药物的机理开发

• 批准号: 6173022
• 负责人: ZAHID H SIDDIK
• 金额: $ 15.57万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173022
• 关键词: antineoplastics; cell growth regulation; cell line; cis platinum compound; diaminopyrimidine; drug design /synthesis /production; drug resistance; gene induction /repression; human tissue; neoplasm /cancer genetics; ovary neoplasms; p53 gene /protein; pharmacokinetics; platinum; transfection

DESCRIPTION: (Applicant's Abstract) Ovarian cancer, which results in higher mortality than any other gynecologic malignancy, is the fourth leading cause of cancer deaths in women in the United States. According to the American Cancer Society, ovarian cancer was responsible for 15,000 deaths and was diagnosed in 27,000 women in 1997. Although, platinum-based antitumor agents (i.e. cisplatin and carboplatin) play critical roles in the treatment of this disease, a major impediment concerns relapse in a majority of patients, who fail subsequent challenge with the platinum agent due to the onset of drug resistance in their tumor cells. Reduced drug accumulation, increased intracellular glutathione, increased adduct tolerance and increased DNA adduct repair are usually identified as key mechanisms of resistance to cisplatin in ovarian and other cancers. An A2780-derived cisplatin-resistant ovarian tumor model in the applicant's laboratory typifies these mechanisms. However, he has found that the resistant model, in contrast to the sensitive line, lacks expression of p53 tumor suppressor gene when challenged with cisplatin. A platinum analog, however, can induce p53 in both lines. The applicant believes that the cell's inability to increase p53 protein in response to DNA damage by cisplatin is a fundamental mechanism of its resistance to this platinum complex. The proposed specific aims are designed to characterize the ability of the analog to induce p53 and reduce the threshold of DNA adduct tolerance. He will also establish the importance of p53 induction for cell death, and explore whether p53 is induced by up-regulation at the transcriptional or post-translational level. He will utilize transfection approaches to modulate p53 induction and/or function to test his hypothesis. Other specific aims will be accomplished through biochemical, pharmacologic, and molecular techniques involving RNA/protein isolation, protein immunoprecipitation, gel electrophoresis, detection by monoclonal/polyclonal antibodies, flow cytometry, DNA strand breaks, etc. It is likely that his investigations will establish how the analog restores inducibility of p53 and circumvents cisplatin resistance, and may provide an opportunity to treat refractory ovarian cancers on a more rational basis.

描述：（申请人摘要）卵巢癌，导致 死亡率高于任何其他妇科恶性肿瘤，是第四位 是美国女性癌症死亡的主要原因。根据 美国癌症协会认为，卵巢癌是导致 1997 年，有 15,000 人死亡，27,000 名女性被确诊。尽管如此， 铂类抗肿瘤药物（即顺铂和卡铂）发挥作用 在这种疾病的治疗中发挥着关键作用，这是一个主要障碍 担心大多数患者会复发，随后失败 由于耐药性的出现而对铂类药物产生挑战 在他们的肿瘤细胞中。减少药物蓄积，增加细胞内 谷胱甘肽，增加加合物耐受性和增加 DNA 加合物修复 通常被认为是顺铂耐药的关键机制 卵巢癌和其他癌症。 A2780 衍生的顺铂耐药卵巢 申请人实验室的肿瘤模型代表了这些机制。 然而，他发现抵抗模型与 敏感系，缺乏p53肿瘤抑制基因的表达 顺铂挑战。然而，铂类似物可以诱导 p53 在两条线上。申请人认为该细胞无法 增加 p53 蛋白以响应顺铂的 DNA 损伤是一种 其抵抗这种铂络合物的基本机制。这 提出的具体目标旨在表征 类似物诱导 p53 并降低 DNA 加合物耐受阈值。 他还将确定 p53 诱导对细胞死亡的重要性， 并探讨p53是否是由上调诱导的 转录或翻译后水平。他将利用 调节 p53 诱导和/或功能的转染方法 检验他的假设。其他具体目标将通过 涉及生物化学、药理学和分子技术 RNA/蛋白质分离、蛋白质免疫沉淀、凝胶电泳、 单克隆/多克隆抗体、流式细胞术、DNA检测 链断裂等。他的调查很可能会确定 类似物如何恢复 p53 的诱导性并规避顺铂 抵抗力，并可能提供治疗难治性卵巢的机会 癌症的治疗更加理性。