MECHANISTIC DEVELOPMENT OF PLATINUM BASED DRUGS

描述：(申请人摘要)卵巢癌，导致 死亡率比其他任何妇科恶性肿瘤都要高，是第四位 是美国女性癌症死亡的主要原因。根据 对美国癌症协会来说，卵巢癌是导致 1997年有15,000人死亡，并在27,000名妇女中确诊。虽然， 铂类抗肿瘤药物(即顺铂和卡铂)的作用 在这种疾病的治疗中发挥关键作用，这是一种主要障碍 担忧在大多数患者中复发，这些患者随后失败 由于出现耐药性而与铂类药物一起挑战 在他们的肿瘤细胞中。减少药物积累，增加细胞内 谷胱甘肽，增强加合物耐受性，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。一种A2780衍生的顺铂耐药卵巢 申请人实验室中的肿瘤模型是这些机制的典型代表。 然而，他发现，与传统的 敏感品系，缺乏P53抑癌基因表达 用顺铂挑战。然而，白金类似物可以诱导p53 在两条线上都有。申请人认为细胞没有能力 顺铂引起DNA损伤时增加P53蛋白是一种 它对这种铂络合物的抗性的基本机制。这个 提出的具体目标旨在表征 类似物可诱导P53蛋白表达，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是否是通过上调 转录或翻译后水平。他将利用 调控P53诱导和/或功能的转染法 检验他的假设。其他具体目标将通过以下方式实现 生化、药理学和分子技术涉及 RNA/蛋白质分离，蛋白质免疫沉淀，凝胶电泳法， 单抗/多克隆抗体、流式细胞仪、DNA检测 断股等。他的调查很可能会确定 该类似物如何恢复p53的诱导性并绕过顺铂 耐药性，并可能提供治疗难治性卵巢的机会 在更理性的基础上研究癌症。

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.