MECHANISTIC DEVELOPMENT OF PLATINUM BASED DRUGS

描述：（申请人的摘要）卵巢癌，其导致 死亡率高于任何其他妇科恶性肿瘤，是第四个 是美国女性癌症死亡的主要原因。根据 对于美国癌症协会来说，卵巢癌是导致 1997年，15，000人死亡，27，000名妇女被诊断。不过， 基于铂的抗肿瘤剂（即顺铂和卡铂）发挥 在治疗这种疾病中起着至关重要的作用， 关注大多数患者的复发，他们随后失败 由于出现耐药性，使用铂类药物进行挑战 在他们的肿瘤细胞中。减少药物蓄积，增加细胞内 谷胱甘肽、加合物耐受性增加和DNA加合物修复增加 通常被认为是顺铂耐药的关键机制， 卵巢癌和其他癌症。A2780来源的顺铂耐药卵巢癌 本申请人实验室中的肿瘤模型代表了这些机制。 然而，他发现，与 敏感细胞系，缺乏p53肿瘤抑制基因的表达， 用顺铂攻击。然而，铂类似物可以诱导p53 在两条线上。申请人认为，细胞无法 顺铂引起DNA损伤后p53蛋白增加是一种 这是它对这种铂络合物的抵抗力的基本机制。的 拟议的具体目标旨在描述 类似物诱导p53和降低DNA加合物耐受的阈值。 他还将确定p53诱导细胞死亡的重要性， 并探讨p53是否是由在 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， 测试他的假设。其他具体目标将通过 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/多克隆抗体检测、流式细胞术、DNA 链断裂等。很可能他的调查将建立 类似物如何恢复p53的诱导并绕过顺铂 耐药性，并可能提供治疗难治性卵巢癌的机会， 癌症在更理性的基础上

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.