Polyamine Catabolism in Platinum Drug Action

铂类药物作用中的多胺分解代谢

• 批准号: 7046818
• 负责人: LAKSHMI PENDYALA
• 金额: $ 30.54万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046818
• 关键词: RNA interference; acyltransferase; antineoplastics; athymic mouse; biotransformation; combination chemotherapy; drug interactions; drug metabolism; drug resistance; enzyme induction /repression; genetically modified animals; human genetic material tag; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; ovary neoplasms; platinum; polyamines; small interfering RNA; spermine; therapy design /development; transfection; xenotransplantation

DESCRIPTION (provided by applicant): Platinum (Pt) drugs play a significant role in the clinical management of cancer. The antitumor response caused by Pt agents is believed to be due to Pt-DNA adduct formation. Recent, validated microarray data from this laboratory indicate that both oxaliplatin and cisplatin potently induce gene expression of the key polyamine (PA) catabolic enzyme, spermidine/ spermine N1-acetyltransferase (SSAT), in cultured A2780 ovarian carcinoma cells. Other PA catabolic enzymes were also found to be induced. Since induction of SSAT by other means has been previously linked to growth inhibition and apoptosis, it is likely that the 10-15-fold induction in mRNA seen with oxaliplatin contributes to overall drug action. At clinically achievable drug concentrations and exposure times, oxaliplatin produces a significant induction of SSAT activity due to transcriptional activation of the SSAT gene. The combination of oxaliplatin and N1, N11-diethylnorspermine (DENSPM), a PA analog known to transcriptionally and post-transcriptionally activate SSAT expression, synergistically induces massive amounts of SSAT mRNA and activity and a greater than additive growth inhibition. DENSPM has been shown to be clinically safe and continues to under go clinical testing. The overall goals of this application are to investigate the role of SSAT induction in Pt drug action and to devise therapeutic strategies that exploit synergistic drug interactions at the level of SSAT induction. Thus, specific aims propose to: (1) characterize Pt drug effects alone and in combination with DENSPM on PA metabolism and growth in ovarian cancer cells and Pt drug resistant variants, (2) investigate the mechanistic relationship between PA catabolism and Pt drug action (3) assess the therapeutic potential of the Pt-drug /DENSPM combination against human tumor xenografts. Studies will use biochemical and molecular techniques, novel mouse models, and human tumor xenografts. Overall, we expect to define mechanism-based rationale for clinical trials evaluating the combined use of Pt-drugs and DENSPM.

描述（由申请人提供）：铂（Pt）药物在癌症的临床治疗中发挥着重要作用。 Pt 剂引起的抗肿瘤反应被认为是由于 Pt-DNA 加合物的形成。该实验室最近经过验证的微阵列数据表明，奥沙利铂和顺铂均可有效诱导培养的 A2780 卵巢癌细胞中关键多胺 (PA) 分解代谢酶、亚精胺/精胺 N1-乙酰转移酶 (SSAT) 的基因表达。还发现其他 PA 分解代谢酶也被诱导。由于之前通过其他方式诱导 SSAT 与生长抑制和细胞凋亡有关，因此奥沙利铂观察到的 mRNA 10-15 倍诱导可能有助于整体药物作用。在临床可达到的药物浓度和暴露时间下，奥沙利铂由于 SSAT 基因的转录激活而显着诱导 SSAT 活性。奥沙利铂和 N1, N11-二乙基去甲精胺 (DENSPM) 的组合（一种 PA 类似物，已知可在转录和转录后激活 SSAT 表达），协同诱导大量的 SSAT mRNA 和活性，并产生大于加性的生长抑制。 DENSPM 已被证明具有临床安全性，并将继续接受临床测试。本申请的总体目标是研究 SSAT 诱导在 Pt 药物作用中的作用，并设计在 SSAT 诱导水平上利用协同药物相互作用的治疗策略。因此，具体目标是：（1）表征单独的 Pt 药物作用以及与 DENSPM 组合对卵巢癌细胞和 Pt 耐药变体中 PA 代谢和生长的影响，（2）研究 PA 分解代谢和 Pt 药物作用之间的机制关系（ 3) 评估Pt-药物/DENSPM组合针对人类肿瘤异种移植物的治疗潜力。研究将使用生化和分子技术、新型小鼠模型和人类肿瘤异种移植物。总体而言，我们期望为评估 Pt 药物和 DENSPM 联合使用的临床试验定义基于机制的基本原理。