Polyamine Catabolism in Platinum Drug Action

描述（由申请人提供）：铂类（Pt）药物在癌症的临床管理中发挥着重要作用。铂剂引起的抗肿瘤反应被认为是由于Pt-DNA加合物的形成。该实验室最近验证的微阵列数据表明，奥沙利铂和顺铂均能有效诱导培养的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。其他PA分解代谢酶也被发现诱导。由于先前已将通过其他方式诱导SSAT与生长抑制和细胞凋亡联系起来，因此奥沙利铂观察到的mRNA 10-15倍诱导可能有助于总体药物作用。在临床可达到的药物浓度和暴露时间下，由于SSAT基因的转录激活，奥沙利铂可显著诱导SSAT活性。奥沙利铂和N1，N11-二乙基去甲精胺（DENSPM）（一种已知可在转录和转录后激活SSAT表达的PA类似物）的组合可协同诱导大量SSAT mRNA和活性以及大于累加的生长抑制。DENSPM已被证明是临床安全的，并继续进行临床测试。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诱导水平利用协同药物相互作用的治疗策略。因此，提出了具体目标：（1）表征Pt药物单独和与DENSPM联合对卵巢癌细胞和Pt耐药变体中PA代谢和生长的作用，（2）研究PA催化剂与Pt药物作用之间的机制关系，（3）评估Pt-药物/DENSPM联合对人肿瘤异种移植物的治疗潜力。研究将使用生物化学和分子技术、新型小鼠模型和人类肿瘤异种移植物。总体而言，我们希望为评价铂类药物和DENSPM联合使用的临床试验定义基于机制的基本原理。

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.