Polyamine Catabolism in Platinum Drug Action

描述(由申请人提供)：铂(铂)药物在癌症的临床治疗中发挥着重要作用。铂制剂的抗肿瘤作用可能是由于铂-DNA加合物的形成所致。来自本实验室的最近验证的微阵列数据表明，奥沙利铂和顺铂都能有效地诱导培养的A2780卵巢癌细胞中关键的多胺(PA)分解代谢酶-精胺/精胺N1-乙酰转移酶(SSAT)的基因表达。其他PA分解代谢酶也被诱导。由于以前用其他方法诱导SSAT与生长抑制和细胞凋亡有关，所以奥沙利铂对mRNA的10-15倍诱导很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基因的转录激活而产生显著的SSAT活性诱导。奥沙利铂与N1，N11-二乙基去甲精胺(DENSPM)(一种已知在转录和转录后激活SSAT表达的PA类似物)联合使用，协同诱导大量SSAT mRNA和活性，并比相加作用更大的生长抑制。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诱导在铂药物作用中的作用，并设计出在SSAT诱导水平上利用药物协同相互作用的治疗策略。因此，有针对性地提出：(1)研究铂药物单独和联合应用对卵巢癌细胞和铂耐药变异体中PA代谢和生长的影响；(2)研究PA分解代谢与铂药物作用之间的机制关系；(3)评估铂药物/DENSPM联合抗人肿瘤移植瘤的治疗潜力。研究将使用生化和分子技术、新的小鼠模型和人类肿瘤异种移植。总体而言，我们希望为评估铂类药物和DENSPM联合使用的临床试验确定基于机制的理论基础。

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.