Polyamine Catabolism in Platinum Drug Action

铂类药物作用中的多胺分解代谢

• 批准号: 7555372
• 负责人: LAKSHMI PENDYALA
• 金额: $ 30.16万
• 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/7555372
• 关键词: Acetyltransferase; Animals; Antitumor Response; Apoptosis; Apoptotic; Biochemical; Catabolism; Cell Death; Cell Line; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical Management; Clinical Trials; Colorectal; DNA Adduction; DNA Adducts; Data; Drug Interactions; Drug Tolerance; Drug effect disorder; Drug resistance; Embryo; Enzymes; Fibroblasts; Gene Expression; Genes; Goals; Growth; Human; Inhibition of Apoptosis; Knock-out; Laboratories; Link; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of ovary; Messenger RNA; Metabolism; Molecular; Mus; Ovarian Carcinoma; Pharmaceutical Preparations; Phase; Platinum; Play; Polyamine Catabolism; Polyamines; Resistance; Role; Small Interfering RNA; Spermidine; Spermidine/Spermine N1-Acetyltransferase; Spermine; System; Techniques; Testing; Therapeutic; Time; Transcriptional Activation; Transfection; Transgenic Animals; Transgenic Organisms; Variant; analog; base; cancer cell; cell type; cytotoxicity; drug sensitivity; enzyme activity; in vivo; knock-down; mouse model; novel; oxaliplatin; research clinical testing; response; tumor xenograft

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）药物在癌症的临床管理中起重要作用。 PT剂引起的抗肿瘤反应被认为是由于PT-DNA加合物的形成。该实验室的最新验证的微阵列数据表明，在培养的A2780卵巢癌细胞中，奥沙利铂和顺铂都有效诱导关键多胺（PA）分解代谢酶，精子/精子N1-乙酰基转移酶（SSAT）的基因表达。还发现其他PA分解代谢酶是诱导的。由于先前通过其他方式诱导SSAT与生长抑制和凋亡有关，因此奥沙利铂看到的mRNA的10-15倍诱导有助于总体药物作用。在临床上可实现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SSAT活性的显着诱导。奥沙利铂和N1，N11-二乙基植物（denSPM）的组合是一种已知在转录和转录后已知的PA类似物，可以激活SSAT的表达，协同诱导大量的SSAT mRNA和活性，并且活性大，并且比添加性生长抑制大。 denSPM已显示在临床上是安全的，并且继续进行临床测试。该应用的总体目标是研究SSAT诱导在PT药物作用中的作用，并设计出在SSAT诱导水平上利用协同药物相互作用的治疗策略。因此，具体目的提出：（1）单独表征PT药物作用，并与eNSPM结合对PA代谢和卵巢癌细胞和PT药物耐药性变异的生长，（2）研究PA分解代谢和PT药物作用之间的机械关系（3）评估PT-DRUG /DENSPM Combination PT-DRUG /DENSPM COMBINTION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，我们期望定义基于机制的基本原理，以评估PT-Strugs和DenSPM的综合使用。

项目成果

Combination effects of platinum drugs and N1, N11 diethylnorspermine on spermidine/spermine N1-acetyltransferase, polyamines and growth inhibition in A2780 human ovarian carcinoma cells and their oxaliplatin and cisplatin-resistant variants.

• DOI: 10.1007/s00280-010-1334-9
• 发表时间: 2011-02
• 期刊: CANCER CHEMOTHERAPY AND PHARMACOLOGY
• 影响因子: 3
• 作者: Tummala, Ramakumar;Diegelman, Paula;Hector, Suzanne;Kramer, Debora L.;Clark, Kimberly;Zagst, Patricia;Fetterly, Gerald;Porter, Carl W.;Pendyala, Lakshmi
• 通讯作者: Pendyala, Lakshmi