Novel Dithiolethiones for Bladder Cancer Prevention

用于预防膀胱癌的新型二硫代硫酮

• 批准号: 7317109
• 负责人: YUESHENG ZHANG
• 金额: $ 29.52万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-05 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7317109
• 关键词: Behavior; Bladder; Carcinogens; Cells; Chemopreventive Agent; Clinical Trials; Clostridium perfringens delta-toxin; Dose; Drug Kinetics; Enzyme Induction; Enzymes; Epithelial Cells; Excretory function; Future; Glucuronosyltransferase; Glutathione S-Transferase; Goals; Human; In Vitro; Knockout Mice; Liver; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediating; Metabolism; Molecular; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NQO1 gene; Phase; Play; Prevention; Preventive; Property; Protein Isoforms; Radiolabeled; Rattus; Reporting; Research Personnel; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Structure-Activity Relationship; Testing; Thiones; Tissues; Toxic effect; UGT1A1 gene; Variant; analog; bladder cancer prevention; carcinogenesis; cell injury; chemical carcinogen; chemical carcinogenesis; dithiolethione; genotoxicity; glutathione S-transferase M1; glutathione transferase A1-1; in vivo; novel; oltipraz; pre-clinical; programs; protective effect; radiotracer; response; tumorigenesis

DESCRIPTION (provided by applicant): This project is focused on identifying and developing novel dithiolethiones for the prevention of urinary bladder cancer. Many lines of evidence show that carcinogen-detoxifying Phase 2 enzymes play a major role in bladder cancer prevention. We have recently found that 5,6-dihydrocyclopenta[c]-1,2-dithiole-3(4H)-thione (CPDT) is an extremely efficacious inducer of Phase 2 enzymes in rodent bladders in vivo and hypothesize that CPDT or a more potent analog would be a highly effective protector against bladder cancer. Aim 1 of the project is to further characterize the Phase 2 enzyme-inducing property of CPDT, to examine the toxicity and pharmacokinetic behavior of CPDT, and to test CPDT analogs for identification of more potent inducers of Phase 2 enzymes. These studies will be performed in rats; the impact of the test compound on three important Phase 2 enzymes (GST, NQO1 and UGT) will be measured; CPDT analogs will be synthesized; various parameters of toxicity and pharmacokinetics of CPDT will be measured. Aim 2 is to determine which GST and UGT isoforms are induced by CPDT and its more potent analogs (identified in Aim 1), whether such induction is species specific, and if CPDT is metabolized in cells to a new inducer form. The response of the isoforms of GST and UGT which were shown to play important roles in bladder cancer prevention will be examined using bladder epithelial cells from humans and rodents. CPDT metabolism will be investigated using radiolabeled CPDT and LC/MS/MS. Aim 3 is to elucidate the molecular mechanism responsible for the induction of Phase 2 enzymes by CPDT and its analogs. We hypothesize that Nrf2 (a transcriptional factor) plays a major role in mediating such an induction. Aim 4 is to assess the protective effects of CPDT or a more promising analog against the genotoxicities of bladder carcinogens in bladder cells both in vitro and in vivo, as measured by DMA damage and cell/tissue proliferation, and to investigate the role of the Nrf2 signaling pathway in mediating such an effect, using cultured bladder epithelial cells and mice with and without Nrf2 function. Studies carried out in Aim 4 will also serve to identify the appropriate dose levels of the dithiolethione for further experimentation in Aim 5. Aim 5 is to determine the inhibitory effect of the dithiolethione examined in Aim 4 on bladder tumorigenesis induced by a chemical carcinogen in vivo and the role of Nrf2 signaling in mediating such an effect, using wild type and Nrf2 knockout mice.

描述（由申请人提供）：该项目的重点是识别和开发用于预防膀胱癌的新型二硫酸硫酸盐。许多证据表明，毒致癌期2酶在预防膀胱癌中起主要作用。我们最近发现，5,6-二氢细胞[C] -1,2-二硫代-3（4H）-Thione（CPDT）是一种非常有效的诱导剂，对体内啮齿动物膀胱中的2阶段酶的诱导剂非常有效，并假设CPDT或更有效的类似物是一个非常有效的保护癌。该项目的目标1是进一步表征CPDT的2阶段酶诱导性能，检查CPDT的毒性和药代动力学行为，并测试CPDT类似物以鉴定2期2酶的更有效的诱导剂。这些研究将在大鼠中进行；测试化合物对三种重要阶段2酶（GST，NQO1和UGT）的影响； CPDT类似物将合成；将测量CPDT的毒性和药代动力学的各种参数。 AIM 2是确定CPDT诱导了哪些GST和UGT同工型及其更有效的类似物（在AIM 1中鉴定），是否是特定于物种的，以及是否将CPDT在细胞中代谢为新诱导剂形式。 GST和UGT的同工型的反应显示在预防膀胱癌中起重要作用，将使用来自人类和啮齿动物的膀胱上皮细胞进行检查。 CPDT代谢将使用放射性标记的CPDT和LC/MS/MS研究。目标3是阐明CPDT及其类似物诱导2期酶的分子机制。我们假设NRF2（转录因子）在介导这种诱导中起着重要作用。目的4是评估CPDT或更有前途的类似物对膀胱细胞中膀胱致癌物的遗传毒性的保护作用，如DMA损伤和细胞/组织增殖，以及使用此类效应的NRF2信号传导在不使用培养基的NRF2信号传导过程中，使用培养和使用培养基的bladdr andf和MICEF和MICEF的作用来测量，并研究NRF2信号的作用。 AIM 4中进行的研究还将有助于确定在目标5中进一步实验的依次的适当剂量水平。目的5是确定AIM 4中对垂直甲硫酸磷的抑制作用对膀胱癌在体内诱导的膀胱肿瘤发生的抑制作用，并在体内和NRF2信号中使用这种效应和NRRER效应，并在nrf2信号中使用效果和NRRER效应。