Isothiocyanates in the Chemoprevention of Bladder Cancer

异硫氰酸盐在膀胱癌的化学预防中的作用

• 批准号: 6929861
• 负责人: YUESHENG ZHANG
• 金额: $ 21.81万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929861
• 关键词: NAD(P)H dehydrogenase; acetylcysteine; antineoplastics; apoptosis; biomarker; bladder neoplasm; cell growth regulation; cell proliferation; chemical structure function; chemoprevention; detoxification; enzyme induction /repression; female; genetic markers; glucuronosyltransferase; glutathione; glutathione transferase; isothiocyanates; laboratory rat; nutrition aspect of cancer; nutrition related tag; proliferating cell nuclear antigen; terminal nick end labeling

DESCRIPTION (provided by applicant): This Project focuses on determining the cancer-preventive activity of isothiocyanates (ITCs) in the bladder. The hypothesis to be tested is that selected ITCs can suppress bladder carcinogenesis by disrupting multiple steps in the carcinogenic process: induction of Phase 2 enzymes, induction of apoptosis, and inhibition of cell proliferation. Molecular markers relevant to these biological events, as well as inhibition of tumorigenesis, will be studied. Bladder cancer is an important health problem; effective chemopreventive agents are needed. ITCs are abundant in vegetables and many are known anticarcinogens in non-bladder animal organs. Ingested ITCs are efficiently absorbed and almost exclusively excreted in urine as N-acetylcysteine conjugates (NAC-ITCs), which also are anticarcinogens and can release ITCs, making the bladder epithelium the most exposed tissue to ITCs/NAC-ITCs. The overwhelming majority of bladder cancers originate from the epithelial cells. Four dietary ITCs that displayed potent anti-carcinogenic activity in non-bladder animal organs and their NAC conjugates will be evaluated. Aim 1 is designed to see whether ITCs or NAC-ITCs effectively induce critical Phase 2 detoxification enzymes, including glutathione transferase, quinone reductase-1, and UDPglucuronosyltransferase, whose deficiencies have been linked to increased bladder carcinogenesis. Aim 2 will determine the protective efficacy of ITCs or NAC-ITCs against carcinogen-induced DNA damage in bladder epithelial cells, using total DNA adducts and unscheduled DNA synthesis (UDS) as markers. Imbalance between apoptosis and proliferation also is a risk factor of bladder cancer. Aim 3 will determine whether ITCs or NAC-ITCs can correct the imbalance between apoptosis and proliferation associated with bladder carcinogenesis: Do ITCs or NAC-ITCs induce apoptosis and/or inhibit cell cycle progression in bladder cancer cells? If so, what is the underlying mechanism(s)? Aim 4 will evaluate in rivo the effect of orally administered ITCs on important biomarkers, including the Phase 2 enzymes described in Aim 1, apoptosis (TUNEL), and proliferation (PCNA) in the bladder epithelium of F344 rats. Aim 5 will determine the efficacy of an orally administered ITC in inhibiting N-butyl-N- (4-hydroxybutyl)-nitrosamine-induced bladder tumorigenesis in F344 rats.

描述（由申请人提供）：该项目的重点是确定异硫氰酸盐（ITC）在膀胱中的预防癌症活性。待测试的假设是，选定的 ITC 可以通过破坏致癌过程中的多个步骤来抑制膀胱癌的发生：诱导第 2 相酶、诱导细胞凋亡和抑制细胞增殖。将研究与这些生物事件以及肿瘤发生抑制相关的分子标记。膀胱癌是一个重要的健康问题；需要有效的化学预防剂。 ITC 在蔬菜中含量丰富，许多在非膀胱动物器官中也是已知的抗癌物质。摄入的 ITC 被有效吸收，并且几乎完全以 N-乙酰半胱氨酸结合物 (NAC-ITC) 的形式从尿液中排出，它也是抗癌剂，并且可以释放 ITC，使膀胱上皮成为最容易接触 ITC/NAC-ITC 的组织。绝大多数膀胱癌起源于上皮细胞。将评估四种在非膀胱动物器官中表现出有效抗癌活性的膳食 ITC 及其 NAC 结合物。目标 1 旨在了解 ITC 或 NAC-ITC 是否能有效诱导关键的第 2 相解毒酶，包括谷胱甘肽转移酶、醌还原酶-1 和 UDP 葡萄糖醛酸基转移酶，这些酶的缺陷与膀胱癌发生增加有关。目标 2 将使用总 DNA 加合物和计划外 DNA 合成 (UDS) 作为标记，确定 ITC 或 NAC-ITC 对膀胱上皮细胞中致癌物诱导的 DNA 损伤的保护功效。细胞凋亡与增殖失衡也是膀胱癌的危险因素。目标 3 将确定 ITC 或 NAC-ITC 是否可以纠正与膀胱癌发生相关的细胞凋亡和增殖之间的不平衡：ITC 或 NAC-ITC 是否会诱导膀胱癌细胞凋亡和/或抑制细胞周期进展？如果是这样，其根本机制是什么？目标 4 将在体内评估口服 ITC 对重要生物标志物的影响，包括目标 1 中描述的 2 期酶、F344 大鼠膀胱上皮细胞凋亡 (TUNEL) 和增殖 (PCNA)。目标 5 将确定口服 ITC 在抑制 F344 大鼠中 N-丁基-N-(4-羟丁基)-亚硝胺诱导的膀胱肿瘤发生中的功效。