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: 6681181
• 负责人: YUESHENG ZHANG
• 金额: $ 21.54万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6681181
• 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）：该项目着重于确定膀胱中异硫氰酸盐（ITC）的癌症预防活性。要检验的假设是，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致癌：诱导2期酶，诱导凋亡和抑制细胞增殖。将研究与这些生物事件有关的分子标记物以及抑制肿瘤发生。膀胱癌是一个重要的健康问题。需要有效的化学预防剂。 ITC在蔬菜中很丰富，许多在非叶片动物器官中是已知的抗癌药物。摄入的ITC被有效吸收，几乎完全排泄在尿液中，因为N-乙酰半胱氨酸结合物（NAC-ITC）也是抗癌药物，可以释放ITC，从而使膀胱上皮上皮是ITCS/NAC-ITC的最暴露的组织。绝大多数膀胱癌源自上皮细胞。将评估四个在非叶片动物器官及其NAC结合物中表现出有效抗癌活性的饮食ITC。 AIM 1旨在查看ITCS还是NAC-ITC是否有效诱导关键阶段2解毒酶，包括谷胱甘肽转移酶，喹酮还原酶1和Udpglucurohonosylysylysylansylansylansylansylansylansferase，其缺陷已与膀胱癌的增加有关。 AIM 2将使用总DNA加合物和不定的DNA DNA合成（UDS）作为标记来确定ITC或NAC-ITC对膀胱上皮细胞中致癌物诱导的DNA损伤的保护性疗效。凋亡与增殖之间的不平衡也是膀胱癌的危险因素。 AIM 3将确定ITC或NAC-ITC是否可以纠正与膀胱癌变相关的凋亡与增殖之间的失衡：ITC或NAC-ITC是否诱导凋亡和/或抑制膀胱癌细胞中细胞周期的进展？如果是这样，基本机制是什么？ AIM 4将在RIVO中评估口服ITC对重要生物标志物的影响，包括AIM 1中描述的2期酶，凋亡（TUNEL）和F344大鼠膀胱上皮中的增殖（PCNA）。 AIM 5将确定口服ITC在抑制N-丁基N-（4-羟基丁基） - 硝基胺诱导的F344大鼠膀胱肿瘤发生的功效。