MARKERS OF BLADDER CANCER AND THEIR MODULATION BY DFMO

膀胱癌标志物及其 DFMO 的调节

• 批准号: 2414326
• 负责人: EDWARD M MESSING
• 金额: $ 20万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-22 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414326
• 关键词: biological signal transduction; biopsy; bladder neoplasm; cooperative study; difluoromethylornithine; dosage; enzyme activity; epidermal growth factor; gene expression; genetic markers; growth factor receptors; high performance liquid chromatography; human subject; immunocytochemistry; longitudinal human study; molecular oncology; protein isoforms; protein kinase C; radioimmunoassay; urinalysis; urinary bladder epithelium; urine acidity

As a companion to a recently funded contract (N01 CN-25434-01) for the chemoprevention of superficial transitional cell cancer (TCC) of the bladder, we propose to investigate intermediate molecular markers of TCC and their modulation by difluoro-methylornithine (DFMO), an irreversible inhibitor of the polyamine (PA) synthesizing enzyme, ornithine decarboxylase (ODC). In N01 CN-25434, 40 TCC and 20 non-TCC patients will have the biologic effects of 2 doses of DFMO (or placebo) determined in relevant targets (malignant and normal urothelial cells and tissues, and urine) to determine a biologically active DFMO dose to use in a placebo-controlled, Phase III, preventative trial in 240 patients with completely resected superficial TCC. The present investigation will utilize subjects in these studies to focus on interacting molecular pathways which are known to be altered in TCC and/or with ODC blockade/PA depletion. These include: 1) Pa metabolism; 2) the interaction of urinary epidermal growth factor (EGF) and its urothelial receptor (EGF-R) which is known to induce ODC activity in TCC cells; and 3) protein kinase C (PKC) which is an integral component of EGF signaling and ODC activation. Acetylated and unconjugated PA levels in urothelial tissues and urine (determined by HPLC) will be correlated with urothelial ODC activity (radiobioassay) expression (immunohistology) in patients with and without TCC and in those who are and are not receiving DFMO. Urinary [EGF] (RIA) and urothelial EGF-R expression (immunohistology/immunocytology) in these patients will be correlated with factors that influence (e.g. urinary pH), or result from (e.g. proliferation [Ki67 staining]) the EGF/EGF-R interaction, and with PA/ODC parameters. These will also be correlated with tissue profiles of predominant PKC isoforms (immunohistology) which are known to be differentially expressed in normal versus malignant cells in non-urothelial tissues. By comparing these parameters in patients with and without TCC, and particularly by repeating measurements in a longitudinal fashion in which disease outcome is being monitored, the effects of disease and its recurrence, as well as of ODC blockade will be better defined. These studies should provide important clinical information about molecular markers of malignant urothelial transformation, PA metabolism, and DFMO's biological effects as well as insights into the biology of TCC development, growth, and recurrence.

作为最近资助的合同 (N01 CN-25434-01) 的配套文件 浅表性移行细胞癌（TCC）的化学预防 膀胱，我们建议研究TCC的中间分子标志物 及其通过二氟甲基鸟氨酸 (DFMO) 的调节，这是一种不可逆的 多胺 (PA) 合成酶鸟氨酸抑制剂 脱羧酶（ODC）。 在 N01 CN-25434 中，40 名 TCC 患者和 20 名非 TCC 患者 将确定 2 剂 DFMO（或安慰剂）的生物效应 在相关目标（恶性和正常尿路上皮细胞和组织， 和尿液）以确定用于生物活性的 DFMO 剂量 在 240 名患有以下疾病的患者中进行的安慰剂对照 III 期预防性试验 完全切除表层TCC。 目前的调查将 利用这些研究中的主题来关注相互作用的分子 已知在 TCC 和/或 ODC 阻断/PA 中改变的途径 消耗。 这些包括：1）Pa代谢； 2）相互作用 尿表皮生长因子（EGF）及其尿路上皮受体（EGF-R） 已知可诱导 TCC 细胞中的 ODC 活性； 3) 蛋白激酶 C (PKC) 是 EGF 信号传导和 ODC 的组成部分 激活。 尿路上皮组织和尿液中乙酰化和未结合的 PA 水平 （通过 HPLC 测定）与尿路上皮 ODC 活性相关 （放射生物测定）在患有和不患有这种疾病的患者中的表达（免疫组织学） TCC 以及接受和未接受 DFMO 的患者。 尿 [EGF] (RIA) 和尿路上皮 EGF-R 表达（免疫组织学/免疫细胞学） 患者将与影响因素（例如尿 pH），或来自（例如增殖[Ki67染色]）EGF/EGF-R 相互作用，以及与 PA/ODC 参数。 这些也将相互关联 具有主要 PKC 同种型的组织概况（免疫组织学） 已知在正常细胞和恶性细胞中存在差异表达 在非尿路上皮组织中。 通过比较患有和不患有 TCC 的患者的这些参数，并且 特别是通过纵向重复测量，其中 正在监测疾病结果、疾病及其影响 复发以及 ODC 封锁将得到更好的定义。 这些 研究应提供有关分子的重要临床信息 恶性尿路上皮转化、PA 代谢和 DFMO 的标志物 生物效应以及对 TCC 生物学的见解 发育、生长和复发。