PHASE IIB-OLTIPRAZ CHEMOPREVENTION TRAIL

描述：(申请人描述)保护的主要机制 抗癌作用是提高与致癌物质有关的酶 解毒。诱导这些2相酶似乎是一种足够的 获得化学预防的条件，并可在许多目标中实现 通过给药一系列不同的天然或合成的 化学制品。虽然这一策略在实验中广泛适用 模型，它还没有在人类的背景下得到严格的评估 致癌。事实上，奥替拉兹是这些药物中第一个取得进展的 进入临床试验。利用黄曲霉毒素-白蛋白加合物的测定 作为终点，最近进行了一项IIa期临床试验 中国启东，确定奥替拉的剂量和时间表，可以 调节高危人群中这些生物标志物的水平 肝细胞癌。每周服用500毫克奥替拉唑，为期2个月 导致黄曲霉毒素-白蛋白水平略有但显著下降 加合物。因此，这一后续阶段IIb干预的目标是 试验将进行一项随机、双盲、安慰剂对照试验 目的：(1)确定每周服用500毫克奥替拉兹是否 1年来持续降低黄曲霉毒素-DNA加合物水平 尿中排泄和/或血清中黄曲霉毒素-白蛋白加合物至少25%； (2)确定每周服用小剂量(250毫克)奥替拉兹是否 程序调节黄曲霉毒素生物标志物；(3)评价药物动力学 奥替拉兹通过测定2相酶活性、mRNA水平发挥作用 受试者淋巴细胞的转录本和基因分型 在整个干预过程中；以及(4)确定最大安全剂量为500 mg 在IIa期试验中定义的每周一次的奥替拉兹。总而言之，这些 结果将为正在进行的开发提供几个关键的见解 化学防护剂。首先，这项临床试验应该澄清 奥替拉兹作为高优先级化学预防药物的地位 在高危人群中对其疗效的合理估计，以及 提供有关其药效学作用的进一步信息和 剂量限制的副作用。其次，这场审判将提供一个严格的 调控致癌物表达的有用性评价 解毒酶作为人类化学预防的一般策略。

DESCRIPTION: (Applicant's Description) A major mechanism for protection against carcinogenesis is the elevation of enzymes involved in carcinogen detoxication. Induction of these phase 2 enzymes appears to be a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of natural or synthetic chemicals. While this strategy is broadly applicable in experimental models, i t has not yet been rigorously evaluated in the context of human carcinogenesis. Indeed, oltipraz is the first of these agents to progress into clinical trials. Using measurements of aflatoxin-albumin adducts in serum as endpoints, a phase IIa clinical trial was recently conducted in Qidong, P. R. China to identify a dose and schedule of oltipraz that could modulate levels of these biomarkers in a population at high risk for hepatocellular carcinoma. A weekly schedule of 500 mg oltipraz for 2 months produced a small but, significant reduction in levels of aflatoxin-albwnin adducts. Thus, the objectives of this follow-up phase IIb intervention trial are to conduct a randomized, double masked, placebo-controlled trial to: (1) determine whether the administration of 500 mg of oltipraz weekly for 1 year persistently decreases the levels of aflatoxin-DNA adducts excreted in urine and/or aflatoxin-albumin adducts in serum by at least 25%; (2) determine whether a lower dose (250 mg) of oltipraz on the weekly schedule modulates aflatoxin biomarkers; (3) assess the phannacodynamic action of oltipraz by measuring phase 2 enzyme activities, levels of mRNA transcripts, and genotypes in lymphocytes obtained from participants throughout the intervention; and (4) confirm the maximum safe dose of 500 mg oltipraz weekly as defined during the phase IIa trial. Collectively, these results will provide several pivotal insights for the ongoing development of chemopreventive agents. First, this clinical trial should clarify the status of oltipraz as a high priority chemopreventive agent by providing a reasonable estimate of its efficacy in a high-risk population, as well as providing further information regarding its pharmacodynamic action and dose-limiting side effects. Second, this trial will provide a rigorous assessment of the usefulness of modulating expression of carcinogen detoxication enzymes as a general strategy for chemoprevention in humans.