Yarom Nirit, Stewart David, Malik Rajesh, Wells Julie, Avruch Leonard, Jonker Derek J
Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Ontario, Canada.
Curr Clin Pharmacol. 2013 Feb 1;8(1):81-8.
ADH-1 (Exherin™) is a pentapeptide, which competitively inhibits N-cadherin, resulting in vascular disruptive effect of tumor vasculature in preclinical models. This study was designed to assess the toxicity of ADH-1 and to determine the maximal tolerated dose (MTD).
Adult patients with advanced measurable solid tumors were stratified according to their tumor N-cadherin status. ADH-1 was administered as a short infusion, every six weeks. Assessment of response was done every 6 weeks. PK parameters included: estimated volume of distribution of the central compartment, the α and β phase half-lives, area under the plasma concentration- time curve (AUC), clearance, and volume of distribution. Target lesions were assessed by dynamic contrast enhancing- magnetic resonance imaging (DCE-MRI).
46 patients were enrolled, 25 (54%) had N-cadherin positive status. The doses administered ranged from 50 mg/m2 to 1000 mg/m2, and the MTD was not reached. The PK analysis of the concentration-time data displayed a biphasic profile. Most of the toxicities were grade 1 and 2 with fatigue, nausea, chest pain and dysgeusia being the most common. Eleven patients had disease control, the single patient who had partial response had N-cadherin positive tumor.
ADH-1 is a well tolerated drug with a modest anti tumor effect in tumors which express N-cadherin.
ADH-1（Exherin™）是一种五肽，在临床前模型中可竞争性抑制N-钙黏蛋白，从而对肿瘤血管产生血管破坏作用。本研究旨在评估ADH-1的毒性并确定最大耐受剂量（MTD）。
患有晚期可测量实体瘤的成年患者根据其肿瘤N-钙黏蛋白状态进行分层。ADH-1每六周进行一次短时间输注给药。每6周进行一次疗效评估。药代动力学参数包括：中央室估计分布容积、α和β相半衰期、血浆浓度-时间曲线下面积（AUC）、清除率和分布容积。通过动态对比增强磁共振成像（DCE-MRI）评估靶病变。
共纳入46例患者，其中25例（54%）N-钙黏蛋白呈阳性状态。给药剂量范围为50mg/m²至1000mg/m²，未达到最大耐受剂量。浓度-时间数据的药代动力学分析显示为双相曲线。大多数毒性反应为1级和2级，最常见的是疲劳、恶心、胸痛和味觉障碍。11例患者病情得到控制，唯一出现部分缓解的患者其肿瘤N-钙黏蛋白呈阳性。
ADH-1耐受性良好，对表达N-钙黏蛋白 的肿瘤具有一定的抗肿瘤作用。
