Perotti A, Sessa C, Mancuso A, Noberasco C, Cresta S, Locatelli A, Carcangiu M L, Passera K, Braghetti A, Scaramuzza D, Zanaboni F, Fasolo A, Capri G, Miani M, Peters W P, Gianni L
Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
Ann Oncol. 2009 Apr;20(4):741-5. doi: 10.1093/annonc/mdn695. Epub 2009 Feb 3.
Upregulation of N-cadherin promotes dysregulated cell growth, motility, invasiveness, plus maintenance of vascular stability and is associated with cancer progression in several human tumour types. N-cadherin is expressed also on tumour cells and the anti-N-cadherin cyclic pentapeptide ADH-1, tested in the present study, can exert a direct antitumour effect.
Adult patients with advanced solid malignancies expressing N-cadherin on tumour biopsies carried out in the previous 12 months received escalating i.v. doses of ADH-1 given weekly (initially for 3 of 4 weeks, then every week). Plasma pharmacokinetics (PK) was studied at cycle 1. Blood flow changes were assessed after first dosing in all patients treated in the initial regimen.
In all, 129 patients were screened, 65 (50%) were N-cadherin positive, and 30 were enrolled. The doses ranged from 150 to 2400 mg/m(2); no maximum tolerated dose was reached. Treatment was well tolerated with asthenia as the most frequent adverse event. Two patients with ovarian cancer showed prolonged disease stabilisation while one patient with fallopian tube carcinoma achieved a mixed response. PK was linear in the range of doses tested.
ADH-1 is the first anti-N-cadherin compound tested in humans. In N-cadherin-positive patients, ADH-1 showed an acceptable toxicity profile, linear PK and hints of antitumour activity in gynaecological cancers.
N-钙黏蛋白的上调促进细胞生长失调、运动性、侵袭性以及血管稳定性的维持，并与多种人类肿瘤类型的癌症进展相关。N-钙黏蛋白也在肿瘤细胞上表达，本研究中测试的抗N-钙黏蛋白环五肽ADH-1可发挥直接的抗肿瘤作用。
在过去12个月内进行的肿瘤活检中显示表达N-钙黏蛋白的晚期实体恶性肿瘤成年患者接受静脉注射递增剂量的ADH-1，每周给药（最初4周中的3周给药，然后每周给药）。在第1周期研究血浆药代动力学（PK）。在初始方案治疗的所有患者首次给药后评估血流变化。
总共筛选了129例患者，65例（50%）为N-钙黏蛋白阳性，30例入组。剂量范围为150至2400mg/m²；未达到最大耐受剂量。治疗耐受性良好，乏力是最常见的不良事件。两名卵巢癌患者疾病稳定期延长，一名输卵管癌患者有混合反应。在所测试的剂量范围内PK呈线性。
ADH-1是首个在人体中测试的抗N-钙黏蛋白化合物。在N-钙黏蛋白阳性患者中，ADH-1显示出可接受的毒性特征、线性PK以及在妇科癌症中的抗肿瘤活性迹象。
