Eccles D M, Cummings J, Stewart M E, Nicolson M, Cornbleet M A, Leonard R C, Smyth J F
Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.
Cancer Chemother Pharmacol. 1992;29(5):375-8. doi: 10.1007/BF00686006.
GR63178A is a water-soluble analogue of mitoquidone, a pentacyclic pyrroloquinone. This group of drugs exhibit a novel structure and activity against several murine solid tumours and xenografts. In the present phase I study the toxicity and pharmacokinetics of GR63178A given on 5 consecutive days of a 21-day cycle were examined. A total of 24 patients presenting with a wide range of tumours were treated at 5 doses escalated to reach the maximal tolerated dose (MTD). Linear pharmacokinetics was documented over the dose range studied, and there was no difference in parent drug handling between day 1 and day 4 of dosing. A number of metabolites were detected. The toxicity profile was unusual in that pain occurred in 20/24 patients, most often at the site of known disease. This was the dose-limiting toxicity. Other side effects included nausea and vomiting (23/24), phlebitis at the infusion site (6/24) and headache (7/24). No treatment response was seen in this study. The MTD was demonstrated to be 160 mg/m2 daily (total, 800 mg/m2 per treatment cycle). The drug has now entered phase II trials at 120 mg/m2 daily x 5, repeated every 21 days.
GR63178A是米托醌（一种五环吡咯并醌）的水溶性类似物。这类药物具有新颖的结构，对多种小鼠实体瘤和异种移植瘤具有活性。在当前的I期研究中，对在21天周期内连续5天给予GR63178A的毒性和药代动力学进行了研究。共有24例患有多种肿瘤的患者接受了5种剂量的治疗，剂量逐步递增以达到最大耐受剂量（MTD）。在所研究的剂量范围内记录到线性药代动力学，给药第1天和第4天母体药物的处理情况无差异。检测到多种代谢产物。毒性特征不同寻常，20/24例患者出现疼痛，最常出现在已知疾病部位。这是剂量限制性毒性。其他副作用包括恶心和呕吐（23/24）、输液部位静脉炎（6/24）和头痛（7/24）。本研究中未观察到治疗反应。最大耐受剂量为每日160mg/m²（每个治疗周期总计800mg/m²）。该药物现已进入II期试验，剂量为每日120mg/m²×5天，每21天重复一次。
