Saez R, Craig J B, Kuhn J G, Weiss G R, Koeller J, Phillips J, Havlin K, Harman G, Hardy J, Melink T J
Department of Medicine/Oncology, University of Texas Health Science Center, San Antonio 78284.
J Clin Oncol. 1989 Sep;7(9):1351-8. doi: 10.1200/JCO.1989.7.9.1351.
Amonafide (benzisoquinolinedione, NSC 308847) is a new synthetic imide antineoplastic agent with DNA intercalative properties that has been evaluated in a phase I clinical trial. The drug was administered as a single intravenous (IV) infusion over 30 to 120 minutes repeated every 28 days. Ninety-five courses of therapy at doses ranging from 18 to 1,104 mg/m2 were administered to 38 patients with refractory solid tumors. Granulocytopenia was dose limiting. Leukopenia was seen in 13 of 31 courses at doses of 690 mg/m2 or greater. Life-threatening granulocytopenia (less than or equal to 250 microliters) was noted in 1/6 patients treated at 800 mg/m2, 1/8 patients treated at 918 mg/m2, and 2/5 patients treated at 1,104 mg/m2. No definite relationship between myelotoxicity and prior treatment status was noted. Rate-of-infusion dependent, nonhematologic toxicities included diaphoresis, flushing, dizziness, and tinnitus, all of which were ameliorated by increasing the duration of drug infusion to 120 minutes. In addition, nausea and vomiting (grades 1 and 2) were seen in 29/56 courses at doses greater than or equal to 519 mg/m2, but were easily controlled by phenothiazine antiemetics. Amonafide plasma and urine concentrations were determined by high-pressure liquid chromatography (HPLC). Plasma concentrations declined biexponetially with a terminal harmonic mean terminal half-life (t 1/2) of 5.5 h. The mean apparent volume of distribution at steady-state and total body clearance were 532 L/m2 and 84 L/h/m2, respectively. Less than 5% of the total dose of amonafide was excreted unchanged in the urine. Antitumor activity has been noted in one patient with non-small-cell lung cancer (one complete response exceeding 29 months duration) and in one patient with prostatic cancer (complete pain relief and improvement in bone scan for 9 months). The recommended dose for phase II trials with this schedule of amonafide is 918 mg/m2 with dose escalation to amonafide is 918 mg/m2 with dose escalation to myelotoxicity.
氨萘非特（苯并异喹啉二酮，NSC 308847）是一种新型合成酰亚胺类抗肿瘤药物，具有DNA嵌入特性，已在一项I期临床试验中进行了评估。该药物通过单次静脉输注给药，输注时间为30至120分钟，每28天重复一次。对38例难治性实体瘤患者给予了95个疗程的治疗，剂量范围为18至1104mg/m²。粒细胞减少是剂量限制性毒性。在690mg/m²或更高剂量的31个疗程中，有13个疗程出现白细胞减少。在接受800mg/m²治疗的1/6患者、918mg/m²治疗的1/8患者和1104mg/m²治疗的2/5患者中，观察到危及生命的粒细胞减少（小于或等于250微升）。未发现骨髓毒性与既往治疗状态之间有明确关系。与输注速率相关的非血液学毒性包括出汗、潮红、头晕和耳鸣，通过将药物输注时间延长至120分钟，所有这些症状均得到改善。此外，在剂量大于或等于519mg/m²的56个疗程中，有29个疗程出现恶心和呕吐（1级和2级），但很容易通过吩噻嗪类止吐药控制。氨萘非特的血浆和尿液浓度通过高压液相色谱法（HPLC）测定。血浆浓度呈双指数下降，终末谐波平均终末半衰期（t1/2）为5.5小时。稳态时的平均表观分布容积和全身清除率分别为532L/m²和84L/h/m²。氨萘非特总剂量中不到5%以原形从尿液中排泄。在1例非小细胞肺癌患者（1例完全缓解，持续时间超过29个月）和1例前列腺癌患者（完全缓解疼痛，骨扫描改善9个月）中观察到抗肿瘤活性。氨萘非特按此给药方案进行II期试验的推荐剂量为918mg/m²，根据骨髓毒性情况逐步增加剂量。
