Smith D B, Ewen C, Mackintosh J, Fox B W, Thatcher N, Scarffe J H, Vezin R, Crowther D
CRC Department of Medical Oncology, Christie Hospital, Manchester, UK.
Br J Cancer. 1988 Jun;57(6):623-7. doi: 10.1038/bjc.1988.142.
Amphethinile is a new spindle poison with a novel structure that has shown activity in the L1210, ADJ/PC6 and Walker carcinoma rodent tumours. In addition the agent appeared to have an improved therapeutic ratio compared to existing spindle poisons and is well absorbed when administered orally. The starting dose for the phase I study was 40 mg m-2 (1/10th mouse LD10) and further patients were studied at 200, 400, 800 and 1200 mg m-2, dose escalation being based on pharmacological monitoring. Significant toxic effects were seen only at 800 and 1200 mg m-2. At these doses patients experienced nausea and vomiting, light headedness during the infusion and varying degrees of lethargy following therapy. Two of six patients at 800 mg m-2 developed severe pain in the tumour bearing area 1-2 h after treatment and one experienced colicky abdominal pain. At 1200 mg m-2 two patients died within 48 h of treatment from what appeared to be vascular causes. Following these episodes the trial was discontinued. Neutropenia and alopecia occurred in two patients, one at 800 and one at 1200 mg m-2. These patients achieved the highest drug exposure in terms of area under the concentration x time curve. It was not possible to achieve an AUC consistently high enough to produce cytotoxic effects due to the occurrence of dose limiting toxicities thus amphethinile cannot at present be recommended for phase II testing by the i.v. route. The dose escalation scheme based on pharmacological monitoring resulted in a considerable saving in the duration of the trial. Further evaluation of this methodology is recommended.
安非他明是一种具有新型结构的新型纺锤体毒素，已在L1210、ADJ/PC6和Walker癌啮齿动物肿瘤中显示出活性。此外，与现有的纺锤体毒素相比，该药物的治疗指数似乎有所提高，口服时吸收良好。I期研究的起始剂量为40mg/m²（小鼠LD10的1/10），进一步的患者分别在200、400、800和1200mg/m²剂量下进行研究，剂量递增基于药理监测。仅在800和1200mg/m²剂量时观察到显著的毒性作用。在这些剂量下，患者出现恶心、呕吐、输液期间头晕以及治疗后不同程度的嗜睡。800mg/m²剂量组的6名患者中有2名在治疗后1 - 2小时出现肿瘤部位严重疼痛，1名患者出现绞痛。在1200mg/m²剂量时，2名患者在治疗后48小时内死于看似血管性的原因。在这些事件发生后，试验停止。两名患者出现中性粒细胞减少和脱发，一名在800mg/m²剂量组，一名在1200mg/m²剂量组。就浓度×时间曲线下面积而言，这些患者的药物暴露量最高。由于出现剂量限制性毒性，无法持续获得足够高的AUC以产生细胞毒性作用，因此目前不建议通过静脉途径将安非他明用于II期试验。基于药理监测的剂量递增方案在试验持续时间方面节省了大量时间。建议对该方法进行进一步评估。
