Kasturi V K, Dearing M P, Piscitelli S C, Russell E K, Sladek G G, O'Neil K, Turner G A, Morton T L, Christian M C, Johnson B E, Kelley M J
Medicine Branch, National Cancer Institute, Bethesda, Maryland 20889-5105, USA.
Clin Cancer Res. 1998 Sep;4(9):2095-102.
The mammalian pulmonary toxin 4-ipomeanol (IPO) is activated by the cytochrome P450 system in bronchial Clara cells in animals. The resulting metabolites bind rapidly to macromolecules, producing localized cytotoxicity. IPO has in vitro and in vivo antitumor activity in non-small cell lung cancer (NSCLC) and thus was proposed as a lung cancer-specific antitumor agent. We have completed a directed Phase I trial in patients with NSCLC. Forty-four patients (34 men and 10 women) with NSCLC were treated with IPO. All but two patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. They received 91 courses of therapy with i.v. IPO; 82 courses were administered daily for five days, and 9 were single bolus doses. The dose-limiting toxicity of elevated serum transaminases was observed in three of seven patients at 922 mg/m2/day. The maximum tolerated dose was 693 mg/m2/day on 5 consecutive days every 3 weeks. One patient developed grade 4 pulmonary toxicity at 167 mg/m2/day. There was no significant hematological or renal toxicity. No objective antitumor responses were observed. Pharmacokinetic analysis of 39 patients from day 1 of IPO administration showed biexponential elimination with mean half-lives of 8.6 (alpha half-life) and 76 min (beta half-life). There was a linear relationship between the area under the plasma drug concentration-time curve and the dose of IPO. There was no significant difference between the pharmacokinetic parameters measured on day 1 and day 5. Using a 4-day in vitro cytotoxicity assay, two tumor cell lines established from patients treated at 693 mg/m2/day had IC50s of approximately 6 mM, a concentration more than 75-fold higher than the plasma levels measured in these patients. Thus, although the total amount of drug administered per cycle on a daily times five dose schedule is more than 2.5-fold higher than the recommended single daily dose, IPO is unlikely to be a useful drug for patients with lung cancer.
哺乳动物肺毒素4-异戊二烯醇（IPO）在动物支气管克拉拉细胞中被细胞色素P450系统激活。产生的代谢产物迅速与大分子结合，产生局部细胞毒性。IPO在非小细胞肺癌（NSCLC）中具有体外和体内抗肿瘤活性，因此被提议作为一种肺癌特异性抗肿瘤药物。我们已完成一项针对NSCLC患者的定向I期试验。44例（34例男性和10例女性）NSCLC患者接受了IPO治疗。除两名患者外，所有患者的东部肿瘤协作组体能状态均为0或1。他们接受了91个疗程的静脉注射IPO治疗；82个疗程每天给药，持续5天，9个疗程为单次推注剂量。在922 mg/m²/天的剂量下，7名患者中有3名出现血清转氨酶升高的剂量限制性毒性。最大耐受剂量为每3周连续5天693 mg/m²/天。一名患者在167 mg/m²/天的剂量下出现4级肺毒性。未观察到明显的血液学或肾脏毒性。未观察到客观的抗肿瘤反应。对39例患者从IPO给药第1天开始进行的药代动力学分析显示为双指数消除，平均半衰期分别为8.6分钟（α半衰期）和76分钟（β半衰期）。血浆药物浓度-时间曲线下面积与IPO剂量之间存在线性关系。第1天和第5天测量的药代动力学参数之间无显著差异。使用为期4天的体外细胞毒性试验，从接受693 mg/m²/天治疗的患者中建立的两个肿瘤细胞系的半数抑制浓度（IC50）约为6 mM，该浓度比这些患者中测得的血浆水平高75倍以上。因此，尽管每日5次给药方案下每个周期给药的药物总量比推荐的单日剂量高2.5倍以上，但IPO对肺癌患者不太可能是一种有用的药物。
