Elias A D, Wheeler C, Ayash L J, Schwartz G, Ibrahim J, Mills L, McCauley M, Coleman N, Warren D, Schnipper L, Antman K H, Teicher B A, Frei E
Division of Clinical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Clin Cancer Res. 1998 Jun;4(6):1443-9.
Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain, predominantly in stocking glove distribution, occurring between day -3 and day 0, and a sensory peripheral neuropathy with similar distribution peaking around day +60. The maximal achievable dose of etanidazole (16 g/m2 dose level) resulted in a mean serum level of 38 micrograms/ml (25-55 micrograms/ml). Etanidazole significantly enhanced host toxicity of high-dose ICE. Effective modulatory doses of etanidazole could not be given with acceptable toxicity using this schedule.
多种耐药机制导致治疗失败。尽管高剂量疗法试图通过药理学手段突破这些防御机制，但这种方法仅在部分接受治疗的患者中取得成功。许多耐药机制在恶性细胞和正常细胞之间是共有的，但与缺氧相关的各种耐药机制的表达主要局限于肿瘤组织。因此，逆转这种机制可能会给宿主带来治疗优势。本研究旨在确定在给予高剂量异环磷酰胺、卡铂和依托泊苷（ICE）并辅以造血干细胞支持的情况下，同时给予乙磺半胱氨酸时的剂量限制性毒性和最大耐受剂量。高剂量ICE的最大耐受剂量与缺氧细胞增敏剂乙磺半胱氨酸的剂量递增同时给药。所有药物均从第-7天开始通过96小时持续静脉输注给药。给予美司钠进行尿路保护。自体骨髓和细胞因子动员的外周血祖细胞在第0天回输。回输后给予粒细胞集落刺激因子，直至粒细胞恢复至>1000/微升。55名患有晚期恶性肿瘤的成年人被纳入每组5至9名患者的队列中。评估了乙磺半胱氨酸在3至5.5克/平方米/天（总剂量12、16、20和22克/平方米）之间的四个剂量水平以及两种剂量的卡铂（总剂量1600和1800毫克/平方米）。7名患者死于器官毒性（13%）；其中2名死于肝静脉闭塞病和败血症；1名死于猝死、肾衰竭和难治性血小板减少性出血。5例死亡发生在最高剂量水平。另外1名患者因心室颤动发生目击性心肺骤停并被复苏。观察到剂量依赖性且大多可逆的周围神经病变，包括两种综合征：严重的痉挛性肌痛/神经痛，主要呈手套袜套样分布，发生在第-3天至第0天之间；以及分布相似的感觉性周围神经病变，在第+60天左右达到峰值。乙磺半胱氨酸的最大可达到剂量（16克/平方米剂量水平）导致平均血清水平为38微克/毫升（25 - 55微克/毫升）。乙磺半胱氨酸显著增强了高剂量ICE对宿主的毒性。按照此方案，无法以可接受的毒性给予有效的调节剂量的乙磺半胱氨酸。
