Intraventricular immunotoxin therapy for leptomeningeal neoplasia
Intraventricular immunotoxin therapy for leptomeningeal neoplasia
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DOI：
10.1097/00006123-199711000-00005
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发表时间：
1997-11-01
期刊：
影响因子：
4.8
通讯作者：
Youle, RJ
中科院分区：
文献类型：
--
作者：
Laske, DW;Muraszko, KM;Youle, RJ
目的：探讨454A12-RRA脑室给药的剂量限制性毒性，评价454A12-RRA单剂脑室给药的药代动力学，检测其抗肿瘤活性。方法：对8例软脑膜播散性系统性肿瘤患者进行免疫毒素454A12-RRA脑室给药的初步研究。免疫毒素454A12-RRA是抗人转铁蛋白受体的单抗和重组蓖麻毒素A链的结合物，重组蓖麻毒素A链是蛋白毒素蓖麻毒素的酶活性亚基。结果：454A12-RRA在脑室脑脊液中的早期半衰期平均为44±21分钟，晚期半衰期平均为237±86分钟。免疫毒素的清除速度比共注射的~(99m)Te-二乙三胺五乙酸的清除速度快，平均高出2.4倍。脑室脑脊液Western印迹分析检测到24小时内无454A12-RRA降解，脑脊液中生物活性与免疫毒素浓度平行。在脑室注射454A12-RRA小于或等于38微克的患者中，没有发现急性或慢性药物毒性。剂量大于或等于120毫克会引起脑脊液炎症反应，与一过性头痛、呕吐和精神状态改变有关，这种急性综合征对类固醇和脑脊液引流有反应。未检测到全身毒性。在8名患者中，有4名患者在脑室注射454A12-RRA后5~7天内腰部脑脊液中的肿瘤细胞数量减少了50%以上，但没有患者的脑脊液肿瘤被清除，8名患者中有7名患者在治疗后有临床或磁共振成像证据表明肿瘤进展。结论：免疫毒素454A12-RRA在软脑膜肿瘤扩散患者的脑脊液中可以安全地达到杀瘤浓度。
OBJECTIVE: The goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity.METHODS: We performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454A12-rRA is a conjugate of a monoclonal antibody against the human transferrin receptor and recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. Patients were treated with single doses of 454A12-rRA ranging from 1.2 to 1200 mu g.RESULTS: The early phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (CSF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than the clearance of coinjected technetium-99m-diethylenetriamine penta-acetic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degradation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling the concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 mu g of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 mu g caused a CSF inflammatory response that was associated with transient headache, vomiting, and altered mental status, This acute syndrome was responsive to steroids and CSF drainage. No systemic toxicity was detected. In four of the eight patients, a greater than 50% reduction of tumor cell counts in the lumbar CSF occurred within 5 to 7 days after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance imaging evidence of tumor progression was demonstrated in seven of the eight patients after treatment.CONCLUSION: Tumoricidal concentrations of the immunotoxin 454A12-rRA can be attained safely in the CSF of patients with leptomeningeal tumor spread.