Berry J M, Jacobs C, Sikic B, Halsey J, Borch R F
Department of Medicine, Stanford University School of Medicine, CA 94301.
J Clin Oncol. 1990 Sep;8(9):1585-90. doi: 10.1200/JCO.1990.8.9.1585.
Diethyldithiocarbamate (DDTC), a heavy metal-chelating agent, has been shown to decrease cisplatin (CP) toxicity in preclinical studies. This phase I dose-escalation study was undertaken to investigate DDTC as a chemoprotector in patients with advanced cancer. Thirty-five courses of CP in doses ranging from 120 to 160 mg/m2 were given intravenous (IV) bolus to 19 patients. DDTC at 4 g/m2 was infused over 1 hour, starting 45 minutes after CP. There was minimal nephrotoxicity with a mean creatine clearance of 99 mL/min +/- 4 pretreatment and 86 mL/min +/- 4 on day 21. Two courses were associated with a WBC count less than 2,000/mm3 and one course with a platelet count of 15,000/mm3. Two patients had grade 2 neurotoxicity. Hearing loss occurred in 11 patients: five greater than or equal to 20 dB, five greater than or equal to 40 dB, and one greater than or equal to 60 dB. All patients who received cranial irradiation had ototoxicity compared with 43% of those without radiation (P less than .05). All patients experienced toxicity during the DDTC infusion, including hypertension, flushing, diaphoresis, agitation, and local burning. We conclude that DDTC can protect against CP nephrotoxicity at doses up to 160 mg/m2. Ototoxicity became the dose-limiting factor.
二乙基二硫代氨基甲酸盐（DDTC）是一种重金属螯合剂，临床前研究表明它可降低顺铂（CP）的毒性。本项I期剂量递增研究旨在调查DDTC对晚期癌症患者的化学保护作用。对19例患者静脉推注剂量范围为120至160mg/m²的CP，共35个疗程。在CP给药45分钟后开始，将4g/m²的DDTC在1小时内输注完毕。肾毒性极小，预处理时平均肌酐清除率为99mL/min±4，第21天时为86mL/min±4。两个疗程出现白细胞计数低于2000/mm³，一个疗程出现血小板计数为15000/mm³。两名患者出现2级神经毒性。11例患者出现听力损失：5例听力损失≥20dB，5例≥40dB，1例≥60dB。所有接受颅脑照射的患者均出现耳毒性，而未接受放疗的患者中这一比例为43%（P<0.05）。所有患者在DDTC输注期间均出现毒性反应，包括高血压、面部潮红、多汗、躁动和局部烧灼感。我们得出结论，DDTC在剂量高达160mg/m²时可预防CP肾毒性。耳毒性成为剂量限制因素。
