Brown T D, Ettinger D S, Donehower R C
J Clin Oncol. 1986 Aug;4(8):1270-6. doi: 10.1200/JCO.1986.4.8.1270.
Spirohydantoin mustard (spiromustine, NSC 172112) is a classical bifunctional alkylating agent synthesized in an effort to develop antitumor agents effective against CNS tumors. The rationale was to combine the reactive moiety of an active antitumor agent with the hydantoin part of the molecule, which might serve as a carrier to cross the blood brain barrier. Thirty-eight patients with refractory solid tumors received spiromustine as part of a phase I trial at the Johns Hopkins Oncology Center. Three schedules were investigated: intravenously (IV) daily for three consecutive days, IV every other day for 3 days, and IV on a weekly basis for three doses, all cycled every 28 days. Hematologic toxicity was infrequently seen. Mild to moderate nausea and vomiting occurred on all schedules. The dose limiting toxicity was CNS toxicity characterized by mydriasis, xerostomia, lethargy, confusion, and hallucinations. This CNS toxicity was dose related, cumulative, and reversible. IV physostigmine appeared to diminish the neurotoxicity if administered before spiromustine and at frequent intervals following the drug. The maximum tolerated dose of spiromustine (without concomitant physostigmine) on the three times a week schedule is 6 mg/m2. With physostigmine pretreatment, 8 mg/m2 can be administered. The three times daily and every other day for three days schedules are not recommended for further study due to the severity of neurotoxicity. It is recommended that 6 mg/m2 be used as the starting dose for any phase II studies using the three times weekly schedule, and that physostigmine be used as needed to minimize neurotoxicity. Dose escalation above this level can be considered when individual tolerance has been established. Phase II trials to investigate the activity of this agent against primary and metastatic CNS malignancies appear indicated on the basis of three transient radiographic responses in refractory malignancies metastatic to the CNS.
螺环乙内酰脲氮芥（螺莫司汀，NSC 172112）是一种经典的双功能烷化剂，其合成目的是研发对中枢神经系统肿瘤有效的抗肿瘤药物。基本原理是将活性抗肿瘤药物的反应性部分与分子中的乙内酰脲部分结合，后者可能作为载体穿过血脑屏障。38例难治性实体瘤患者在约翰霍普金斯肿瘤中心接受了螺莫司汀治疗，作为I期试验的一部分。研究了三种给药方案：连续三天每日静脉注射（IV），隔日静脉注射3天，以及每周静脉注射一次，共三剂，均每28天为一个周期。血液学毒性罕见。所有给药方案均出现轻至中度恶心和呕吐。剂量限制性毒性是中枢神经系统毒性，表现为瞳孔散大、口干、嗜睡、意识模糊和幻觉。这种中枢神经系统毒性与剂量相关、具有累积性且可逆。静脉注射毒扁豆碱如果在螺莫司汀给药前及给药后频繁间隔使用，似乎可减轻神经毒性。每周三次给药方案中螺莫司汀（不联合毒扁豆碱）的最大耐受剂量为6mg/m²。进行毒扁豆碱预处理时，可给予8mg/m²。由于神经毒性严重，不建议进一步研究每日三次和隔日三次给药方案。建议在任何使用每周三次给药方案的II期研究中，将6mg/m²作为起始剂量，并根据需要使用毒扁豆碱以尽量减少神经毒性。当确定个体耐受性后，可考虑高于此水平的剂量递增。基于在转移至中枢神经系统的难治性恶性肿瘤中出现的三次短暂影像学反应，似乎有必要进行II期试验以研究该药物对原发性和转移性中枢神经系统恶性肿瘤的活性。
