Sessa C, Pagani O, Zurlo M G, de Jong J, Hofmann C, Lassus M, Marrari P, Strolin Benedetti M, Cavalli F
Division of Oncology, Ospedale San Giovanni, Bellinzona, Switzerland.
Ann Oncol. 1994 Dec;5(10):901-7. doi: 10.1093/oxfordjournals.annonc.a058728.
Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds to A-T rich regions of DNA in the minor groove producing highly sequence-specific alkylations. Its main preclinical features are a significant antitumor activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in animals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs.
Forty adult patients (pts) with solid malignancies were entered in the study. The drug was administered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week following the first cycle. From the starting dose of 50 micrograms/m2, corresponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there were increases through 10 dose levels, with reliance only on the features of the myelotoxicity observed.
The main toxic effect was neutropenia which was dose-limiting, selective and short-lasting. Only previously-untreated pts received doses of 750 micrograms/m2 or more, with grade 4 neutropenia occurring in > or = 75% of the cycles. The maximally tolerable dose (MTD) was defined as 1250 micrograms/m2, with 3 of 3 pts developing febrile neutropenia requiring IV antibiotics. A platelet count of < 100 x 10(3)/microliters was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharmacokinetic studies performed at 1000 micrograms/m2 and 1250 micrograms/m2 showed a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previously-untreated pt with cutaneous recurrences of malignant mesothelioma.
The report of some antitumour efficacy, the high selectivity of neutropenia, the lack of significant non-hematological toxic effects and the occurrence of detectable but still low plasma drug concentrations suggest that further clinical evaluation of higher doses of tallimustine in combination with colony-stimulating factors would be justified.
他利莫司汀是抗病毒药物偏端霉素A的苯甲酰氮芥衍生物，是一种新型烷化剂，可与DNA小沟中富含A - T的区域结合，产生高度序列特异性烷基化。其主要临床前特征是在动物模型中具有显著的抗肿瘤活性，并且在体外和体内与左旋苯丙氨酸氮芥不存在交叉耐药性。在动物中，骨髓毒性是剂量限制性的，小鼠和狗的骨髓敏感性相差100倍以上。
40例成年实体恶性肿瘤患者进入本研究。药物每4周静脉推注给药一次。每周重复进行两次全血细胞计数，并在第一个周期后的一周内对肾功能进行系列评估。从50微克/平方米的起始剂量开始，该剂量相当于狗的最高无毒剂量（HNTD）的1/3，剂量通过10个水平增加，仅依据观察到的骨髓毒性特征来调整。
主要毒性作用是中性粒细胞减少，这是剂量限制性的、选择性的且持续时间短。只有先前未接受过治疗的患者接受了750微克/平方米或更高的剂量，在≥75%的周期中出现4级中性粒细胞减少。最大耐受剂量（MTD）定义为1250微克/平方米，3例患者中有3例发生发热性中性粒细胞减少，需要静脉使用抗生素。仅1例患者观察到血小板计数<100×10³/微升。在第8天和第15天对选定患者进行的骨髓穿刺证实，他利莫司汀对髓系谱系有高度选择性损伤，增殖区迅速恢复。在1000微克/平方米和1250微克/平方米剂量下进行的药代动力学研究表明，血浆水平在最初2小时内迅速下降，在第1小时内药物浓度在100纳克/毫升至400纳克/毫升之间。1例先前未接受过治疗的恶性间皮瘤皮肤复发患者报告了持续4个月的部分缓解。
一些抗肿瘤疗效的报告、中性粒细胞减少的高选择性、缺乏显著的非血液学毒性作用以及可检测到但仍较低的血浆药物浓度的出现表明，对更高剂量的他利莫司汀联合集落刺激因子进行进一步临床评估是合理的。
