Fichtner I, Becker M, Baumgart J
Max-Delbrueck-Center for Molecular Medicine, Experimental Pharmacology, Berlin-Buch, Germany.
Eur J Cancer. 2003 Apr;39(6):801-7. doi: 10.1016/s0959-8049(02)00767-0.
Treosulfan (L-threitol-1,4-bis-methanesulphonate; Ovastat(R)) is a bifunctional alkylating drug indicated for the treatment of advanced ovarian carcinoma. Recent data revealed immunosuppressive characteristics and substantial haematopoietic stem cell toxicity after repeated dosing of mice. Therefore, treosulfan is considered to be an alternative conditioning agent to busulfan (for example) administered prior to allogeneic/autologous stem cell transplantation of patients with haematological malignancies. An antineoplastic activity for treosulfan has been previously shown in preclinical models of melanoma, breast, lung and renal-cell carcinomas. Here, in vivo antileukaemic activity of treosulfan is compared with the activity of equitoxic doses of cyclophosphamide or busulfan for the first time using human acute lymphoblastic leukaemia (ALL)-models of paediatric origin xenotransplanted into non-obese diabetic (NOD)/severe combined immunodeficient (SCID) mice. Treosulfan treatment achieved an optimum treated to control (T/C) value of 159% (survival time) against B-ALL-SCID 7 and a T/C value of 0% (tumour growth) against T-ALL-SCID 4 and proB-ALL-SCID 19, respectively. Complete regression of established subcutaneously (s.c.) growing nodules of ALL-SCID 4 and 19 was obvious and long-term survivors without tumour re-growth were observed. Equitoxic doses of busulfan (ALL-SCID 4, 7, 19) or cyclophosphamide (ALL-SCID 19) were less effective with regard to the numbers of complete regressions and the number of cured animals. Side-effects included myelotoxicity and a small reduction in body weight, but these were tolerable. Treosulfan can be considered a highly active antileukaemic drug whose corresponding clinical value is to be tested in appropriate protocols with leukaemic patients.
曲奥舒凡（L-苏糖醇-1,4-双甲磺酸酯；Ovastat(R)）是一种双功能烷化剂，用于治疗晚期卵巢癌。近期数据显示，对小鼠重复给药后，曲奥舒凡具有免疫抑制特性和显著的造血干细胞毒性。因此，曲奥舒凡被认为是一种替代白消安（例如）的预处理药物，用于血液系统恶性肿瘤患者的异基因/自体干细胞移植前给药。此前在黑色素瘤、乳腺癌、肺癌和肾细胞癌的临床前模型中已显示曲奥舒凡具有抗肿瘤活性。在此，首次使用移植到非肥胖糖尿病（NOD）/重症联合免疫缺陷（SCID）小鼠体内的小儿来源的人类急性淋巴细胞白血病（ALL）模型，将曲奥舒凡的体内抗白血病活性与等毒性剂量的环磷酰胺或白消安的活性进行比较。曲奥舒凡治疗对B-ALL-SCID 7的最佳治疗与对照（T/C）值为159%（生存时间），对T-ALL-SCID 4和proB-ALL-SCID 19的T/C值分别为0%（肿瘤生长）。皮下（s.c.）生长的ALL-SCID 4和19结节完全消退明显，并且观察到无肿瘤复发的长期存活者。就完全消退的数量和治愈动物的数量而言，等毒性剂量的白消安（ALL-SCID 4、7、19）或环磷酰胺（ALL-SCID 19）效果较差。副作用包括骨髓毒性和体重略有减轻，但这些都是可耐受的。曲奥舒凡可被认为是一种高活性抗白血病药物，其相应的临床价值有待在白血病患者的适当方案中进行测试。
