Sillaber C, Mayerhofer M, Böhm A, Vales A, Gruze A, Aichberger K J, Esterbauer H, Pfeilstöcker M, Sperr W R, Pickl W F, Haas O A, Valent P
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.
Eur J Clin Invest. 2008 Jan;38(1):43-52. doi: 10.1111/j.1365-2362.2007.01892.x.
Recent data suggest that the mammalian target of rapamycin (mTOR) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia (CML).
We treated six patients with imatinib-resistant CML in haematological relapse (leukocytes > 20,000 microL(-1)) with rapamycin at 2 mg per os daily for 14 consecutive days, with dose-adjustment allowed to reach a target rapamycin serum concentration of 10-20 pg mL(-1).
A major leukocyte response with decrease to less than 10,000 microL(-1) was obtained in two patients, and a minor transient response was seen in two other patients. In responding patients, we also observed a decrease in vascular endothelial growth factor (VEGF) mRNA levels in circulating leukaemic cells. Side effects during rapamycin treatment were mild in most patients. In one patient, pneumonia developed. Rapamycin was also found to counteract growth of CML cells in vitro as determined by (3)H-thymidine incorporation. Moreover, rapamycin inhibited the growth of Ba/F3 cells exhibiting various imatinib-resistant mutants of BCR/ABL, including the T315I variant that exhibits resistance against most currently available BCR/ABL kinase inhibitors.
Rapamycin shows antileukaemic effects in imatinib-resistant CML in vitro and in vivo. Larger trials with rapamycin or rapamycin-derivatives in combination with other targeted drugs are warranted to further determine clinical efficacy in CML.
近期数据表明，雷帕霉素的哺乳动物靶点（mTOR）参与慢性粒细胞白血病（CML）肿瘤细胞生长的调控。
我们对6例血液学复发的伊马替尼耐药CML患者（白细胞>20,000 μL⁻¹），每日口服2 mg雷帕霉素，连续服用14天，允许调整剂量以达到雷帕霉素血清目标浓度10 - 20 pg mL⁻¹。
2例患者出现主要白细胞反应，白细胞减少至低于10,000 μL⁻¹，另外2例患者出现轻微短暂反应。在有反应的患者中，我们还观察到循环白血病细胞中血管内皮生长因子（VEGF）mRNA水平降低。大多数患者雷帕霉素治疗期间的副作用较轻。1例患者发生肺炎。通过³H-胸腺嘧啶掺入法测定发现，雷帕霉素在体外也能对抗CML细胞的生长。此外，雷帕霉素抑制表现出各种BCR/ABL伊马替尼耐药突变体的Ba/F3细胞的生长，包括对大多数目前可用的BCR/ABL激酶抑制剂耐药的T315I变体。
雷帕霉素在体外和体内对伊马替尼耐药的CML均显示出抗白血病作用。有必要开展更大规模的试验，研究雷帕霉素或雷帕霉素衍生物与其他靶向药物联合使用，以进一步确定其对CML的临床疗效。
