Thiesing J T, Ohno-Jones S, Kolibaba K S, Druker B J
Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, OR 97201, USA.
Blood. 2000 Nov 1;96(9):3195-9.
Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl-positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl-positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl-expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.
慢性粒细胞白血病（CML）是一种造血干细胞恶性肿瘤，由Bcr-Abl酪氨酸激酶引起。Abl酪氨酸激酶抑制剂STI571（原名CGP 57148B）对Bcr-Abl阳性细胞具有特异性的体外抗白血病活性，目前正处于II期临床试验阶段。由于可能会出现对单一药物的耐药性，因此已对STI571与其他抗白血病药物的联合用药进行了评估，以检测其对Bcr-Abl阳性细胞系的活性以及在体外集落形成试验中的活性。所测试的特异性抗白血病药物包括几种目前用于治疗CML的药物：α干扰素（IFN）、羟基脲（HU）、柔红霉素（DNR）和阿糖胞苷（Ara-C）。在使用表达Bcr-Abl的细胞系进行的增殖试验中，STI571与IFN、DNR和Ara-C联合用药显示出相加或协同作用，而STI571与HU联合用药则表现出拮抗作用。然而，在使用CML患者样本进行的集落形成试验中，与单独使用STI571相比，所有联合用药均显示出增强的抗增殖作用。这些数据表明，STI571与IFN、DNR或Ara-C联合用药在治疗CML方面可能比单独使用STI571更有效，并建议考虑对这些联合用药进行临床试验。
