Majsterek Ireneusz, Slupianek Artur, Blasiak Janusz
Department of Molecular Genetics University of Lodz, Poland.
Anticancer Drugs. 2003 Sep;14(8):625-31. doi: 10.1097/00001813-200309000-00007.
The family of BCR/ABL-related fusion tyrosine kinases (FTKs) is reported to participate in drug resistance in leukemogenesis. Our recent studies revealed a novel potential mechanism of resistance in FTK+ cells underlined by the stimulation of DNA repair. In this work we examined a role of TEL family fusion oncoproteins in the response to idarubicin. We used murine pro-B lymphoid cell line BaF3, and its TEL/ABL, TEL/JAK2 and TEL/PDGFbetaR-transformed clones. The transformed cells, in contrast to their non-transformed counterparts, exhibited resistance to idarubicin in the range 0.01-1 microM. The drug at 0.3 and 1 microM induced DNA damage in the form of strand breaks or/and alkali-labile sites in both transformed and control cells as evaluated by the alkaline Comet assay. The transformed cells removed the damage within 60 min, while the control cells required 120 min to recover. The results obtained suggest that TEL-related FTKs may stimulate the repair of DNA damaged by idarubicin and be relevant to the resistance of the leukemic cells to this drug.
据报道，BCR/ABL相关融合酪氨酸激酶（FTK）家族参与白血病发生过程中的耐药性。我们最近的研究揭示了FTK+细胞中一种由DNA修复刺激所突显的新的潜在耐药机制。在这项工作中，我们研究了TEL家族融合癌蛋白在对伊达比星反应中的作用。我们使用了小鼠前B淋巴细胞系BaF3及其TEL/ABL、TEL/JAK2和TEL/PDGFbetaR转化的克隆。与未转化的对应细胞相比，转化细胞对0.01 - 1微摩尔范围内的伊达比星表现出耐药性。通过碱性彗星试验评估，0.3和1微摩尔的药物在转化细胞和对照细胞中均以链断裂或/和碱不稳定位点的形式诱导DNA损伤。转化细胞在60分钟内修复损伤，而对照细胞需要120分钟才能恢复。所得结果表明，TEL相关的FTK可能刺激伊达比星损伤的DNA修复，并与白血病细胞对该药物的耐药性有关。
