Haberler C, Gelpi E, Marosi C, Rössler K, Birner P, Budka H, Hainfellner J A
Institute of Neurology, Medical University of Vienna, Austria.
J Neurooncol. 2006 Jan;76(2):105-9. doi: 10.1007/s11060-005-4570-9.
Inhibition of tyrosine kinase (TK) receptors by synthetic small molecules has become a promising new therapy option in oncology. The TK inhibitor imatinib mesylate selectively targets PDGFR-alpha, -beta, c-kit, c-abl and arg and has proven successful in the treatment of chronic myeloid leukaemia. In recurrent glioblastoma, phase II therapy trials using imatinib mesylate have been initiated. As only a fraction of patients seems to benefit from imatinib mesylate therapy and due to potential side effects and high costs of imatinib mesylate therapy, selection of the right patients is important. The goal of our study was to assess systematically immunohistochemical expression of the major TKs targeted by imatinib mesylate in glioblastoma, as expression of these factors could be used to select patients for imatinib mesylate therapy. In a cohort of 101 glioblastoma patients, anti-PDGFR-alpha, -beta, c-kit, c-abl and arg protein immunohistochemistry was performed. Expression of these proteins was assessed semi-quantitatively and correlated with patient survival.PDGFR-alpha and arg expression in tumor cells was widespread in 1/101 cases, respectively. Focal PDGFR-alpha, -beta, c-kit, c-abl and arg immunolabeling was detected in 25/101, 19/101, 4/101, 7/101 and 31/101 cases, respectively. Statistical analysis did not reveal any correlation between expression of the TKs and patient survival. We show here for the first time in a large series of glioblastomas that PDGFR-alpha, -beta, c-kit, c-abl and arg expression is immunohistochemically detectable in a fraction of cases. The value of anti-tyrosine kinase immunolabeling as predictive factor for patient selection remains to be clarified by comparative analysis of tumor tissue of therapy-responders versus non-responders.
合成小分子对酪氨酸激酶(TK)受体的抑制作用已成为肿瘤学中一种很有前景的新治疗选择。TK抑制剂甲磺酸伊马替尼选择性靶向血小板衍生生长因子受体α(PDGFR-α)、β(PDGFR-β)、干细胞生长因子受体(c-kit)、原癌基因酪氨酸蛋白激酶(c-abl)和雄激素受体(arg),并已被证明在慢性髓性白血病的治疗中取得成功。在复发性胶质母细胞瘤中,已启动了使用甲磺酸伊马替尼的II期治疗试验。由于似乎只有一小部分患者能从甲磺酸伊马替尼治疗中获益,且鉴于甲磺酸伊马替尼治疗存在潜在副作用和高昂成本,选择合适的患者很重要。我们研究的目的是系统评估胶质母细胞瘤中甲磺酸伊马替尼靶向的主要TKs的免疫组化表达,因为这些因子的表达可用于选择甲磺酸伊马替尼治疗的患者。在一组101例胶质母细胞瘤患者中,进行了抗PDGFR-α、β、c-kit、c-abl和arg蛋白免疫组化检测。对这些蛋白的表达进行半定量评估,并与患者生存率相关联。肿瘤细胞中PDGFR-α和arg的表达分别在1/101例中广泛存在。分别在25/101、19/101、4/101、7/101和31/101例中检测到局灶性PDGFR-α、β、c-kit、c-abl和arg免疫标记。统计分析未发现TKs表达与患者生存率之间存在任何相关性。我们首次在大量胶质母细胞瘤中表明,PDGFR-α、β、c-kit、c-abl和arg表达在部分病例中可通过免疫组化检测到。抗酪氨酸激酶免疫标记作为患者选择预测因子的价值仍有待通过对治疗反应者与无反应者的肿瘤组织进行比较分析来阐明。