Li Junsheng, Kleeff Jörg, Guo Junchao, Fischer Lars, Giese Nathalia, Büchler Markus W, Friess Helmut
Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
Mol Cancer. 2003 Sep 17;2:32. doi: 10.1186/1476-4598-2-32.
Pancreatic cancer is an aggressive malignancy characterized by low responsiveness to chemotherapy and radiotherapy. This resistance is partly due to the overexpression of several tyrosine kinase receptors and their ligands. STI571 has specific activity in inhibiting c-kit, PDGF and Abl receptor tyrosine kinases and has proven successful in the treatment of CML and GIST patients. Here, we investigated the potential role of STI571 in pancreatic cancer.
The GI50 of STI571 as well as the effects of STI571 on growth factor actions in pancreatic cell lines were analyzed using the MTT assay. FACS analysis using Annexin and PI staining was performed to study cell cycle, apoptosis, and cell death. Western blot analysis was carried out to investigate MAP kinase and receptor tyrosine kinase phosphorylation. STI571 inhibited cell proliferation in pancreatic cancer cell lines with GI50 concentrations ranging from 17 to 31.5 microM. EGF, IGF-1, and FGF-2 but not PDGF exerted growth stimulatory effects in pancreatic cancer cell lines. STI571 only partly blocked these effects on cell growth, and did not abrogate growth factor-induced receptor and MAPK phosphorylation.
Our data demonstrate that STI571 inhibits pancreatic cancer cell growth with high GI50 concentrations through tyrosine-kinase receptor independent pathways. The clinical application of STI571 in pancreatic cancer is therefore rather doubtful.
胰腺癌是一种侵袭性恶性肿瘤，其特点是对化疗和放疗反应性低。这种耐药性部分归因于几种酪氨酸激酶受体及其配体的过度表达。STI571在抑制c-kit、血小板衍生生长因子（PDGF）和Abl受体酪氨酸激酶方面具有特异性活性，并且已在慢性粒细胞白血病（CML）和胃肠道间质瘤（GIST）患者的治疗中取得成功。在此，我们研究了STI571在胰腺癌中的潜在作用。
使用MTT法分析STI571的半数生长抑制浓度（GI50）以及其对胰腺癌细胞系中生长因子作用的影响。采用膜联蛋白和碘化丙啶（PI）染色的流式细胞术分析来研究细胞周期、凋亡和细胞死亡。进行蛋白质免疫印迹分析以研究丝裂原活化蛋白激酶（MAP激酶）和受体酪氨酸激酶的磷酸化。STI571抑制胰腺癌细胞系中的细胞增殖，其GI50浓度范围为17至31.5微摩尔。表皮生长因子（EGF）、胰岛素样生长因子-1（IGF-1）和碱性成纤维细胞生长因子-2（FGF-）2而非血小板衍生生长因子（PDGF）在胰腺癌细胞系中发挥生长刺激作用。STI571仅部分阻断这些对细胞生长的影响，并且并未消除生长因子诱导的受体和丝裂原活化蛋白激酶（MAPK）磷酸化。
我们的数据表明，STI571通过酪氨酸激酶受体非依赖性途径以高GI50浓度抑制胰腺癌细胞生长。因此，STI571在胰腺癌中的临床应用相当可疑。
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