Combination-treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774
Combination-treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774
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DOI：
10.1016/j.bcp.2003.12.035
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发表时间：
2004-05-01
影响因子：
5.8
通讯作者：
Halatsch, ME
中科院分区：
文献类型：
--
作者：
Efferth, T;Ramirez, T;Halatsch, ME
目前迫切需要新的药物和组合方式来治疗其他无反应的脑肿瘤。抗疟疾青蒿琥酯（ART）和EGFR酪氨酸激酶抑制剂OSI-774显示出深刻的细胞毒活性。联合治疗的有效性和细胞反应的潜在分子决定因素尚不清楚。在本研究中，我们研究了ART和OSI-774在多形性胶质母细胞瘤（GBM）细胞系。在用缺失突变型组成型活性EGFR基因转导的U-87MG.DeltaEGFR细胞中观察到细胞生长的超累加抑制，而在用野生型EGFR（U-87MG.WT-2N）、激酶缺陷型EGFR（U-87MG.DK-2N）、模拟载体对照（U-87MG.LUX）或未转导的亲本U-87 MG细胞转导的细胞中存在累加效应。在其他9个未转导的GBM细胞系中，在2个细胞系（G-210 GM、G-599 GM）中发现了超累加效应，而ART和OSI-774在其他7个细胞系（G-211 GM、G-750 GM、G-1163 GM、G-1187 GM、G-1265 GM、G-1301 GM和G-1408 GM）中以累加方式起作用。未观察到亚加性或拮抗作用。通过比较基因组杂交评估的非转导细胞系中遗传物质的基因组获得和损失与ART和OSI-774的IC 50值相关，随后进行分层聚类分析和聚类图像映射。检测到预测对ART和OSI-774的细胞应答的不平衡的基因组谱。位于感兴趣的基因组不平衡的基因可以作为GBM细胞对ART和OSI-774的候选抗性基因。总之，ART和OSI-774的组合治疗与每种药物单独相比导致GBM细胞系的生长抑制增加。(C)2004爱思唯尔公司All rights reserved.
New drugs and combination modalities for otherwise non-responsive brain tumors are urgently required. The anti-malarial artesunate (ART) and the EGFR tyrosine kinase inhibitor OSI-774 reveal profound cytotoxic activity. The effectiveness of a combination treatment and the underlying molecular determinants of cellular response are unknown. In the present investigation, we studied ART and OSI-774 in glioblastoma multiforme (GBM) cell lines. Supra-additive inhibition of cell growth was observed in U-87MG.DeltaEGFR cells transduced with a deletion-mutant constitutively active EGFR gene, while additive effects were present in cells transduced with wild-type EGFR (U-87MG.WT-2N), kinase-deficient EGFR (U-87MG.DK-2N), mock vector controls (U-87MG.LUX), or non-transduced parental U-87MG cells. Among nine other non-transduced GBM cell lines, supra-additive effects were found in two cell lines (G-210GM, G-599GM), while ART and OSI-774 acted in an additive manner in the other seven cell lines (G-211GM, G-750GM, G-1163GM, G-1187GM, G-1265GM, G-1301GM, and G-1408GM). Sub-additive or antagonistic effects were not observed. Genomic gains and losses of genetic material in the non-transduced cell lines as assessed by comparative genomic hybridization were correlated with the IC50 values for ART and OSI-774 and subsequently subjected to hierarchical cluster analysis and cluster image mapping. A genomic profile of imbalances was detected that predicted cellular response to ART and OSI-774. The genes located at the genomic imbalances of interest may serve as candidate resistance genes of GBM cells towards ART and OSI-774. In conclusion, the combination treatment of ART and OSI-774 resulted in an increased growth inhibition of GBM cell lines as compared to each drug alone. (C) 2004 Elsevier Inc. All rights reserved.