Nagane M, Narita Y, Mishima K, Levitzki A, Burgess A W, Cavenee W K, Huang H J
Ludwig Institute for Cancer Research--San Diego, Department of Medicine, Center for Molecular Genetics, and Cancer Center, University of California at San Diego, La Jolla 92093-0660, USA.
J Neurosurg. 2001 Sep;95(3):472-9. doi: 10.3171/jns.2001.95.3.0472.
Activation of signaling by the epidermal growth factor receptor (EGFR) through gene amplification or rearrangement is common in human malignancy, especially in a large fraction of de novo glioblastomas multiforme (GBMs). The most common mutant EGFR, (AEGFR, also known as de2-7 EGFR and EGFRvIII) lacks a portion of the extracellular domain, enhances tumorigenicity in vivo, and causes resistance to the chemotherapeutic drug cisplatin (CDDP). This resistance is due to the suppression of CDDP-induced apoptosis by the constitutively active tyrosine kinase activity of the receptor. The authors have investigated whether inhibition of AEGFR signaling by the tyrosine kinase inhibitor, tyrphostin AG1478, could sensitize tumor xenografts to CDDP and, thereby, enhance its therapeutic efficacy in animals.
Nude mice were inoculated either subcutaneously or intracerebrally with human GBM cells expressing AEGFR and were then systemically treated with CDDP and/or AG1478. Tumor volumes were monitored and tumor sections were analyzed by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assays or MIB-1 staining. Expression of AEGFR, but not wild-type EGFR, conferred CDDP resistance to the cells in vivo. Inhibition of receptor signaling by the EGFR-specific tyrosine kinase inhibitor, AG1478. sensitized the xenografts to the cytotoxic effects of CDDP. This combined CDDP/AG1478 treatment significantly suppressed growth of subcutaneous xenografts in nude mice in a synergistic manner (p < 0.01 compared with vehicle control) without causing generalized toxicity, whereas treatments with CDDP or AG1478 alone were ineffective. The synergistic growth suppression by the CDDP/AG1478 combination was not observed in xenografts overexpressing wild-type EGFR or kinase-deficient AEGFR. The combined CDDP/ AG1478 treatment induced tumor growth suppression, which correlated with increased apoptosis and reduced proliferation. This treatment also extended the life span of mice bearing intracerebral xenografts (p < 0.01 compared with controls).
The results of this study may provide the basis for the development of a novel and safe therapeutic strategy for the very aggressive AEGFR-expressing GBM.
通过基因扩增或重排激活表皮生长因子受体（EGFR）信号传导在人类恶性肿瘤中很常见，尤其是在大部分原发性多形性胶质母细胞瘤（GBM）中。最常见的突变型EGFR（AEGFR，也称为de2-7 EGFR和EGFRvIII）缺失部分细胞外结构域，增强体内致瘤性，并导致对化疗药物顺铂（CDDP）耐药。这种耐药性是由于受体组成型激活的酪氨酸激酶活性抑制了CDDP诱导的细胞凋亡。作者研究了酪氨酸激酶抑制剂 tyrphostin AG1478对AEGFR信号传导的抑制是否能使肿瘤异种移植物对CDDP敏感，从而提高其在动物体内的治疗效果。
将表达AEGFR的人GBM细胞皮下或脑内接种到裸鼠体内，然后用CDDP和/或AG1478进行全身治疗。监测肿瘤体积，并使用末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记（TUNEL）试验或MIB-1染色分析肿瘤切片。AEGFR而非野生型EGFR的表达赋予细胞体内CDDP耐药性。EGFR特异性酪氨酸激酶抑制剂AG1478对受体信号传导的抑制使异种移植物对CDDP的细胞毒性作用敏感。这种联合CDDP/AG1478治疗以协同方式显著抑制裸鼠皮下异种移植物的生长（与载体对照相比，p < 0.01），且未引起全身毒性，而单独使用CDDP或AG1478治疗无效。在过表达野生型EGFR或激酶缺陷型AEGFR的异种移植物中未观察到CDDP/AG1478组合的协同生长抑制作用。联合CDDP/AG1478治疗诱导肿瘤生长抑制，这与细胞凋亡增加和增殖减少相关。该治疗还延长了脑内异种移植物小鼠的寿命（与对照组相比，p < 0.01）。
本研究结果可能为开发针对极具侵袭性的表达AEGFR的GBM的新型安全治疗策略提供依据。
