Oude Weernink P A, Verheul E, Kerkhof E, van Veelen C W, Rijksen G
Laboratory for Medical Enzymology, University Hospital Utrecht, The Netherlands.
Neurosurgery. 1996 Jan;38(1):108-13; discussion 113-4. doi: 10.1097/00006123-199601000-00026.
Epidermal growth factor (EGF) and platelet-derived growth (PDGF) are suggested to be involved in the proliferation of human gliomas. We examined the effects of these growth factors on two human malignant glioma cell lines. Treatment of the A172 glioblastoma and the Hs683 glioma cell line with EGF and PDGF resulted in the tyrosine autophosphorylation, and hence activation, of the respective growth factor receptors. In addition, both cell lines responded to EGF and PDGF with increased deoxyribonucleic acid (DNA) synthesis. Because the intrinsic protein tyrosine kinase activity of this class of growth factor receptors is indispensable for their functioning, we tested the effects of specific protein tyrosine kinase inhibitors on growth factor-induced DNA synthesis and glioma cell proliferation. Genistein inhibited both EGF- and PDGF-stimulated autophosphorylation of the receptors and induction of DNA synthesis. However, genistein seemed to be cytotoxic to the cells. The tyrphostins RG 50875 and RG 13022 dose-dependently inhibited DNA synthesis induced by EGF, PDGF, and serum. RG 13022 completely blocked the EGF- and PDGF-induced DNA synthesis at a concentration of 50 mumol/L. The tyrphostins showed no selectivity in blocking either EGF or PDGF signaling. With concentrations up to mumol/L, no cytotoxic side effects of the tyrphostins were observed. Both tyrphostins also inhibit serum-driven cell growth in a dose-dependent manner. These results support the hypothesis that activated protein tyrosine kinase receptors are involved in the proliferation of A172 and Hs683 glioma cells. Selective inhibitors of protein tyrosine kinases, therefore, might have the potential to contribute to the treatment of growth factor-dependent gliomas.
表皮生长因子（EGF）和血小板衍生生长因子（PDGF）被认为与人类胶质瘤的增殖有关。我们研究了这些生长因子对两种人类恶性胶质瘤细胞系的影响。用EGF和PDGF处理A172胶质母细胞瘤和Hs683胶质瘤细胞系，导致各自生长因子受体的酪氨酸自身磷酸化，从而激活这些受体。此外，两种细胞系对EGF和PDGF的反应都是脱氧核糖核酸（DNA）合成增加。由于这类生长因子受体的内在蛋白酪氨酸激酶活性对其功能是不可或缺的，我们测试了特异性蛋白酪氨酸激酶抑制剂对生长因子诱导的DNA合成和胶质瘤细胞增殖的影响。染料木黄酮抑制了受体的EGF和PDGF刺激的自身磷酸化以及DNA合成的诱导。然而，染料木黄酮似乎对细胞具有细胞毒性。酪氨酸磷酸化抑制剂RG 50875和RG 13022剂量依赖性地抑制由EGF、PDGF和血清诱导的DNA合成。RG 13022在浓度为50 μmol/L时完全阻断了EGF和PDGF诱导的DNA合成。酪氨酸磷酸化抑制剂在阻断EGF或PDGF信号传导方面没有显示出选择性。在浓度高达μmol/L时，未观察到酪氨酸磷酸化抑制剂的细胞毒性副作用。两种酪氨酸磷酸化抑制剂也以剂量依赖性方式抑制血清驱动的细胞生长。这些结果支持这样的假设，即活化的蛋白酪氨酸激酶受体参与A172和Hs683胶质瘤细胞的增殖。因此，蛋白酪氨酸激酶的选择性抑制剂可能有潜力用于治疗依赖生长因子的胶质瘤。
