Combs Stephanie E, Schulz-Ertner Daniela, Roth Wilfried, Herold-Mende Christel, Debus Jürgen, Weber Klaus-Josef
Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany.
Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):873-82. doi: 10.1016/j.ijrobp.2007.03.002.
The majority of glioblastoma multiforme (GBM) cells express the epidermal growth factor receptor (EGFR). The present study evaluates the combination of temozolomide (TMZ), EGFR inhibition, and radiotherapy (RT) in GBM cell lines.
Human GBM cell lines U87, LN229, LN18, NCH 82, and NCH 89 were treated with various combinations of TMZ, RT, and the monoclonal EGFR antibody cetuximab. Responsiveness of glioma cells to the combination treatment was measured by clonogenic survival.
Overall, double and triple combinations of RT, TMZ, and cetuximab lead to additive cytotoxic effects (independent toxicity). A notable exception was observed for U87 and LN 18 cell lines, where the combination of TMZ and cetuximab showed substantial antagonism. Interestingly, in these two cell lines, the combination of RT with cetuximab resulted in a substantial increase in cell killing over that expected for independent toxicity. The triple combination with RT, cetuximab, and TMZ was nearly able to overcome the antagonism for the TMZ/cetuximab combination in U87, however only marginally in LN18, GBM cell lines.
It appears that EGFR expression is not correlated with cytotoxic effects exerted by cetuximab. Combination treatment with TMZ, cetuximab and radiation resulted in independent toxicity in three out of five cell lines evaluated, the antagonistic effect of the TMZ/cetuximab combination in two cell lines could indicate that TMZ preferentially kills cetuximab-resistant cells, suggesting for some cross-talk between toxicity mechanisms. Expression of EGFR was no surrogate marker for responsiveness to cetuximab, alone or in combination with RT and TMZ.
大多数多形性胶质母细胞瘤（GBM）细胞表达表皮生长因子受体（EGFR）。本研究评估替莫唑胺（TMZ）、EGFR抑制和放疗（RT）联合应用于GBM细胞系的效果。
用人GBM细胞系U87、LN229、LN18、NCH 82和NCH 89接受TMZ、RT和单克隆EGFR抗体西妥昔单抗的各种联合治疗。通过克隆形成存活率来测定胶质瘤细胞对联合治疗的反应性。
总体而言，RT、TMZ和西妥昔单抗的双重和三重联合产生相加的细胞毒性作用（独立毒性）。U87和LN 18细胞系是一个显著例外，其中TMZ和西妥昔单抗的联合显示出显著的拮抗作用。有趣的是，在这两个细胞系中，RT与西妥昔单抗的联合导致细胞杀伤作用比独立毒性预期的显著增加。RT、西妥昔单抗和TMZ的三重联合几乎能够克服U87细胞系中TMZ/西妥昔单抗联合的拮抗作用，但在LN18 GBM细胞系中仅略有克服。
似乎EGFR表达与西妥昔单抗发挥的细胞毒性作用无关。TMZ、西妥昔单抗和放疗的联合治疗在评估的五个细胞系中有三个产生独立毒性，TMZ/西妥昔单抗联合在两个细胞系中的拮抗作用可能表明TMZ优先杀死西妥昔单抗耐药细胞，提示毒性机制之间存在一些相互作用。EGFR的表达不是单独或与RT和TMZ联合使用时对西妥昔单抗反应性的替代标志物。
