Niyazi Maximilian, Marini Patrizia, Daniel Peter T, Humphreys Robin, Jendrossek Verena, Belka Claus
Department of Radiation Oncology, CCC Tübingen, Tübingen, Germany.
Strahlenther Onkol. 2009 Jan;185(1):8-18. doi: 10.1007/s00066-009-1856-4. Epub 2009 Feb 18.
: Since the efficacy of a single targeted agent in combination with ionizing radiation is limited by putative treatment resistances, a rationally designed triple treatment consisting of an agonistic antibody targeting either TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab), radiation and an epidermal growth factor receptor-(EGFR-)inhibiting antibody (cetuximab) was tested.
: Induction of apoptosis after triple treatment was determined in Colo205, HCT116 and FaDu cells by Hoechst 33342 stain. The degree of interaction was determined by isobologram analysis. A knockout variant of HCT116 was used to examine Bax dependence of the triple treatment. The role of Akt/PKB signaling was analyzed using the phosphatidylinositol 3-kinase inhibitor LY294002. Clonogenic assays were performed to examine the effect on clonogenic survival of tumor cells.
: A synergistic effect of radiation, cetuximab and agonistic TRAIL-R antibodies was demonstrated in cell lines derived from colorectal tumors or head-and-neck cancers. The efficacy of this multimodal approach was dependent on Bax and inhibition of Akt/PKB in the cell systems used. The results also show a positive impact on clonogenic cell death in several cell lines.
: These data suggest that rationally designed multimodal therapy approaches integrating radiation with more than one targeted agent will open new perspectives in radiation oncology.
由于单一靶向药物与电离辐射联合使用的疗效受到假定的治疗抗性限制，因此测试了一种合理设计的三联疗法，该疗法由靶向TRAIL-R1（mapatumumab）或TRAIL-R2（lexatumumab）的激动性抗体、辐射和表皮生长因子受体（EGFR）抑制抗体（西妥昔单抗）组成。
通过Hoechst 33342染色法测定三联疗法后Colo205、HCT116和FaDu细胞中凋亡的诱导情况。通过等效线图分析确定相互作用程度。使用HCT116的基因敲除变体来检查三联疗法对Bax的依赖性。使用磷脂酰肌醇3激酶抑制剂LY294002分析Akt/PKB信号传导的作用。进行克隆形成试验以检查对肿瘤细胞克隆存活的影响。
在源自结直肠癌或头颈癌的细胞系中证明了辐射、西妥昔单抗和激动性TRAIL-R抗体的协同作用。这种多模式方法的疗效取决于所用细胞系统中的Bax和Akt/PKB的抑制。结果还显示对几种细胞系中的克隆细胞死亡有积极影响。
这些数据表明，合理设计的将辐射与多种靶向药物整合的多模式治疗方法将为放射肿瘤学开辟新的前景。
