Hambek Markus, Werner Christian, Baghi Mehran, Gstöttner Wolfgang, Knecht Rainald
ENT-Center, University Clinic Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt / Main, Germany.
Eur J Cancer. 2007 Jul;43(10):1502-7. doi: 10.1016/j.ejca.2005.09.037. Epub 2007 May 23.
Docetaxel has recently taken part in new chemotherapy regimens with promising activity especially in the first line therapy (induction chemotherapy) of head and neck cancer (SCCHN). Nevertheless a major problem concerning the response of SCCHN to chemotherapy is the high percentage of resting cells (G0-phase cells) being resistant to chemotherapy. To overcome this phenomenon we have investigated the capacity of several cytokines to switch on cells into division cycle and progress to the chemosensitive phases (S, M-phase).
Il-6, Serotonin, G-CSF and EGF were used to stimulate G0-phase squamous cell cancer cells (Detroit 562, A431, UM-SCC 10B) for reentry in the cell cycle to enhance the response to docetaxel. The proportion of G0-phase cells was detected through multicolor FACS analysis and Ki67 staining.
Cell cycle reentering was most effective after combination treatment with Serotonin+EGF. The proportion of G0 phase cells was significantly reduced after stimulation with Serotonin+EGF (p<0.05). Corresponding to cell cycle reentry the cytotoxic effect of docetaxel was significantly (p<0.04) enhanced in the prestimulated cells compared to the control (docetaxel monotreatment).
Our investigations demonstrate for the first time that sensitizing G0 phase squamous cell carcinoma cells for docetaxel treatment is possible by prestimulation with target cytokines. Considering that up to 95% of tumor cells are in the resting (G0) phase of the cell cycle at the initiation of chemotherapy, prestimulation with EGF and serotonin could contribute to a synchronization of cancer cells. This would clearly enhance the cytotoxic effect.
多西他赛最近参与了新的化疗方案，显示出有前景的活性，尤其是在头颈部鳞状细胞癌（SCCHN）的一线治疗（诱导化疗）中。然而，SCCHN对化疗反应的一个主要问题是高比例的静止细胞（G0期细胞）对化疗耐药。为克服这一现象，我们研究了几种细胞因子将细胞转入分裂周期并进展至化学敏感阶段（S期、M期）的能力。
使用白细胞介素-6、血清素、粒细胞集落刺激因子（G-CSF）和表皮生长因子（EGF）刺激G0期鳞状细胞癌细胞（底特律562、A431、UM-SCC 10B）重新进入细胞周期，以增强对多西他赛的反应。通过多色荧光激活细胞分选术（FACS）分析和Ki67染色检测G0期细胞的比例。
血清素+EGF联合治疗后细胞周期重新进入最为有效。血清素+EGF刺激后G0期细胞的比例显著降低（p<0.05）。与细胞周期重新进入相对应，与对照（多西他赛单一治疗）相比，预刺激细胞中多西他赛的细胞毒性作用显著增强（p<0.04）。
我们的研究首次证明，通过用靶细胞因子进行预刺激，使G0期鳞状细胞癌细胞对多西他赛治疗敏感是可能的。考虑到在化疗开始时高达95%的肿瘤细胞处于细胞周期的静止（G0）期，用EGF和血清素进行预刺激可能有助于癌细胞同步化。这将明显增强细胞毒性作用。
