Dey Swatee, Spring Paul M, Arnold Suzanne, Valentino Joseph, Chendil Damodaran, Regine William F, Mohiuddin Mohammed, Ahmed Mansoor M
Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
Clin Cancer Res. 2003 Apr;9(4):1557-65.
This study was designed to: (a) evaluate the induction of hyper-radiation sensitivity (HRS), a phenomenon observed at low doses of radiation (<1 Gy); (b) compare the potentiating effects of single dose radiation (2 Gy) versus the effect of low-dose fractionated radiation (LDFRT; <1 Gy) on Paclitaxel; and (c) understand the molecular mechanism of LDFRT-mediated chemo-potentiating effects, in wild-type p53 SCC-61 and p53 mutant SQ-20B head and neck squamous cell carcinoma cell lines. Both cell lines exhibited the HRS phenomenon at low radiation doses. Compared with SCC-61 cells, SQ-20B cells were resistant to radiation and Paclitaxel alone. A significant enhancement of radiation sensitization by Paclitaxel (0.5 or 1 nM) was observed in both cell lines. Chemo-potentiation of Paclitaxel by single 2-Gy radiation was observed in SCC-61 cells but not in SQ-20B cells. However, LDFRT (0.5 Gy in four fractions) significantly chemo-potentiated the effect of Paclitaxel in both cell lines. The cell cycle regulator p53 and its target genes p21(waf1/cip1) and BAX were induced in SCC-61 cells treated with 2 Gy, Paclitaxel, or in combination, but not in SQ-20B cells. These treatments elevated the antiapoptotic BCL-2 protein in SQ-20B cells but not in SCC-61 cells. Interestingly, LDFRT treatment in both cell lines with or without Paclitaxel down-regulated nuclear factor kappa B activity and BCL-2 protein expression and simultaneously up-regulated BAX protein. These findings strongly suggest that LDFRT (at these doses, HRS phenomenon is observed) can be used in combination with Paclitaxel to overcome the antiapoptotic effects of BCL-2 and nuclear factor kappa B.
(a) 评估超辐射敏感性（HRS）的诱导情况，这是一种在低剂量辐射（<1 Gy）时观察到的现象；(b) 比较单剂量辐射（2 Gy）与低剂量分割辐射（LDFRT；<1 Gy）对紫杉醇的增效作用；(c) 了解野生型p53的SCC - 61和p53突变型的SQ - 20B头颈鳞状细胞癌细胞系中LDFRT介导的化疗增效作用的分子机制。两种细胞系在低辐射剂量下均表现出HRS现象。与SCC - 61细胞相比，SQ - 20B细胞对单独的辐射和紫杉醇具有抗性。在两种细胞系中均观察到紫杉醇（0.5或1 nM）对辐射增敏作用的显著增强。在SCC - 61细胞中观察到单次2 - Gy辐射对紫杉醇的化疗增效作用，但在SQ - 20B细胞中未观察到。然而，LDFRT（0.5 Gy分四次照射）在两种细胞系中均显著增强了紫杉醇的化疗效果。在用2 Gy、紫杉醇或联合处理的SCC - 61细胞中诱导了细胞周期调节因子p53及其靶基因p21(waf1/cip1)和BAX，但在SQ - 20B细胞中未诱导。这些处理提高了SQ - 20B细胞中抗凋亡的BCL - 2蛋白水平，但在SCC - 61细胞中未提高。有趣地是，在有或没有紫杉醇的情况下，对两种细胞系进行LDFRT处理均下调了核因子κB活性和BCL - 2蛋白表达，同时上调了BAX蛋白。这些发现强烈表明，LDFRT（在这些剂量下观察到HRS现象）可与紫杉醇联合使用，以克服BCL - 2和核因子κB的抗凋亡作用。
