Inherent cellular radiosensitivity as a basic concept for human tumor radiotherapy

A statistical analysis has been performed on a set of 59 published survival curves of human cell lines. Six fibroblast cell lines derived from patients free of genetic disorders and 36 tumor cell lines were used in this study. Using the linear quadratic (L-Q) model, which provides an overall adequate fitting, especially in the low dose range, we show that great variations in radiosensitivity exist among cell lines. In the low dose range (?2 Gy), these variations cannot be explained on the mere basis of technical factors. Cell type is described as an intrinsic radiosensitivity factor, as variations of mean radiosensitivity among cell types are statistically significant at low doses. A correlation is found between the 95% tumor control dose and the mean surviving fraction at 2 Gy for a given cell type. Higher radiosensitivity is accompanied by lower tumor control dose (TCD 95 % ). This correlation suggests that the moderate radiocurability of certain tumors can be partially explained by the intrinsic radiosensitivity of relevant tumor cells and in particular by a high surviving fraction at 2 Gy.     

A phase II study of radiotherapy after hyperbaric oxygenation combined with interferon-beta and nimustine hydrochloride to treat supratentorial malignant gliomas

Hypoxic cells play a key role in the radioresistance of malignant glioma. Interferon-beta, ACNU as nimustine hydrochloride and radiotherapy (IAR) is a common therapy for malignant glioma in Japan. Since hyperbaric oxygenation (HBO) increases oxygen pressure in glioma tissue, we applied a modified IAR therapy, radiotherapy after HBO combined with interferon-beta and ACNU (HBO/IAR therapy), for supratentorial malignant gliomas. Daily radiation therapy was completed within 15min after HBO. We assessed HBO/IAR with respect to toxicity, response rates and the time of tumor progression (TTP). We also examined the incidence of responses by some prognostic factors before HBO/IAR, namely, age, Karnofsky performance scale (KPS), histological type, tumor size, tumor site and operation type. Of 39 patients who participated in this study, 35 underwent a complete schedule of HBO/IAR therapy in which toxicity was permissible. Thirty patients (76.9%) either maintained or increased KPS during HBO/IAR with a mean duration of 68±14 days. The response rates (CR+PR%) for glioblastoma, anaplastic astrocytoma and overall were 50%, 30% and 43%, respectively. The incidence of therapeutic responses among all prognostic factors before HBO/IAR did not significantly differ. Median TTP for patients with glioblastoma, patients with anaplastic astrocytoma, and overall were 38, 56 and 43 weeks, respectively. The present study suggested that HBO/IAR therapy could be applied to especially patients with poor prognostic factors, because of its short treatment period, its permissible toxicity and identical response to patients with good prognostic factors.     

Huge differences in cellular radiosensitivity due to only very small variations in double-strand break repair capacity

The DNA double-strand break (DSB) repair capacity of normal human fibroblasts was compared with that of cell lines with different genetic alterations. These cell lines are affected either in non-homologous end-joining (180BR), homology directed repair (C2352, C2395), base excision repair (CS1TAN, 46BR) or signalling (AT3, AT2BE, LFS2675, LFS2800, 95P558). Cellular radiosensitivity was determined by colony formation assay, DSB by constant-field gel electrophoresis and apoptosis was detected by caspase3 activity. For the mutated cell lines, the survival fraction at 2 Gy (SF2) varied between 0.013 and 0.49 in contrast to a variation of only 0.15?–?0.53 for normal fibroblasts. There was no variation in the number of initial DSB and only a small variation in the number of DSB remaining 24 h after irradiation. At 100 Gy, the latter number varied between 2 and 5 Gy-equivalents for normal fibroblasts and only between 3 and 7 Gy-equivalents for the mutated cell lines, corresponding to repair capacities of 95?–?98 and 93?–?97%, respectively. There were, however, two outliers (LFS2800, 180BR) where the number of remaining DSB was much higher with 22 and 30 Gy-equivalents, respectively. This elevated number resulted from a delayed repair and apoptotic cells. For all but these two cell lines, the relationship between the number of DSB remaining 24 h after irradiation and SF2 could be described by an identical correlation (r²?=?0.86, p?<?0.0001). This result indicates that the relationship between DSB repair capacity and cellular radiosensitivity appears to be the same for normal and mutated cell lines, and that in both cases huge differences in cellular radiosensitivity result from only a very small variation in DSB repair capacity.     

Multiple sclerosis in a radiosensitive family with low levels of the ATM protein

Multiple sclerosis (MS) is a chronic neurological disease of the central nervous system (CNS) characterized by demyelination associated with progressive disability. The mechanisms underlying the pathogenesis of MS remain a mystery. The highly pleiotropic syndrome known as ataxia telangiectasia (A‐T) overlaps with MS in that it also presents with demyelination in the CNS. Whether demyelination in MS or in A‐T is initiated through neuronal degeneration or immune dysfunction is not yet known. However, unlike MS, the underlying cause of A‐T is known to result from mutations in the A–T gene (ATM) that often result in the complete loss of ATM protein and loss/gain of function. ATM is implicated in neurological degeneration, particularly in the cerebellum, cellular apoptosis, immunodeficiency, double stranded deoxyribonucleic acid (DNA) rejoining, VDJ antibody recombination, tumour suppression, particularly T‐lymphoid malignancies, signal transduction, cell‐cycle control and cellular radiohypersensitivity. In this study, we describe a case of MS in a family with cellular radiosensitivity and abnormally low postinduction levels of the ATM protein. Defective DNA repair/rejoining may impact on autoimmunity.     

奥沙利铂对人肝癌细胞的放射增敏作用

目的：研究奥沙利铂（Ｌ-ＯＨＰ）对人肝癌ＳＭＭＣ-７７２１细胞的放射增敏作用。方法：实验分为单纯用药组及放疗＋药物组，采用ＭＴＴ法观察Ｌ-ＯＨＰ不同药物浓度与不同外放射剂量２４、４８、７２ｈ对人肝癌细胞ＳＭＭＣ-７７２１的抑制作用。计算细胞抑制率和增敏比，应用统计软件ＳＰＳＳ１１.５处理数据，运用方差分析和多元相关方法分析各因素对人肝癌细胞ＳＭＭＣ-７７２１的抑制作用以及各因素之间的交互作用。结果：生长抑制率与放疗剂量、Ｌ-ＯＨＰ浓度呈正相关，而时间因素与生长抑制率无相关性（Ｐ＞０.０５）。结论：在采用Ｌ-ＯＨＰ对肝癌进行放射增敏时，时间因素可忽略不计。当Ｌ ＯＨＰ浓度大于０.６２５ｍｇ／Ｌ，将可获得放疗增敏的效果。     

放疗耐受的宫颈癌Hela细胞的生物学特性

 【目的】研究耐放疗的宫颈癌Hela细胞生物学特性的改变,并探讨其与宫颈癌肿瘤干细胞间的关系。【方法】采用多次分割剂量照射技术建立宫颈癌Hela细胞的耐放疗模型（Hela-R）,实验分4组：Hela-R1组,Hela-R2组,Hela-R3组和对照组。四甲基偶氮唑蓝法检测细胞生长情况,克隆形成实验测定放射敏感性和克隆能力,流式细胞术检测细胞周期分布和增殖能力,球囊培养法检测细胞自我更新能力。【结果】Hela、Hela-R细胞接受照射后均呈现先加速增殖后出现生长抑制的现象。Hela-R1、Hela-R2、Hela-R3的细胞倍增时间分别为（43.4±1.0）h、（49.2±2.0）h和（48.7±3.3）h,克隆形成率分别为（20.3±4.0）%、（49.3±11.6）%和（6.3±5.9）%,S期细胞比例分别为（9.9±0.4）%、（13.0±0.9）%和（9.6±0.7）%,增殖指数（PI）分别为（27.3±2.6）%、（31.8±4.9）%和（37.4±8.0）%。与对照组比较,Hela-R3组的放射抗拒性增强。非粘附性球囊培养法培养Hela及Hela-R细胞可得到肿瘤细胞球,四组的球囊形成率分别为（9.9±0.4）%、（13.0±0.9）%、（9.6±0.7）%和（5.0±0.3）%。【结论】多次分割剂量照射可在体外建立宫颈癌Hela细胞的耐放疗模型,并可富集肿瘤干细胞;多次分割照射后,Hela细胞生长速度减慢,增殖能力有升高趋势,自我更新能力、克隆能力增强,细胞周期无明显变化。     

PI3K抑制剂对食管癌Eca-109细胞株放射增敏作用及机制

目的:研究PI3K抑制剂对食管癌细胞株Eca-109放射增敏作用及机制.方法:以食管癌细胞株Eca-109为实验对象,MTT法观察PI3K抑制剂LY294002对Eca-109细胞增殖抑制;克隆形成实验分析细胞放射敏感性;RT-PCR检测DNA双链断裂修复基因DNA-PKcs mRNA表达;流式细胞技术检测细胞周期.结果:PI3K抑制剂LY294002对Eca-109细胞有生长抑制作用,且呈剂量依赖性,在较低浓度(10μmol/L)时即可降低Eca-109细胞的克隆形成率,其放射增敏比为1.58.药物LY294002组DNA-PKcs mRNA表达受抑,但与对照组比较差异无统计学意义;照射组表达较对照组明显升高(P<0.05);药物LY294002+照射组的表达较照射组下降(P<0.05).药物LY294002组G2期细胞比例与对照组比较差异无统计学意义,照射组较对照组升高(P<0.01),药物LY294002+照射组G2期细胞比例较照射组下降(P<0.05).结论:PI3K抑制剂LY294002对Eca-109细胞有放射增敏作用,其机制可能与抑制肿瘤细胞DNA双链断裂修复基因DNA-PKcs及减少G2期细胞...     

SiRNA-Survivin增强鼻咽癌细胞对放射敏感性的实验研究

目的 研究Survivin表达抑制对鼻咽癌放射敏感性的影响,探讨Survivin基因为靶的分子干预在鼻咽癌放疗中作用.方法 采用脂质体将Survivin特异性siRNA转染鼻咽癌5-8F细胞系,半定量RT-PCK、流式细胞仪检测Survivin基因表达;Survivin特异性siKNA转染5-8F细胞,培养24 h后,用6 GY的放射线处理细胞,继续培养24h后,收集细胞.流式细胞仪、镜下计数检测细胞增殖、凋亡与细胞周期.结果 Survivin特异性的siRNA能有效地阻断5-8F细胞系中Survivin基因表达.特异性SiRNA加放射组,细胞抑制率 (33.7±1.5%) 显著高于特异性SiRNA组[ (23.8±4.3) %,(P<0.05) ]和随机序列的siRNA加放射组[ (15.5±1.7) %,(P<0.01) ].特异性SiPNA加放射组,细胞凋亡率 (24.67±0.50) 显著高于特异性SiRNA组[ (20.30±0.44) ,(P<0.05) 1和随机序列的siRNA加放射组[ (6.58±0.38) ,(P<0.01) ].特异性siRNA加放射组,S/G_1比率 (2.76±0.186) 显著高于特异性siRNA组[ (1.91±0.067) ,(P<0.01) ]与随机序列的siRNA加放射组[ (0.585±0.066) ,(P<0.01) ].结论 有效干预Survivin基因表达能提高鼻咽癌细胞的放射敏感性,增强鼻咽癌的放疗效果.