肿瘤放射治疗中MnSOD的生物学效应及治疗作用研究进展

MnSOD是一个定位于线粒体基质中主要的抗氧化酶,在肿瘤的发生、发展和肿瘤放射治疗中的辐射保护、放疗增敏等方面有着重要的作用。调控MnSOD在正常组织和肿瘤组织中的表达有望成为肿瘤临床放射治疗的重要靶点。     

临床放射治疗中增敏比的计算法

肿瘤是临床常见病、多发病，放射治疗是目前对恶性肿瘤治疗的主要方法，治疗失败的主要原因是原发灶局部复发和远处转移。放射增敏方法是提高放疗疗效的重要途径，是现代放射治疗领域研究的热点之一。如何准确地评价这些增敏方法的效能，筛选出真正有效的药物和方法对推动放射治疗的发展、提高放疗对肿瘤治疗的疗效，具有重要的意义。……     

恶性肿瘤放射增敏剂研究进展简

放射治疗是治疗恶性肿瘤的重要手段。随着精确放疗技术的发展,放射治疗的疗效和精确性已取得长足的进步。然而,如何在不增加周围正常组织毒副反应的基础上,进一步提高放疗疗效仍是目前肿瘤放射治疗学领域亟待解决的难题。放射增敏剂作为解决以上难题的重要方法之一,正越来越成为放射治疗学的研究热点。合理应用放射增敏剂将有效地提高恶性肿瘤放射敏感性,从而改善患者生活质量,减少肿瘤局部复发,延长患者的生存时间。     

中药安替可配合放射治疗食管癌的近期疗效观察

目的 :评价中药安替可对食管癌的放疗增敏作用及毒副作用。方法 :6 4例确诊为食管癌的患者被随机分为治疗组 (放射治疗 中药安替可 )和对照组 (单纯放射治疗 ) ,根据放疗半量及全量时肿瘤的消退情况 ,比较两组的有效率及全消率 ,做为增敏的评价指标。两组患者的放疗剂量均为DT总量 6 0～ 6 5Gy。治疗组在放疗同时口服安替可胶囊 ,每天 3次 ,每次 0 .4 4 ,连服 5周。结果 :放疗半量时 ,治疗组有效率 6 2 .5% ,对照组 12 .5% ,P <0 .0 0 1;放疗全量时 ,治疗组肿瘤完全缓解率 75% ,对照组 37 5% ,P <0 .0 5。在毒性反应方面 ,治疗组恶心、呕吐等胃肠道反应较多。结论 :中药安替可对食管癌的放疗有显著增敏作用 ,值得临床进一步推广     

宫颈癌后装治疗用甘氨双唑钠增敏40例

目的：探讨宫颈癌患者后装治疗用甘氨双唑钠放射治疗的增敏作用。方法：85例接受放射治疗的宫颈癌患者,随机分为增敏组40例和常规组45例,常规组常规放疗,增敏组放疗方案同常规组,但后装治疗时用甘氨双唑钠增敏。结果：增敏组肿瘤完全消退38例（95％）,肿瘤消退平均后装次数2．9次,优于常规组肿瘤完全消退35例（85％）,肿瘤消退平均后装次数4．5次（P〈0．05）,肿瘤消退时间约提前1．6周。两组急性放射性肠炎、骨髓抑制发生率无统计学差异。结论：后装治疗前使用甘氨双唑钠可达放射增敏目的。     

宫颈癌后装治疗用甘氨双唑钠增敏40例

目的:探讨宫颈癌患者后装治疗用甘氨双唑钠放射治疗的增敏作用.方法:85例接受放射治疗的宫颈癌患者,随机分为增敏组40例和常规组45例,常规组常规放疗,增敏组放疗方案同常规组,但后装治疗时用甘氨双唑钠增敏.结果:增敏组肿瘤完全消退38例(95%),肿瘤消退平均后装次数2.9次,优于常规组肿瘤完全消退35例(85%),肿瘤消退平均后装次数4.5次(P＜0.05),肿瘤消退时间约提前1.6周.两组急性放射性肠炎、骨髓抑制发生率无统计学差异.结论:后装治疗前使用甘氨双唑钠可达放射增敏目的.     

动脉灌注顺铂放射增敏治疗晚期宫颈癌近期疗效观察

 本文对26例晚期宫颈癌放射治疗疗效进行近期临床观察。所有病例均经病理学证实。26例病人分为两组:放射增敏组和对照组,其中11例病人行动脉灌注顺铂放射增敏,15例行单纯放射治疗。对增敏组11例患者共行24次动脉灌注顺铂加栓塞治疗。所有病人皆接受根治性放疗。结果显示:放射增敏组的放疗半量、全量疗效皆优于对照组(P<0.05),放疗达PR、CR时的顺铂增敏比分别为134和118,同时也可看到较轻的副作用如恶心、呕吐等。     

咖啡因促进放疗增敏的机制研究

放射治疗是恶性肿瘤三大治疗手段之一,但是有些肿瘤放射敏感性较差,因此治疗效果不佳.咖啡因作为辐射增敏剂,可以逆转辐射引起的G2期阻滞,提高放疗敏感性.本文就咖啡因的放疗增敏机制进行综述如下.     

基于纳米技术的肿瘤热放疗增敏的研究进展

放疗是治疗恶性肿瘤的重要手段之一,通过物理技术提高放疗的治疗增益比是现代精确放疗技术的发展方向。由于高能放射线固有的物理特性,通过放射物理技术提高放疗的治疗增益比必然遭遇瓶颈。应用热疗增敏放疗,可提高肿瘤细胞的放射敏感性、降低肿瘤细胞的放射抵抗性,在放疗中具有非常重要的临床实用价值。具有良好的生物相容性和安全性的多功能纳米材料在肿瘤光热疗治疗研究中已经受到广泛的关注并展现出了良好的潜力,将纳米热疗技术作为增敏载体结合放疗,在热放疗增敏的同时,高原子序数纳米材料亦可单独作为放疗增敏载体,使肿瘤热疗和放疗二者协同增效,有可能克服目前制约肿瘤放疗的诸多难题,为推动放疗的进一步发展提供了新的发展机遇。本文对基于纳米技术的肿瘤热放疗增敏的研究进展进行综述。      

三氧化二砷对鼻咽癌放疗增敏作用及其机制的研究

目的：探讨三氧化二砷（As2O3）注射液对鼻咽癌放疗增敏作用与肿瘤血管生成素表达的关系。方法：将74例鼻咽癌患者随机分为单纯放疗组（放疗组）和As2O3放射增敏组（增敏组），观察两组患者鼻咽肿瘤消退情况。每个病例在治疗前及放疗20Gy后24h各取材1次。免疫组化SP法检测血管生成素1（Ang-1）和血管生成素2（Ang-2）蛋白表达。结果：放疗40Gy时增敏组和放疗组的鼻咽肿瘤消退率分别为43．6％（17／39）和20．0％（7／35），Х^2=4．684，P=0．003。增敏组Ang-1和Ang-2蛋白在放射治疗剂量20Gy时均表达下调，z分别为-2．147和-2．985，P值分别为0．032和0．003。在40Gy肿瘤消退组，Ang-2蛋白下调，z=-02．183，P=0．029。结论：As2O3注射液对鼻咽癌患者放射治疗具有增敏作用，其增敏机制可能与Ang-1和Ang-2蛋白抑制肿瘤血管形成有关。     

Molecular targets for potentiation of radiation-induced cell killing

Molecular target-based drugs have been emerging as a cancer treatment. Clinical trials using the combined approach of radiation therapy and molecular target-based drugs have been performed to evaluate the feasibility of this approach, and improve the response of tumors to radiation. To achieve maximum radiotherapeutic gain, understanding of the interaction of radiation and drugs are indispensable. Preclinical data have already demonstrated synergistic enhancement of radiation-induced cell killing by several molecular target-based drugs. Among these, the effect of drugs that target receptor tyrosine kinase and its signal transduction pathways on radiosensitivity has been intensively investigated. In this review, established and potential molecular targets for potentiation of radiation-induced cell killing are summarized, and preclinical data regarding investigations of new molecular targets for radiosensitization will be introduced. In addition, the results and toxicities of clinical trials using combined radiation therapy and molecular target-based drugs are summarized.     

Ethanolic Extract from Derris scandens Benth Mediates Radiosensitzation via Two Distinct Modes of Cell Death in Human Colon Cancer HT-29 Cells

Enhancing of radioresponsiveness of tumors by using radiosensitizers is a promising approach to increase theefficacy of radiation therapy. Recently, the ethanolic extract of the medicinal plant, Derris scandens Benth hasbeen identified as a potent radiosensitizer of human colon cancer HT29 cells. However, cell death mechanismsunderlying radiosensitization activity of D scandens extract have not been identified. Here, we show that treatmentof HT-29 cells with D scandens extract in combination with gamma irradiation synergistically sensitizes HT-29cells to cell lethality by apoptosis and mitotic catastrophe. Furthermore, the extract was found to decrease Erk1/2activation. These findings suggest that D scandens extract mediates radiosensitization via at least two distinctmodes of cell death and silences pro-survival signaling in HT-29 cells.     

紫杉醇对骨肉瘤细胞放射增敏作用的研究

目的观察体外环境下紫杉醇对骨肉瘤（osteosarcoma,OS）细胞的放射增敏效果及其与药物作用时间的关系。方法以MG-63细胞为实验对象,采用MTT法检测不同浓度紫杉醇（6、0.6、0.06、0.006和0.000 6μg/mL）对MG-63细胞的抑制作用,确定IC10作为后续实验的药物浓度;采用克隆形成分析法分别测定MG-63细胞在紫杉醇作用24h后照射以及单纯照射的存活分数（SF）,拟合细胞生存曲线并计算放射增敏比,分析紫杉醇对MG-63细胞的放射增敏作用;采用克隆形成分析法测定紫杉醇作用于MG-63细胞12、24和36h后细胞生存率的变化,确定最佳照射时间。组间比较采用单因素方差分析。结果 MTT实验结果显示,当紫杉醇浓度分别为0.000 6、0.006、0.06、0.6和6μg/mL时,其细胞抑制率分别为（3.25±2.58）%、（9.98±3.83）%、（20.35±3.91）%、（21.55±3.70）%和（55.36±4.67）%。提示,紫杉醇对MG-63细胞的生长抑制作用呈浓度依赖性,F=83.70,P〈0.01,IC10为0.01μg/mL;IC10浓度紫杉醇増敏比分别为1.14（D0比）、1.20（Dq比）和1.08（SF2比）;MG-63细胞α/β值为2.23,IC10浓度紫杉醇作用后α/β值为2.32。紫杉醇作用于MG-63细胞12、24和36h后再进行照射,细胞存活分数分别为（9.21±0.81）%、（5.39±0.75）%和（0.38±0.13）%,显著低于对照组的（12.86±1.07）%,差异有统计学意义,F=144.11,P〈0.01。结论紫杉醇对MG-63细胞有放射增敏作用,增敏作用呈时间依赖性,有一定的临床应用前景。     

ANTP-SmacN7融合肽对H460细胞的辐射增敏作用

背景与目的肿瘤的辐射耐受制约了放疗疗效,第二个线粒体衍生的半胱氨酸蛋白酶激活剂（Second mitochondria-derived activator of caspase, Smac）蛋白类似物可明显提高辐射诱导的肿瘤细胞凋亡,有望成为新型肿瘤辐射增敏药物。本研究旨在探讨新型Smac蛋白类似物ANTP-SmacN7融合肽对肺癌细胞系H460的辐射增敏作用。方法合成ANTP-SmacN7融合肽,连接荧光素FITC以观察融合肽能否进入细胞。对数生长期H460细胞分为空白对照组、单纯照射组、ANTP-SmacN7组和照射联合ANTP-SmacN7组,单纯照射组给予0 Gy、2 Gy、4 Gy、6 Gy照射,照射联合ANTP-SmacN7组中ANTP-SmacN7的浓度为20μmol/L,WST-1测定H460细胞的增殖。流式细胞仪测定细胞处理后24 h和48 h的细胞凋亡率。Western blot实验检测caspase3和cleaved caspase3的表达水平。结果 ANTP-SmacN7融合能够顺利进入细胞,且能够增强H460细胞的辐射敏感性（F=25.1,P<0.01,增敏比为1.86）,照射联合ANTP-SmacN7可明显降低H460细胞的克隆形成率（χ2=45.2,P<0.01;χ2=40.3,P<0.01）,提高cleaved caspase3的表达量,促进caspase3的活化,增加辐射诱导的细胞凋亡率。结论 ANTP-SmacN7融合肽可明显提高H460细胞的辐射敏感性,作为一种新的Smac蛋白类似物有望用于肿瘤的辐射增敏治疗。     

Differential radiosensitization in DNA mismatch repair-proficient and -deficient human colon cancer xenografts with 5-iodo-2-pyrimidinone-2'-deoxyribose.

PURPOSE: 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a pyrimidinone nucleoside prodrug of 5-iododeoxyuridine (IUdR) under investigation as an orally administered radiosensitizer. We previously reported that the mismatch repair (MMR) proteins (both hMSH2 and hMLH1) impact on the extent (percentage) of IUdR-DNA incorporation and subsequent in vitro IUdR-mediated radiosensitization in human tumor cell lines. In this study, we used oral IPdR to assess in vivo radiosensitization in MMR-proficient (MMR+) and -deficient (MMR-) human colon cancer xenografts. EXPERIMENTAL DESIGN: We tested whether oral IPdR treatment (1 g/kg/d for 14 days) can result in differential IUdR incorporation in tumor cell DNA and subsequent radiosensitization after a short course (every day for 4 days) of fractionated radiation therapy, by using athymic nude mice with an isogenic pair of human colon cancer xenografts, HCT116 (MMR-, hMLH1-) and HCT116/3-6 (MMR+, hMLH1+). A tumor regrowth assay was used to assess radiosensitization. Systemic toxicity was assessed by daily body weights and by percentage of IUdR-DNA incorporation in normal bone marrow and intestine. RESULTS: After a 14-day once-daily IPdR treatment by gastric gavage, significantly higher IUdR-DNA incorporation was found in HCT116 (MMR-) tumor xenografts compared with HCT116/3-6 (MMR+) tumor xenografts. Using a tumor regrowth assay after the 14-day drug treatment and a 4-day radiation therapy course (days 11-14 of IPdR), we found substantial radiosensitization in both HCT116 and HCT116/3-6 tumor xenografts. However, the sensitizer enhancement ratio (SER) was substantially higher in HCT116 (MMR-) tumor xenografts (1.48 at 2 Gy per fraction, 1.41 at 4 Gy per fraction), compared with HCT116/3-6 (MMR+) tumor xenografts (1.21 at 2 Gy per fraction, 1.20 at 4 Gy per fraction). No substantial systemic toxicity was found in the treatment groups. CONCLUSIONS: These results suggest that IPdR-mediated radiosensitization can be an effective in vivo approach to treat "drug-resistant" MMR-deficient tumors as well as MMR-proficient tumors.     

End-joining deficiency and radiosensitization induced by gemcitabine

The mechanism of radiosensitization by gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) is not exactly known. We investigated the possible role of inhibition of the repair of DNA double-strand breaks by dFdC by measuring the extent of radiosensitization in different cell lines deficient and proficient in components of nonhomologous end-joining and in the parental cell lines. Different cell lines were incubated with 0.5 and 5 microM dFdC for 4 h. Cells deficient in DNA-dependent protein-kinase catalytic subunit (V3) showed sensitization similar to that of wild-type cells (AAS) and complemented cells (V3+YAC). Ku80-deficient cells (xrs5 and xrs6) showed even more radiosensitization by dFdC as compared with wild-type CHO-K1. However, Ku80-complemented cell lines (xrs5+huKu80 and xrs6+haKu80) did not show radiosensitization. The differences in dFdC-mediated radiosensitization were not attributable to different changes in deoxynucleotide triphosphate levels and cell cycle distribution. We conclude that a functional nonhomologous end-joining pathway is not required for dFdC-mediated radiosensitization.     

Effects of azetidine-2-carboxylic acid on treatments of hepatoma cells with single or fractionated X-ray irradiations and on thermal radiosensitization in normal and thermotolerant cells

The amino acid analog azetidine-2-carboxylic acid (azetidine) is a potent sensitizer to both hyperthermia and ionizing radiation. Incubation of H35 hepatoma cells with 2.5 mM azetidine before or after treatments with X-rays causes a time- and sequence-dependent enhancement of cell killing. Exposure of cells to 1-1.5 mM azetidine for 96 h in combination with repeated doses of 3 Gy X-rays at 24 h intervals causes an enhanced reduction of the surviving cell population due to both radiosensitization and an additional growth inhibition. Azetidine does not prevent the induction of thermotolerance after a heat shock. This thermotolerance proportionally reduces thermal radiosensitization but does not seem to affect azetidine radiosensitization. It is suggested that thermal radiosensitization and azetidine radiosensitization operate by different mechanisms.     

纳米金颗粒的基本特性及其对肿瘤放射增敏作用的研究进展

纳米金颗粒以其独特的理化性质在医学领域越来越受到重视。近年许多研究证实了纳米金在肿瘤治疗中可以减少组织受照剂量,减轻放射治疗对正常组织的伤害,在放射增敏方面有重要作用,本文从纳米金的基本特性、生物学毒性、放射增敏机制、在细胞和动物模型中增敏实验以及在临床前应用等几方面进行综述。     

Enhanced apoptosis and radiosensitization by combined 13-cis-retinoic acid and interferon-alpha2a; role of RAR-beta gene.

PURPOSE: Combined use of 13-cis-retinoic acid (cRA) and interferon-alpha2a (IFNalpha) induced significant radiosensitization in human cervical cancer ME-180 cell line, whereas it failed to achieve similar radiation enhancement in HeLa cells. The differential radiosensitization could be from the difference of retinoic acid receptor (RAR) expression because RAR-beta was highly expressed in ME-180 cells in contrast to the HeLa cells where RAR-beta was not detectable. We examined the role of this gene in mediating radiosensitization by cRA and IFNalpha, and explored the mechanism of radiation-induced cell killing. METHODS AND MATERIALS: Human cervical cancer cell lines, ME-180 and HeLa, were treated with cRA and IFNalpha followed by radiation. Apoptosis and radiosensitization were quantitated by TUNEL assay (in situ DNA nick end labeling) and colony-forming ability of surviving cells. The cells were transfected with bcl-2 gene and RAR-beta gene to test the role of these genes in mediating radiosensitization and apoptosis. RESULTS: Synergistic radiosensitization and apoptosis was observed by combined use of cRA and IFNalpha with radiation in ME-180 cells which express high level of RAR-beta mRNA, whereas these were not seen in HeLa cells where RAR-beta mRNA is not detectable. Both radiosensitization and apoptosis were abolished by bcl-2 gene in ME-180 cells. RAR-beta gene transfection induced similar radiation enhancement and apoptosis in HeLa cells. CONCLUSION: Apoptosis and radiation response were enhanced in the cells with high level of RAR-beta mRNA expression. The RAR-beta gene appears to mediate the radiation-induced apoptosis by cRA and IFNalpha. These findings indicate that presence of RAR-beta in the cancer cells could be exploited for patient selection in using these drugs for apoptosis and radiosensitization.     

Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by small interfering RNA silencing of tumor necrosis factor receptor-associated factor 2

Radiotherapy combined with chemotherapy is the treatment of choice for glioblastoma and locally advanced lung cancer, but radioresistance of these two types of cancer remains a significant therapeutic hindrance. To identify molecular target(s) for radiosensitization, we screened a small interfering RNA (siRNA) library targeting all protein kinases and E3 ubiquitin ligases in the human genome and identified tumor necrosis factor receptor-associated factor 2 (TRAF2). Silencing of TRAF2 using siRNA caused a significant growth suppression of glioblastoma U251 cells and moderately sensitized these radioresistant cells to radiation. Overexpression of a really interesting new gene (RING)-deleted dominant-negative TRAF2 mutant also conferred radiosensitivity, whereas overexpression of wild-type (WT) TRAF2 significantly protected cells from radiation-induced killing. Likewise, siRNA silencing of TRAF2 in radioresistant lung cancer H1299 cells caused growth suppression and radiosensitization, whereas overexpression of WT TRAF2 enhanced radioresistance in a RING ligase-dependent manner. Moreover, siRNA silencing of TRAF2 in UM-SCC-1 head and neck cancer cells also conferred radiosensitization. Further support for the role of TRAF2 in cancer comes from the observations that TRAF2 is overexpressed in both lung adenocarcinoma tissues and multiple lung cancer cell lines. Importantly, TRAF2 expression was very low in normal bronchial epithelial NL20 cells, and TRAF2 silencing had a minimal effect on NL20 growth and radiation sensitivity. Mechanistically, TRAF2 silencing blocks the activation of the nuclear factor-kappaB signaling pathway and down-regulates several G(2)-M cell cycle control proteins, resulting in enhanced G(2)-M arrest, growth suppression, and radiosensitization. Our studies suggest that TRAF2 is an attractive drug target for anticancer therapy and radiosensitization.