~（125）Ⅰ放射性粒子组织间植入治疗肝癌的实验研究
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摘要
目的
探讨I125籽源组织间植入对裸鼠移植性肝癌的治疗效果、剂量与疗效的关系,外周血的影响以及I125籽源近距离低剂量率持续照射对荷人肝癌裸鼠移植瘤生长和细胞增殖抑制,细胞凋亡,微血管生成和凋亡相关蛋白的影响,为临床I125籽源植入近距离治疗中晚期肝癌提供实验依据。
方法
在BALB/C-nu裸鼠左前肢腋窝皮下注射HEP-G2肝癌细胞7×106/0.3ml建立荷人肝癌HEP-G2裸鼠移植瘤模型40只,选取建立模型成功的36只裸鼠。选取14天后在皮下扪及肿瘤直径约6mm及10mm的荷瘤鼠各18只,把其分别随机分成两个不同治疗剂量组和一个对照组,每组6只裸鼠。通过治疗计划系统TPS确定植入I125粒子剂量。肿瘤直径约6mm治疗组分别植入1粒表面活度为0.7mci,0.9mci的I125粒子,对照组植入无活性的空心粒子,肿瘤直径约10mm治疗组分别植入2粒表面活度为0.7mci,0.9mci的I125粒子,对照组植入无活性的空心粒子,粒子植入后每7d测量一次肿瘤直径并计算各组肿瘤体积抑制率,对裸鼠进行治疗前后血常规检查,28天后处死裸鼠,制作肿瘤组织标本,进行常规病理学检查。通过免疫组织化学来检测Ki67,UEA-1,bcl-2,bax的表达及原位末端标记法(TUNEL)检测凋亡,计算出微血管密度。
结果
1直径约6mm肿瘤经过活度0.7mCi,0.9 mCi 125I粒子治疗后体积变化,实验组肿瘤生长趋停止,前二周体积无明显增大,二周后体积开始缩小;对照组肿瘤继续生长,体积每周都有增大。二组自治疗后第7天起即差异显著(治疗后第7、14、21、28天0.7mci实验组与对照组的P值分别为(P= 0.0045,P<0.0001, P<0.0001和P<0.0001),0.9mci实验组与对照组的P值均小于0.05。直径10mm肿瘤经活度1.4mCi,1.8mCi 125I粒子治疗后体积变化,对照组肿瘤继续生长,体积每周都有增大。1.4mCi,1.8 mCi 125I粒子治疗后7天内与对照组相比体积减少无显著差异(P>0.05),治疗后第7,14、21、28天1.4mci与1.8mci实验组与对照组的P值分别P<0.05。此外治疗后从14天起1.4mci与1.8mci实验组体积相比,P<0.05,说明这两个不同剂量组体积有显著差异。125I粒子治疗各组病理切片肿瘤细胞呈不同程度的变性坏死,剂量越大坏死越严重,但远离粒子处仍可见存活肿瘤细胞。治疗后存活裸鼠各组治疗前后血常规各指标无明显改变,差异无显著性(P>0.05)。
2. Ki67表达强度在0.7mci125 I粒子治疗组为“++-++++,0.9 mci125 I粒子治疗组为“++-+++,对照组为+++-++++”。0.7mci,0.9mci组,对照组三组间有显著性差异(秩和检验,u= 2.923, 0.025 0.7mci及0.9mci125 I粒子治疗组的bcl-2/bax比值为0.37士0.04,0.28士0.02,对照组为0.69士0.07, 0.7mci,0.9mci与对照组之间有显著性差异(P=0.000),0.7mci与0.9mci组间有显著性差异(P=0.008)。1.4mci及1.8mci125 I粒子治疗组的bcl-2/bax比值为0.41士0.06,0.33士0.04,对照组为0.76士0.04, 1.4mci,1.8mci与对照组之间有显著性差异(P=0.000),1.4mci与1.8mci组间有显著性差异(P=0.008)。
0.7mci,0.9mci125 I粒子治疗组MVD分别为6.17士1.47,3.67士0.82,对照组MVD为18.67士2.16,0.7mci,0.9mci与对照组之间有显著性差异〔P=0.000)。1.4mci,1.8mci125 I粒子治疗组MVD分别为10.5士1.87,7.17士1.17,对照组MVD为28.33士2.42,1.4mci,1.8mci与对照组之间有显著性差异〔P=0.000)。
TUNEL法检测凋亡:0.7mci,0.9mci125 I粒子治疗组凋亡指数(%)分别为11.00士2.90,18.33士2.16,对照组凋亡指数(%)为6.00士1.41,0.7mci,0.9mci与对照组之间有显著性差异〔P=0.000)。1.4mci,1.8mci125 I粒子治疗组凋亡指数(%)分别为16.83士2.48,30.67士3.78,对照组凋亡指数(%)为10.4士2.42,1.4mci,1.8mci与对照组之间有显著性差异〔P=0.000)。
结论
125I粒子组织间植入对裸鼠移植性肝癌持续照射可以直接杀死荷瘤鼠肝癌细胞,也可以抑制肿瘤细胞增殖,减少血管生成,诱导肿瘤细胞凋亡,从而可以抑制肿瘤的生长。而且术前的治疗计划对较好的疗效有很好的指导作用。
Objective
The purpose of this thesis is to provide experimental basis for clinical application of iodine -125 seeds implantation by Investigating the therapeutic effect of iodine -125 interstitial brachytherapy seeds on the transplanted liver cancer of BALB/C nude mice and to analyse the influence of doses of radiation to tumor, its surrouding tissue and the blood cells and to analyse the effect of low dose rate and continuous irradiation with iodine -125 seeds in inhibiting proliferation, inducing apoptosis in HEP-G2 cell line and the treatment effect, influence on proliferation, angiogenesis, apoptosis related protein of iodine -125 seeds brathytherapy to liver cancer in nude mice.
Methods
4x106/0.3m1 HEP-G2 cells were transplanted subcutaneously in the left axillary fossa of BALB/C nude mice, and forty transplanted liver cancer models were produced ,thirty-six fitable models were selected to take an animal experimental research. 14 days later nude mice with a tumor of 6mm or 10mm in mean diameter were produced and separately divided into two different therapeutic dose group and a control group. Each group included 6 nude mice. One iodine -125 seed (surface radioactivity 0.7mci,0.9mci) was implanted into each tumor of mice in 6mm treatment group and the tumor in control group was implanted into One iodine -125 seed (surface radioactivity 0mci );two iodine-125 seeds(surface radioactivity 0.7mci,0.9mci) were implanted into each tumor of mice in 10mm treatment group and the tumor in control group was implanted into two iodine -125 seeds (surface radioactivity 0mci ); Tumors' dimensions of two groups were measured per 7 days and tumor volume inhibition rates were calculated. The blood cells of mice were also observed before and after treatment. After 28 days, nude mice were killed and routine pathological slides of tumor tissue were observed under light microscope to evaluate the degree and range of tumor tissues damaged by iodine -125 seeds. The expression of Proliferating Cell related Nuclear Antigen (Ki67), UEA-1 ,bcl-2 and bax were examined with immunohistochemical methods in six groups. The ratio of bcl-2/bax ,apoptosis by TUNEL way and MVD in six group were calculated.
results
1. In two weeks followed I125 seeds implantation, there were no volume difference in 0.7mci,0.9mci treatment group tumor, two weeks later the volume in 0.7mci and 0.9mci treatment group tumor in 6mm tumor beagn to reduce ,the control group tumor had been growing . There were significant differences between the 0.7mci ,0.9mci group and the control group xenograft volumes 7 days ,14 days ,21 days and 28 days later after implantation (P= 0.0045,P<0.0001, P<0.0001和P<0.0001,P<0.05,P<0.05,P<0.05,P<0.05).In seven days after I125 seeds implantation, there were no volume difference between 1.4mci,1.8mci treatment group tumor and the control group , There were significant difference between the 1.4mci ,1.8mci group and the control group xenograft volumes 7 days ,14 days ,21 days and 28 days later after implantation (P <0. 05),in addition there were volume difference between 1.4mci treatment group and 1.8mci treatment group。Routine pathological examination showed that dramatically coagulative necrosis and degenerative necrosis of tumor cells at the periphery of active I125 seeds, while there were still viable cells far away from I125 seed.No significant difference of the blood cells in nude mice were observed before and after treatment (P>0.05)
2. Immunohistochemical examination showed that the expression of ki67 in 0.7mci ,0.9mci I125 seed implantation group was”++-++++,++-+++,”while in control group the expression was“+++一+++++”.There were significant difference among the 0.7mci,0.9mci groups,the control group.(u= 2.923, 0.025 The ratio of bcl-2/bax in 0.7mci,0.9mci treatment group and the control group was 0.37士0.04,0.28士0.02, 0.69士0.07, There were significant difference between the 0.7mci,0.9mci groups and the control group separately(P=0.000,P=0.000)。There were alse significant difference between the 0.7mci and 0.9mci group(P=0.008).The ratio of bcl-2/bax in 1.4mci,1.8mci treatment group and the control group was 0.41士0.06, 0.33士0.04, 0.76士0.04, There were significant difference between the 1.4mci,1.8mci groups and the control group separately(P=0.000,P=0.000)。There were alse significant difference between the 1.4mci and 1.8mci group(P=0.008)。
The value of MVD in 0.7mci,0.9mci treatment group and the control group was 6.17士1.47,3.67士0.82, MVD为18.67士2.16, There were significant difference between the 0.7mci,0.9mci groups and the control group separately(P=0.000,P=0.000)。the value of MVD in 1.4mci,1.8mci treatment group and the control group was 10.5士1.87,7.17士1.17,28.33士2.42,There were significant difference between the 0.7mci,0.9mci groups and the control group separately(P=0.000,P=0.000)。
The index of apoptosis in 0.7mci,0.9mci treatment group and the control group was 11.00士2.90,18.33士2.16, 6.00士1.41。There were significant difference between the 0.7mci,0.9mci groups and the control group separately(P=0.000,P=0.000)。The index of apoptosis in 1.4mci,1.8mci treatment group and the control group was 16.83士2.48,30.67士3.78,10.4士1.67,There were significant difference between the 1.4mci,1.8mci groups and the control group separately(P=0.000,P=0.000)。
Conclusion
Iodine-125 seed implantation brachytherapy may inhabit the growth of the transplanted liver cancer of BALB/C nude mice by killing tumor cells around iodine-125 seed, inhabiting proliferation of tumor cells, inducing apoptosis and down-regulating angiogenesis.Preoperation treatment plan system alse has a very good guidence in the therapeutic effect.
探讨I125籽源组织间植入对裸鼠移植性肝癌的治疗效果、剂量与疗效的关系,外周血的影响以及I125籽源近距离低剂量率持续照射对荷人肝癌裸鼠移植瘤生长和细胞增殖抑制,细胞凋亡,微血管生成和凋亡相关蛋白的影响,为临床I125籽源植入近距离治疗中晚期肝癌提供实验依据。
方法
在BALB/C-nu裸鼠左前肢腋窝皮下注射HEP-G2肝癌细胞7×106/0.3ml建立荷人肝癌HEP-G2裸鼠移植瘤模型40只,选取建立模型成功的36只裸鼠。选取14天后在皮下扪及肿瘤直径约6mm及10mm的荷瘤鼠各18只,把其分别随机分成两个不同治疗剂量组和一个对照组,每组6只裸鼠。通过治疗计划系统TPS确定植入I125粒子剂量。肿瘤直径约6mm治疗组分别植入1粒表面活度为0.7mci,0.9mci的I125粒子,对照组植入无活性的空心粒子,肿瘤直径约10mm治疗组分别植入2粒表面活度为0.7mci,0.9mci的I125粒子,对照组植入无活性的空心粒子,粒子植入后每7d测量一次肿瘤直径并计算各组肿瘤体积抑制率,对裸鼠进行治疗前后血常规检查,28天后处死裸鼠,制作肿瘤组织标本,进行常规病理学检查。通过免疫组织化学来检测Ki67,UEA-1,bcl-2,bax的表达及原位末端标记法(TUNEL)检测凋亡,计算出微血管密度。
结果
1直径约6mm肿瘤经过活度0.7mCi,0.9 mCi 125I粒子治疗后体积变化,实验组肿瘤生长趋停止,前二周体积无明显增大,二周后体积开始缩小;对照组肿瘤继续生长,体积每周都有增大。二组自治疗后第7天起即差异显著(治疗后第7、14、21、28天0.7mci实验组与对照组的P值分别为(P= 0.0045,P<0.0001, P<0.0001和P<0.0001),0.9mci实验组与对照组的P值均小于0.05。直径10mm肿瘤经活度1.4mCi,1.8mCi 125I粒子治疗后体积变化,对照组肿瘤继续生长,体积每周都有增大。1.4mCi,1.8 mCi 125I粒子治疗后7天内与对照组相比体积减少无显著差异(P>0.05),治疗后第7,14、21、28天1.4mci与1.8mci实验组与对照组的P值分别P<0.05。此外治疗后从14天起1.4mci与1.8mci实验组体积相比,P<0.05,说明这两个不同剂量组体积有显著差异。125I粒子治疗各组病理切片肿瘤细胞呈不同程度的变性坏死,剂量越大坏死越严重,但远离粒子处仍可见存活肿瘤细胞。治疗后存活裸鼠各组治疗前后血常规各指标无明显改变,差异无显著性(P>0.05)。
2. Ki67表达强度在0.7mci125 I粒子治疗组为“++-++++,0.9 mci125 I粒子治疗组为“++-+++,对照组为+++-++++”。0.7mci,0.9mci组,对照组三组间有显著性差异(秩和检验,u= 2.923, 0.025
0.7mci,0.9mci125 I粒子治疗组MVD分别为6.17士1.47,3.67士0.82,对照组MVD为18.67士2.16,0.7mci,0.9mci与对照组之间有显著性差异〔P=0.000)。1.4mci,1.8mci125 I粒子治疗组MVD分别为10.5士1.87,7.17士1.17,对照组MVD为28.33士2.42,1.4mci,1.8mci与对照组之间有显著性差异〔P=0.000)。
TUNEL法检测凋亡:0.7mci,0.9mci125 I粒子治疗组凋亡指数(%)分别为11.00士2.90,18.33士2.16,对照组凋亡指数(%)为6.00士1.41,0.7mci,0.9mci与对照组之间有显著性差异〔P=0.000)。1.4mci,1.8mci125 I粒子治疗组凋亡指数(%)分别为16.83士2.48,30.67士3.78,对照组凋亡指数(%)为10.4士2.42,1.4mci,1.8mci与对照组之间有显著性差异〔P=0.000)。
结论
125I粒子组织间植入对裸鼠移植性肝癌持续照射可以直接杀死荷瘤鼠肝癌细胞,也可以抑制肿瘤细胞增殖,减少血管生成,诱导肿瘤细胞凋亡,从而可以抑制肿瘤的生长。而且术前的治疗计划对较好的疗效有很好的指导作用。
Objective
The purpose of this thesis is to provide experimental basis for clinical application of iodine -125 seeds implantation by Investigating the therapeutic effect of iodine -125 interstitial brachytherapy seeds on the transplanted liver cancer of BALB/C nude mice and to analyse the influence of doses of radiation to tumor, its surrouding tissue and the blood cells and to analyse the effect of low dose rate and continuous irradiation with iodine -125 seeds in inhibiting proliferation, inducing apoptosis in HEP-G2 cell line and the treatment effect, influence on proliferation, angiogenesis, apoptosis related protein of iodine -125 seeds brathytherapy to liver cancer in nude mice.
Methods
4x106/0.3m1 HEP-G2 cells were transplanted subcutaneously in the left axillary fossa of BALB/C nude mice, and forty transplanted liver cancer models were produced ,thirty-six fitable models were selected to take an animal experimental research. 14 days later nude mice with a tumor of 6mm or 10mm in mean diameter were produced and separately divided into two different therapeutic dose group and a control group. Each group included 6 nude mice. One iodine -125 seed (surface radioactivity 0.7mci,0.9mci) was implanted into each tumor of mice in 6mm treatment group and the tumor in control group was implanted into One iodine -125 seed (surface radioactivity 0mci );two iodine-125 seeds(surface radioactivity 0.7mci,0.9mci) were implanted into each tumor of mice in 10mm treatment group and the tumor in control group was implanted into two iodine -125 seeds (surface radioactivity 0mci ); Tumors' dimensions of two groups were measured per 7 days and tumor volume inhibition rates were calculated. The blood cells of mice were also observed before and after treatment. After 28 days, nude mice were killed and routine pathological slides of tumor tissue were observed under light microscope to evaluate the degree and range of tumor tissues damaged by iodine -125 seeds. The expression of Proliferating Cell related Nuclear Antigen (Ki67), UEA-1 ,bcl-2 and bax were examined with immunohistochemical methods in six groups. The ratio of bcl-2/bax ,apoptosis by TUNEL way and MVD in six group were calculated.
results
1. In two weeks followed I125 seeds implantation, there were no volume difference in 0.7mci,0.9mci treatment group tumor, two weeks later the volume in 0.7mci and 0.9mci treatment group tumor in 6mm tumor beagn to reduce ,the control group tumor had been growing . There were significant differences between the 0.7mci ,0.9mci group and the control group xenograft volumes 7 days ,14 days ,21 days and 28 days later after implantation (P= 0.0045,P<0.0001, P<0.0001和P<0.0001,P<0.05,P<0.05,P<0.05,P<0.05).In seven days after I125 seeds implantation, there were no volume difference between 1.4mci,1.8mci treatment group tumor and the control group , There were significant difference between the 1.4mci ,1.8mci group and the control group xenograft volumes 7 days ,14 days ,21 days and 28 days later after implantation (P <0. 05),in addition there were volume difference between 1.4mci treatment group and 1.8mci treatment group。Routine pathological examination showed that dramatically coagulative necrosis and degenerative necrosis of tumor cells at the periphery of active I125 seeds, while there were still viable cells far away from I125 seed.No significant difference of the blood cells in nude mice were observed before and after treatment (P>0.05)
2. Immunohistochemical examination showed that the expression of ki67 in 0.7mci ,0.9mci I125 seed implantation group was”++-++++,++-+++,”while in control group the expression was“+++一+++++”.There were significant difference among the 0.7mci,0.9mci groups,the control group.(u= 2.923, 0.025
The value of MVD in 0.7mci,0.9mci treatment group and the control group was 6.17士1.47,3.67士0.82, MVD为18.67士2.16, There were significant difference between the 0.7mci,0.9mci groups and the control group separately(P=0.000,P=0.000)。the value of MVD in 1.4mci,1.8mci treatment group and the control group was 10.5士1.87,7.17士1.17,28.33士2.42,There were significant difference between the 0.7mci,0.9mci groups and the control group separately(P=0.000,P=0.000)。
The index of apoptosis in 0.7mci,0.9mci treatment group and the control group was 11.00士2.90,18.33士2.16, 6.00士1.41。There were significant difference between the 0.7mci,0.9mci groups and the control group separately(P=0.000,P=0.000)。The index of apoptosis in 1.4mci,1.8mci treatment group and the control group was 16.83士2.48,30.67士3.78,10.4士1.67,There were significant difference between the 1.4mci,1.8mci groups and the control group separately(P=0.000,P=0.000)。
Conclusion
Iodine-125 seed implantation brachytherapy may inhabit the growth of the transplanted liver cancer of BALB/C nude mice by killing tumor cells around iodine-125 seed, inhabiting proliferation of tumor cells, inducing apoptosis and down-regulating angiogenesis.Preoperation treatment plan system alse has a very good guidence in the therapeutic effect.
引文
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[11]Ling CC . Permanent implams using Au — l98 , Pd 一 53 and I-125.Radiohiological considerations based on the linear quadratic model[J] Int J Radiat Oncol Biol Phys.1992 23 81—87.
[12]Ragde ,KorbLJ,ElgamalAA,etal 。 Modern prostate Brachytherapy prostate specific antigen results in patients with up to 12 years of observed follow-up[J]Cancer,2000,89(1):135~141
[13]罗开元,李 波,杨 嵘,等 1125I 粒子组织间放射治疗恶性肿瘤的临床应用[J] 中华医学杂志,2001,81(12):754~755
[14]罗开元,郑江华,李 波,等 1125I 粒子永久性植入组织间放射治疗肝癌[J] 肝胆胰外科杂志,2004,16(1):29~31
[15]宋金龙,邵文博,唐宪民 1125I 粒子近距离照射治疗原发性肝癌的实验研究[J] 肿瘤防治杂志,2005,12(10):750~752 [16」李勇,冯贤松.i2s1 粒子术中植入治疗腹腔恶性肿瘤.腹部外科杂志,2005, 18(2):96-97
[17] Martinez-Monge R, Nag S, Nieroda CA, et al. Iodione-125 Brachytherapy in the treatment of colorectal adenocarcinoma metastasis to the liver. Cancer, 1999, 85(6):1218-1225.
[18] 徐静,梅铭惠,陈谦,等。术中组织间植入 125I 粒子治疗肝恶性肿瘤。中华实验外科杂志,2004,16(1):29-31。
[19] 程宝兴,吴浩荣,吴锦昌。碘-125 组织间植入治疗大鼠移植性肝癌的实验研究。苏州大学学报,2002,22:13-16。
[20] Williamson JF, Coursey BM, DeWara LA, et al. Guidence to users of Nycomed Amersham and North American Acientific, Inc. I-125 interstitial sources:dosinietry and calibration changes: Recommendations of the American Association of physicists in Medicine Radiation Therapy Committee Ad Hoc Subcommittee on low-energy. Med Phys, 1999, 26: 570-573
[21]徐静,梅铭惠,陈谦,等.术中组织间植入 125 I 粒子治疗肝恶性肿瘤。中华实 验外科杂志,2005 , 22 : 368-369
[22]罗开元,郑江华,李波,等. 125 I 粒子永久性植入组织间放射治疗肝癌。肝胆 胰外科杂志,2004, 16:29-31
[23] Donath D, Nori D, Turnbull A, et al. Brachytherapy in the treatment of solitary colorectal metastases to the liver. J Surg. Onco1,1990, 44:55-61
[24] Blasko JC, et al. Prostate specific antigen based disease control following ultrasound guider 125 I implantation T1/T2 prostate carcinoma. J Urol, 1995,154: 1096-1099.
[25] Hilaris BS, et al. Value of perioperative branchtherapy in the management of non-oat cell carcinoma of the lung. Int J Radiat Oncol Biol Phys, 1983, 9: 1161-1166.
[26] Peretz T, et al. Treatment of primary unresectable carcinoma of the pancreas with125 implantation. Int J Radiat Oncol Biol Phys, 1989, 17: 931-935.
[27] Martinez, et al.125I brachytherapy for colorectal adenocarcinoma recurrent in the pelvis and paraortics. Int J Radiat Oncol Biol Phys, 1998, 41: 545-550.
[28] Kreth FW, et al. Interstitial radiosurgery of low-grade gliomas. J Neurosurg , 1995, 82:418-429.
[29] Arstrong JG,et al. Treatment of liver metastases from colorectal cancer with ratioactive implants .Cancer,1994,73:1800-1804.
[30].Steel GG。 The dose-rate effect: brachytherapy. In: Steel GG, editor Bacic clinical radiooiology. 2"' London: Edward Arnold 1997 163-172.
[31] Dewey WC, Ling CC, Meyn RE. Radiation-induced apoptosis: relevance to radiotherapy. Int JRadiat Oncol Biol Phys, 1995, 33: 781-796.
[32] Tsujimoto Y, Shimizu S, Eguchi Y, et al. Bcl-2 and Bcl-Xlblock apoptosis as well as necrosis:possible involvement of common mediators in apoptotic necrotic signal transduction pathways. Leukemia. 1997;11{suppl 3):380-387
[33] Elizabeth Y, Yang E, Korsmeyer SJ, et al. Molecular thantopsis: a discourse on the bcl-2 family and cell death. Blood, 1996,88:386-401 [34 ] Del Poeta G, VendittiA, Del PrincipeM I, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio p redicts outcome in acute myeloid leukemia (AML ) [ J ]. Blood, 2003, 101 ( 6 ) :2125-2131.
[35] Narayan S, Chandra J, Sharma M, et al. Exp ression of apoptosisRegulatorsBcl-2 and Bax in childhood acute lymphoblastic leukemia[ J ]. Hematology, 2007, 12 (1) : 39-43.
[36] Reed JC. Double identity for proteins of the Bcl-2 family. Nature,1997,387:773-776.
[37] Oshikawa T, Okamoto M, Ahmed SU, et al. The relationship between gene exp ression of Bcl-2 and Bax and the therapeutic effectin oral cancer patients [ J ]. Gan ToKagaku Ryoho, 2006, 33(12) : 1723-1725.
[38] Adhya AK, Srinivasan R, Patel FD, at el. Radiation therapy induced changes in apoptosis and its major regulatory p roteins, Bcl-2, Bcl-XL, and Bax, in locally advanced invasive squamous cell carcinoma of the cervix[ J ]. Int J Gynecol Pathol, 2006, 25 ( 3) :281-287.
[39] 杨连君,王文亮,司晓辉. 肝细胞癌细胞凋亡相关蛋白Bcl - 2 和 bax 的表达及意义[J ] . 中国肿瘤临床,2001 ,28(6) : 411
[40] 郭琳琅,曹长安,郭颖等. 肝硬变和肝癌组织bcl - 2 及相关蛋白 bax 的表达意义[J ] . 实用癌症杂志,1999 ,13(3) :204
[41] Pizem J ,Marolt VF ,Luzar B ,et al . Proliferative and apoptotic activity in hepatocellular carcinoma and surrounding non - neoplastic liver tissue[J ] . Pflugers Arch ,2001 ,442(6 Suppl 1) :R174
[42] Mullerat J,Deroide F,Winslet MC,et al.Proliferation and P53 expression in anal cancer precursor lesions [J」。Anticancer Res,2003,23(3C):2995-2999.
[43] Liu M,lawson G,Delos M,etal.Predictive value of the action Of cancer cells immuno1abeled for proliferating Cell nuclear antigen or Ki67 in bioPsies Of head and neck carcinomas to identify lymPh node metastasis :comParison with clinical and radiologic examinations[J].Head Neck,2003,25(4):280-288.
[44]韩圣华,黄建富.肝细胞癌Ki67抗原表达以及意义。中国普通外科杂志,2000,9(1):42-43
[45]PeterC,RakeshKJ.Angiogenesis in cancer and other disease.Nature,2000,407:249-257.
[46] Pervan M, Pajonk F, Sun JR, et al. Molecular pathways that modify tumor radiation response. Am J Clin Oncol, 2001, 24(5): 481-485
[47] Kim JY, Cho HY, Lee KC, et al. Tumor apoptosis in cervical cancer: its role as a prognostic factor in 42 radiotherapy patients .Int J Cancer, 2001,96(5): 305-312 11.WithersHR: Radiation biology and trearment options in radiation oncology. Cancer Tes, suppl, 1999, 59:1676s
[48]李为苏,刘福坤,陈忠豪,等.术前放射治疗对直肠癌血管生成的影响.中 华普通外科杂志 2004 19 (6): 331-333
[49] Folkman J. What is the evidence that tumors are angiogenesis dependent? Nat J CancerInst,1990, 82 (1): 4 一 6.
[50] Bicknell R, Harris AJ. Novel growth regulatory factors and tumor angiogenesis. EurJ Cancer, 1991,27(6): 781 一 784.
[51] Ivshikawa F, Miyazono K, Hellman U, et al. Identification of angiogenic activity and the cloning and expression of platelet 一 derived endothelial growth factor.Nature, 1989, 338 (6216): 557 一 562
[52] 马旺扣,洛永基,曹钟华,等.125 碘粒子组织内放疗在肿瘤外科中的应用. 陕西肿瘤医学,2002,10(4):241-245.
[53] 邵庆华,罗开元,杨镛,等.胃肠道恶性肿瘤根治术中 碘-125 放射性粒子近距离治疗疗效观察. 中国实用外科杂志,2002,22(9):541-542.
[1] Lee WR,McQuellon RP, Harris Henderson K, et al. Apreliminary analysis of health related quality of life in the first year after permanent source interstitial brachytherap (PIB)for clinically localized prostate cancer.In J Radiat Oncol Biol Phys,2000,46:77-81.
[2] 李力军,马林,吕大鹏,等.现代高新技术治疗恶性肿瘤[M] .北京:人民军医出版社,2003,133~153.
[3] 尹伯元.临床核素治疗学[M].北京:人民军医出版社,2003,169~180.
[4] 王俊杰,唐劲天,黎功.放射性粒子近距离治疗肿瘤[M].北京:北京医科大学出版社,2001.112~124.
[5] Pommer P,Delannes M,Lefloch O,et al.The French preliminary experience of the use of a seed-projector for exclusive iodine 125 Prostate brachytheray :feasibility and acute toxicity [J] . Cancer Radiother ,2006,9:5.
[6] 潘中允,放射性核素治疗学.[北京]人民军医出版[M].2006,451.
[7] Ragde H , Grado GL ,Nadir BS.Brachytheray for clinically localized prostate cancer thirteen-year disease –free survical of 769 consecutive prostate cancer patients treated with permanent implants alone.Arch Esp Urol 2001,54(3):739-747.
[8] Sharkey ,Cantor A ,Sole Z ,et al .Brachytheray versus radical prostatectomy in patient with clinically localized prostate cancer Curr Urol Rep,2002,3 250-257.
[9] Merrick GS,Butter WM,Dorsey AT,et a1. Seed fixity in the prostate/Reriprostic region following brachytherapy[J]。 Int J Radiat Oncol Biol Phys,2000,46(1):215-240.
[10] Zelefsky MJ,Hollister T, Raben A, et al. Five-year biochemical outcome And toxicity with transperineal CT-panned permanent I-125 prostate implantation for patients with localized prostate cancer.Int J Radiat Oncol Bio Phys,2001,47:1261-1266.
[11] Livsey J,Cowan RA,Wylie JP,et al. Hypofractionated conformal radio-Therapy incarcinoma of the prostate:five-year outcome analysis. Int J Radiat Oncol Bio Phys,2003,57:1254-1259.
[12] Blasko JC, Grimm PD, Sylvester JE,etal.Palladium-103 brachytherap For prostate carcinoma. Int J Radiat Oncol Bio Phys,2000,46:839-850.
[13] Larson DA, Suplica JM,Chang SM, Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme. Neuro-oncol.2004 April,6(2):119-126
[14] Wilkowski R,Thoma M,Duhmke E, et al.Concurrent chemoradiotherapy withgemcitabine and cisplatin after incomplete (R1) resection of locally advanced pancreatic carcinoma. Int J Radiat Oncol Biol Phys,2004,58(3):768-772.
[15] Martinez-Monge R, Nag S, Nieroda CA, et al. Iodione-125 Brachytherapy in the treatment of colorectal adenocarcinoma metastasis to the liver. Cancer, 1999, 85(6):1218-1225.
[16] 徐静,梅铭惠,陈谦,等。术中组织间植入 125I 粒子治疗肝恶性肿瘤。中华实验外科杂志,2004,16(1):29-31。
[17] 程宝兴,吴浩荣,吴锦昌。碘-125 组织间植入治疗大鼠移植性肝癌的实验研究。苏州大学学报,2002,22:13-16。
[18] 邵文博,宋金龙等。l25I粒子近距离照射对BEL一7402肝癌细胞增殖和细胞周期的影响。中国医学物理学杂志,2005,22(4):567。
[2] Pisani P , Parkin DM , Bray F , et al.Estimates of worldwide mortality from25cancers in 1990.Int J Caner,1999,83:18-29.,
[3]Ono Y ,YoshikagaR, et al .Long term results of lipidol transcatheter arteial embolizationwith cisplatin or doxorubicin for unrect hepatocellular carcinomas.Am J Clin Oncol,2000,23(6):564-568
[4]Seong J,Keum KC,HanKH,eta1.Combined transcatheter arterial chemombolieation and Iocaj radiotherapy of unresectable hepatpcdlnler Carcinoma.Int J Radiat oncol Biol phys,1999,43:393—397.
[5]李玉,闫英,张波,等.适形放射治疗结合介入治疗不宜手术的原发性肝癌.中华放射肿瘤学杂志.2003,12(1):30
[6] Lee WR,McQuellon RP,Harris Henderson K,etal. Apreliminary analysis of health related quality of life in the first year after permanent source interstitial brachytherap (PIB)for clinically localized prostate cancer.In J Radiat Oncol Biol Phys,2000,46:77-81.
[7]李力军,马林,吕大鹏,等.现代高新技术治疗恶性肿瘤[M].北京:人民军医出版社,2003,133~153.
[8] 尹伯元.临床核素治疗学[M].北京:人民军医出版社,2003,169~180.
[9] 王俊杰,唐劲天,黎功.放射性粒子近距离治疗肿瘤[M].北京:北京医科大学出版社,2001.112~124.
[10]Lazarescu GR,Batfista JJ.AⅡal ￡s of the radiobiology of Ytterbium一1 69 and Iodine一125 perrllaDeD1- braehytherapy implants[J].Phys Med Bio1.1997 42:1727-1736.
[11]Ling CC . Permanent implams using Au — l98 , Pd 一 53 and I-125.Radiohiological considerations based on the linear quadratic model[J] Int J Radiat Oncol Biol Phys.1992 23 81—87.
[12]Ragde ,KorbLJ,ElgamalAA,etal 。 Modern prostate Brachytherapy prostate specific antigen results in patients with up to 12 years of observed follow-up[J]Cancer,2000,89(1):135~141
[13]罗开元,李 波,杨 嵘,等 1125I 粒子组织间放射治疗恶性肿瘤的临床应用[J] 中华医学杂志,2001,81(12):754~755
[14]罗开元,郑江华,李 波,等 1125I 粒子永久性植入组织间放射治疗肝癌[J] 肝胆胰外科杂志,2004,16(1):29~31
[15]宋金龙,邵文博,唐宪民 1125I 粒子近距离照射治疗原发性肝癌的实验研究[J] 肿瘤防治杂志,2005,12(10):750~752 [16」李勇,冯贤松.i2s1 粒子术中植入治疗腹腔恶性肿瘤.腹部外科杂志,2005, 18(2):96-97
[17] Martinez-Monge R, Nag S, Nieroda CA, et al. Iodione-125 Brachytherapy in the treatment of colorectal adenocarcinoma metastasis to the liver. Cancer, 1999, 85(6):1218-1225.
[18] 徐静,梅铭惠,陈谦,等。术中组织间植入 125I 粒子治疗肝恶性肿瘤。中华实验外科杂志,2004,16(1):29-31。
[19] 程宝兴,吴浩荣,吴锦昌。碘-125 组织间植入治疗大鼠移植性肝癌的实验研究。苏州大学学报,2002,22:13-16。
[20] Williamson JF, Coursey BM, DeWara LA, et al. Guidence to users of Nycomed Amersham and North American Acientific, Inc. I-125 interstitial sources:dosinietry and calibration changes: Recommendations of the American Association of physicists in Medicine Radiation Therapy Committee Ad Hoc Subcommittee on low-energy. Med Phys, 1999, 26: 570-573
[21]徐静,梅铭惠,陈谦,等.术中组织间植入 125 I 粒子治疗肝恶性肿瘤。中华实 验外科杂志,2005 , 22 : 368-369
[22]罗开元,郑江华,李波,等. 125 I 粒子永久性植入组织间放射治疗肝癌。肝胆 胰外科杂志,2004, 16:29-31
[23] Donath D, Nori D, Turnbull A, et al. Brachytherapy in the treatment of solitary colorectal metastases to the liver. J Surg. Onco1,1990, 44:55-61
[24] Blasko JC, et al. Prostate specific antigen based disease control following ultrasound guider 125 I implantation T1/T2 prostate carcinoma. J Urol, 1995,154: 1096-1099.
[25] Hilaris BS, et al. Value of perioperative branchtherapy in the management of non-oat cell carcinoma of the lung. Int J Radiat Oncol Biol Phys, 1983, 9: 1161-1166.
[26] Peretz T, et al. Treatment of primary unresectable carcinoma of the pancreas with125 implantation. Int J Radiat Oncol Biol Phys, 1989, 17: 931-935.
[27] Martinez, et al.125I brachytherapy for colorectal adenocarcinoma recurrent in the pelvis and paraortics. Int J Radiat Oncol Biol Phys, 1998, 41: 545-550.
[28] Kreth FW, et al. Interstitial radiosurgery of low-grade gliomas. J Neurosurg , 1995, 82:418-429.
[29] Arstrong JG,et al. Treatment of liver metastases from colorectal cancer with ratioactive implants .Cancer,1994,73:1800-1804.
[30].Steel GG。 The dose-rate effect: brachytherapy. In: Steel GG, editor Bacic clinical radiooiology. 2"' London: Edward Arnold 1997 163-172.
[31] Dewey WC, Ling CC, Meyn RE. Radiation-induced apoptosis: relevance to radiotherapy. Int JRadiat Oncol Biol Phys, 1995, 33: 781-796.
[32] Tsujimoto Y, Shimizu S, Eguchi Y, et al. Bcl-2 and Bcl-Xlblock apoptosis as well as necrosis:possible involvement of common mediators in apoptotic necrotic signal transduction pathways. Leukemia. 1997;11{suppl 3):380-387
[33] Elizabeth Y, Yang E, Korsmeyer SJ, et al. Molecular thantopsis: a discourse on the bcl-2 family and cell death. Blood, 1996,88:386-401 [34 ] Del Poeta G, VendittiA, Del PrincipeM I, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio p redicts outcome in acute myeloid leukemia (AML ) [ J ]. Blood, 2003, 101 ( 6 ) :2125-2131.
[35] Narayan S, Chandra J, Sharma M, et al. Exp ression of apoptosisRegulatorsBcl-2 and Bax in childhood acute lymphoblastic leukemia[ J ]. Hematology, 2007, 12 (1) : 39-43.
[36] Reed JC. Double identity for proteins of the Bcl-2 family. Nature,1997,387:773-776.
[37] Oshikawa T, Okamoto M, Ahmed SU, et al. The relationship between gene exp ression of Bcl-2 and Bax and the therapeutic effectin oral cancer patients [ J ]. Gan ToKagaku Ryoho, 2006, 33(12) : 1723-1725.
[38] Adhya AK, Srinivasan R, Patel FD, at el. Radiation therapy induced changes in apoptosis and its major regulatory p roteins, Bcl-2, Bcl-XL, and Bax, in locally advanced invasive squamous cell carcinoma of the cervix[ J ]. Int J Gynecol Pathol, 2006, 25 ( 3) :281-287.
[39] 杨连君,王文亮,司晓辉. 肝细胞癌细胞凋亡相关蛋白Bcl - 2 和 bax 的表达及意义[J ] . 中国肿瘤临床,2001 ,28(6) : 411
[40] 郭琳琅,曹长安,郭颖等. 肝硬变和肝癌组织bcl - 2 及相关蛋白 bax 的表达意义[J ] . 实用癌症杂志,1999 ,13(3) :204
[41] Pizem J ,Marolt VF ,Luzar B ,et al . Proliferative and apoptotic activity in hepatocellular carcinoma and surrounding non - neoplastic liver tissue[J ] . Pflugers Arch ,2001 ,442(6 Suppl 1) :R174
[42] Mullerat J,Deroide F,Winslet MC,et al.Proliferation and P53 expression in anal cancer precursor lesions [J」。Anticancer Res,2003,23(3C):2995-2999.
[43] Liu M,lawson G,Delos M,etal.Predictive value of the action Of cancer cells immuno1abeled for proliferating Cell nuclear antigen or Ki67 in bioPsies Of head and neck carcinomas to identify lymPh node metastasis :comParison with clinical and radiologic examinations[J].Head Neck,2003,25(4):280-288.
[44]韩圣华,黄建富.肝细胞癌Ki67抗原表达以及意义。中国普通外科杂志,2000,9(1):42-43
[45]PeterC,RakeshKJ.Angiogenesis in cancer and other disease.Nature,2000,407:249-257.
[46] Pervan M, Pajonk F, Sun JR, et al. Molecular pathways that modify tumor radiation response. Am J Clin Oncol, 2001, 24(5): 481-485
[47] Kim JY, Cho HY, Lee KC, et al. Tumor apoptosis in cervical cancer: its role as a prognostic factor in 42 radiotherapy patients .Int J Cancer, 2001,96(5): 305-312 11.WithersHR: Radiation biology and trearment options in radiation oncology. Cancer Tes, suppl, 1999, 59:1676s
[48]李为苏,刘福坤,陈忠豪,等.术前放射治疗对直肠癌血管生成的影响.中 华普通外科杂志 2004 19 (6): 331-333
[49] Folkman J. What is the evidence that tumors are angiogenesis dependent? Nat J CancerInst,1990, 82 (1): 4 一 6.
[50] Bicknell R, Harris AJ. Novel growth regulatory factors and tumor angiogenesis. EurJ Cancer, 1991,27(6): 781 一 784.
[51] Ivshikawa F, Miyazono K, Hellman U, et al. Identification of angiogenic activity and the cloning and expression of platelet 一 derived endothelial growth factor.Nature, 1989, 338 (6216): 557 一 562
[52] 马旺扣,洛永基,曹钟华,等.125 碘粒子组织内放疗在肿瘤外科中的应用. 陕西肿瘤医学,2002,10(4):241-245.
[53] 邵庆华,罗开元,杨镛,等.胃肠道恶性肿瘤根治术中 碘-125 放射性粒子近距离治疗疗效观察. 中国实用外科杂志,2002,22(9):541-542.
[1] Lee WR,McQuellon RP, Harris Henderson K, et al. Apreliminary analysis of health related quality of life in the first year after permanent source interstitial brachytherap (PIB)for clinically localized prostate cancer.In J Radiat Oncol Biol Phys,2000,46:77-81.
[2] 李力军,马林,吕大鹏,等.现代高新技术治疗恶性肿瘤[M] .北京:人民军医出版社,2003,133~153.
[3] 尹伯元.临床核素治疗学[M].北京:人民军医出版社,2003,169~180.
[4] 王俊杰,唐劲天,黎功.放射性粒子近距离治疗肿瘤[M].北京:北京医科大学出版社,2001.112~124.
[5] Pommer P,Delannes M,Lefloch O,et al.The French preliminary experience of the use of a seed-projector for exclusive iodine 125 Prostate brachytheray :feasibility and acute toxicity [J] . Cancer Radiother ,2006,9:5.
[6] 潘中允,放射性核素治疗学.[北京]人民军医出版[M].2006,451.
[7] Ragde H , Grado GL ,Nadir BS.Brachytheray for clinically localized prostate cancer thirteen-year disease –free survical of 769 consecutive prostate cancer patients treated with permanent implants alone.Arch Esp Urol 2001,54(3):739-747.
[8] Sharkey ,Cantor A ,Sole Z ,et al .Brachytheray versus radical prostatectomy in patient with clinically localized prostate cancer Curr Urol Rep,2002,3 250-257.
[9] Merrick GS,Butter WM,Dorsey AT,et a1. Seed fixity in the prostate/Reriprostic region following brachytherapy[J]。 Int J Radiat Oncol Biol Phys,2000,46(1):215-240.
[10] Zelefsky MJ,Hollister T, Raben A, et al. Five-year biochemical outcome And toxicity with transperineal CT-panned permanent I-125 prostate implantation for patients with localized prostate cancer.Int J Radiat Oncol Bio Phys,2001,47:1261-1266.
[11] Livsey J,Cowan RA,Wylie JP,et al. Hypofractionated conformal radio-Therapy incarcinoma of the prostate:five-year outcome analysis. Int J Radiat Oncol Bio Phys,2003,57:1254-1259.
[12] Blasko JC, Grimm PD, Sylvester JE,etal.Palladium-103 brachytherap For prostate carcinoma. Int J Radiat Oncol Bio Phys,2000,46:839-850.
[13] Larson DA, Suplica JM,Chang SM, Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme. Neuro-oncol.2004 April,6(2):119-126
[14] Wilkowski R,Thoma M,Duhmke E, et al.Concurrent chemoradiotherapy withgemcitabine and cisplatin after incomplete (R1) resection of locally advanced pancreatic carcinoma. Int J Radiat Oncol Biol Phys,2004,58(3):768-772.
[15] Martinez-Monge R, Nag S, Nieroda CA, et al. Iodione-125 Brachytherapy in the treatment of colorectal adenocarcinoma metastasis to the liver. Cancer, 1999, 85(6):1218-1225.
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