~（125）I粒子组织间植入对人胃癌裸鼠皮下移植瘤微血管的影响
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摘要
胃癌是危害人类健康的常见消化道肿瘤之一,目前治疗方法主要是以手术切除为主,结合化疗、放疗等综合治疗。但多数胃癌患者确诊时已属晚期,手术后50%病人死于腹腔复发转移,化放疗治疗效果不佳,预后较差,因此,在医学界不断探索新的治疗方法。由于受到正常胃组织耐受剂量的限制,无法达到胃癌外放疗根治剂量,以致胃癌的放射治疗应用很有限。腹腔复发转移的治疗是临床医生最棘手的问题。放射性125I粒子组织间植入是近距离放疗的一种较新的治疗手段,是指将放射源植入肿瘤内或受肿瘤侵犯组织中,通过其持续发出低能量γ射线,具有对靶区肿瘤产生高剂量杀伤作用,对周围正常组织损伤小,易防护等优势,使肿瘤组织受到最大程度毁灭性杀伤,而正常组织不损伤或损伤轻微。在临床应用中已经取得了较为理想的治疗效果,但对于其基础研究较少。我们在这方面进行了动物实验研究,主要观察125I放射性粒子对肿瘤血管作用的形态变化,以及相关免疫组织化学研究,初步探讨125I放射性粒子的作用机制。
第一部分
125I粒子植入对人胃癌裸鼠皮下移植瘤微血管作用的形态观察
目的:观察125I粒子植入对人胃癌裸鼠皮下移植瘤微血管形态的影响。
方法:建立人胃低分化腺癌BGC-823细胞裸鼠皮下移植瘤模型40只,按随机数字表随机分为实验组和对照组,实验组植入125I粒子,根据计算机三维治疗计划系统,周边剂量为120Gy,对照组植入冷源粒子。粒子植入后第15d、第30d时进行组织取材、固定、切片等,光镜、电镜下观察裸鼠皮下移植瘤微血管结构的变化。
结果:对照组见肿瘤细胞微血管数目多,血管内皮细胞结构明显,弹性结缔组织层清晰;电镜下见血管腔面微绒毛结构完整、吞引小泡数目多。实验组见肿瘤细胞微血管数目减少;血管内皮细胞增生、肿大、脱落;电镜下见血管腔内微绒毛数目减少,线粒体嵴融合、粗面内质网吞引小泡数量减少等结构改变。第15d和30d对照、实验组组内肿瘤微血管结构变化不明显。
结论:125I粒子植入直接破坏移植瘤微血管结构,影响移植瘤微血管生成。
第二部分
125I粒子组织间放疗对人胃癌裸鼠移植瘤细胞VEGF,MVD表达的影响
目的:初步探讨125I粒子植入对人胃癌细胞血管内皮生长因子(VEGF)、组织内微血管密度(MVD)表达的影响。方法:建立人胃低分化腺癌BGC-823细胞裸鼠皮下移植瘤模型40只,按随机数字表随机分为实验组和对照组,实验组植入125I粒子,根据计算机三维治疗计划系统,周边剂量为120Gy,对照组植入冷源粒子,粒子植入后第15d、第30d,免疫组化检测CD34标记的微血管密度计数(MVD)及血管内皮生长因子(VEGF)的表达情况。
结果:第15d、30d对照组和实验组胃癌移植瘤微血管数MVD分别为:12.7±0.68个/0.72mm2、(13.5±0.97)个/0.72mm2、(7.6±0.63)个/0.72mm2和3.9±0.87个/0.72mm2;15d、30d对照组的血管内皮生长因子VEGF阳性数分别为6、6,15d、30d实验组VEGF阳性数分别为3、2。实验组与对照组第15d、30d组间差异均有统计学意义(P<0.05)。第15d与第30d组内比较差异无统计学意义。(P>0.05)。
结论:125I粒子植入可抑制肿瘤细胞VEGF的表达,具有抑制肿瘤微血管生成的作用。
The gastric tumor is one of the most digestive tract tumor which does great harm to health of the people. At present, surgical operation is a main procedure which is often combined with other methods in order to improve therapeutic efficacy. The disease is charactered with poor prognosis and higher metastasis and higher mortality. So the medical workers are looking for novel therapeutic methods all the time. because cure dosage of external irradiation is very higher than tolerance dosage of normal gastric body. The application of radiotherapy is limited,interstitial implantation of radioactive Iodine-125 seeds,one kind of brachytherapy,is a good method which can greatly injury tumor by implanting radioactive microsources which can irradiateγrays with low capacity continuously. It has many advantages:strong damage on tumor whereas normal tissue is not or slightly injured. There has derived dream therapeutic efficacy in clinical application. But its study of underlaying is less. We study on it through animal experiment and principal review radioactive iodine-125 seeds effective for tumor vessel. At the same time,the mechanism of radioactive iodine-125 seeds is explored preliminarily.
PartⅠThe microvessel influence of interstitial brachytherapy with 125I seeds in the stomach cancer bare mouse transplant lump
Objective: To observes the morphological influence of interstitial brachytherapy with 125I seeds on the microvessel in nude mice with the human gastric tumor
Methods: 40 nude mice models of the human gastric poorly differentiated gland BGC-823 cell tumor were established first through the injection of the cells into nude mice subcutaneously. Mice were divided into treated group and control group randomly,The 125I seeds were implanted into the tumors according to the treatment plan defined by the computer three dimensional treatment planning system (TPS) in treated group,with a prescription dose of 120 Gy. The control group was given the implantation with cold seeds. The structure of the microvessel was observed by the light microscope and electron microscope at the 15th day and the 30th day after 125I seeds implantation.
Results:In the control group the number of microvessel was multitude; the vascular endothelial cell structure was manifest. The microvilli of lumen of blood vessel structure was integrity; the number of micropinocytotic vesicles was multitude on the electron microscope ; In the treated group the number of microvessel decreased obviously,the vascular endothelial cell proliferation,tumescent,felled off. The microvilli reduced,the line plastochondria was fusion,the number of micropinocytotic vesicles in the rough endoplasmic reticulum,the connective tissue become thinner on the electron microscope. There was not manifest structure change of tumors micrangium between control group and treated group after 15 days and 30days.
Conclusions:The 125I seeds implantation can destruct tumor microvessel structure directly,which can inhibit the formation and growth of microvessel.
PartⅡThe influence of expressions of VEGF and MVD for interstitial brachytherapy with 125I seeds in the stomach cancer bare mouse transplant lump
Objective:To observed the influence of expressions of VEGF and MVD for interstitial brachytherapy with 125I seeds on the cancer cell in nude mice with the human gastric tumor
Methods:40 nude mice models of the human gastric poorly differentiated gland BGC-823 cell tumor were established first through the injection of the cells into nude mice subcutaneously. Mice were divided into treated group and control group randomly,The 125I seeds were implanted into the tumors according to the treatment plan defined by the computer three dimensional treatment planning system (TPS) in treated group,with a prescription dose of 120 Gy. The control group was given the implantation with cold seeds. The expression of VEGF and MVD which signed with CD34 were detected by immunohistochemistry at the 15th day and the 30th day after 125I seeds implantation.
Results:The expression of MVD of control group and treated group after 15 days and 30days were (12.7±0.68) piece/0.72mm2、(13.5±0.97)piece /0.72mm2、(7.6±0.63)piece /0.72mm2 and 3.9±0.87piece/0.72mm2;The expression of VEGF of control group after 15 days and 30days,the positive cell were 6、6,and The expression of VEGF of treated group after 15 days and 30days,the positive cell were 3、2. The expressions of VEGF and MVD in control group were lower than the treated group at the 15th day and the 30th day (P<0.05),but there was no statistically significant differences in same group at two time(P>0.05).
Conclusions:The expressions of VEGF in tumor are suppressed,and the 125I seeds implantation has the anti-tumor capillaries production function which can inhibit the formation and growth of microvessel.
第一部分
125I粒子植入对人胃癌裸鼠皮下移植瘤微血管作用的形态观察
目的:观察125I粒子植入对人胃癌裸鼠皮下移植瘤微血管形态的影响。
方法:建立人胃低分化腺癌BGC-823细胞裸鼠皮下移植瘤模型40只,按随机数字表随机分为实验组和对照组,实验组植入125I粒子,根据计算机三维治疗计划系统,周边剂量为120Gy,对照组植入冷源粒子。粒子植入后第15d、第30d时进行组织取材、固定、切片等,光镜、电镜下观察裸鼠皮下移植瘤微血管结构的变化。
结果:对照组见肿瘤细胞微血管数目多,血管内皮细胞结构明显,弹性结缔组织层清晰;电镜下见血管腔面微绒毛结构完整、吞引小泡数目多。实验组见肿瘤细胞微血管数目减少;血管内皮细胞增生、肿大、脱落;电镜下见血管腔内微绒毛数目减少,线粒体嵴融合、粗面内质网吞引小泡数量减少等结构改变。第15d和30d对照、实验组组内肿瘤微血管结构变化不明显。
结论:125I粒子植入直接破坏移植瘤微血管结构,影响移植瘤微血管生成。
第二部分
125I粒子组织间放疗对人胃癌裸鼠移植瘤细胞VEGF,MVD表达的影响
目的:初步探讨125I粒子植入对人胃癌细胞血管内皮生长因子(VEGF)、组织内微血管密度(MVD)表达的影响。方法:建立人胃低分化腺癌BGC-823细胞裸鼠皮下移植瘤模型40只,按随机数字表随机分为实验组和对照组,实验组植入125I粒子,根据计算机三维治疗计划系统,周边剂量为120Gy,对照组植入冷源粒子,粒子植入后第15d、第30d,免疫组化检测CD34标记的微血管密度计数(MVD)及血管内皮生长因子(VEGF)的表达情况。
结果:第15d、30d对照组和实验组胃癌移植瘤微血管数MVD分别为:12.7±0.68个/0.72mm2、(13.5±0.97)个/0.72mm2、(7.6±0.63)个/0.72mm2和3.9±0.87个/0.72mm2;15d、30d对照组的血管内皮生长因子VEGF阳性数分别为6、6,15d、30d实验组VEGF阳性数分别为3、2。实验组与对照组第15d、30d组间差异均有统计学意义(P<0.05)。第15d与第30d组内比较差异无统计学意义。(P>0.05)。
结论:125I粒子植入可抑制肿瘤细胞VEGF的表达,具有抑制肿瘤微血管生成的作用。
The gastric tumor is one of the most digestive tract tumor which does great harm to health of the people. At present, surgical operation is a main procedure which is often combined with other methods in order to improve therapeutic efficacy. The disease is charactered with poor prognosis and higher metastasis and higher mortality. So the medical workers are looking for novel therapeutic methods all the time. because cure dosage of external irradiation is very higher than tolerance dosage of normal gastric body. The application of radiotherapy is limited,interstitial implantation of radioactive Iodine-125 seeds,one kind of brachytherapy,is a good method which can greatly injury tumor by implanting radioactive microsources which can irradiateγrays with low capacity continuously. It has many advantages:strong damage on tumor whereas normal tissue is not or slightly injured. There has derived dream therapeutic efficacy in clinical application. But its study of underlaying is less. We study on it through animal experiment and principal review radioactive iodine-125 seeds effective for tumor vessel. At the same time,the mechanism of radioactive iodine-125 seeds is explored preliminarily.
PartⅠThe microvessel influence of interstitial brachytherapy with 125I seeds in the stomach cancer bare mouse transplant lump
Objective: To observes the morphological influence of interstitial brachytherapy with 125I seeds on the microvessel in nude mice with the human gastric tumor
Methods: 40 nude mice models of the human gastric poorly differentiated gland BGC-823 cell tumor were established first through the injection of the cells into nude mice subcutaneously. Mice were divided into treated group and control group randomly,The 125I seeds were implanted into the tumors according to the treatment plan defined by the computer three dimensional treatment planning system (TPS) in treated group,with a prescription dose of 120 Gy. The control group was given the implantation with cold seeds. The structure of the microvessel was observed by the light microscope and electron microscope at the 15th day and the 30th day after 125I seeds implantation.
Results:In the control group the number of microvessel was multitude; the vascular endothelial cell structure was manifest. The microvilli of lumen of blood vessel structure was integrity; the number of micropinocytotic vesicles was multitude on the electron microscope ; In the treated group the number of microvessel decreased obviously,the vascular endothelial cell proliferation,tumescent,felled off. The microvilli reduced,the line plastochondria was fusion,the number of micropinocytotic vesicles in the rough endoplasmic reticulum,the connective tissue become thinner on the electron microscope. There was not manifest structure change of tumors micrangium between control group and treated group after 15 days and 30days.
Conclusions:The 125I seeds implantation can destruct tumor microvessel structure directly,which can inhibit the formation and growth of microvessel.
PartⅡThe influence of expressions of VEGF and MVD for interstitial brachytherapy with 125I seeds in the stomach cancer bare mouse transplant lump
Objective:To observed the influence of expressions of VEGF and MVD for interstitial brachytherapy with 125I seeds on the cancer cell in nude mice with the human gastric tumor
Methods:40 nude mice models of the human gastric poorly differentiated gland BGC-823 cell tumor were established first through the injection of the cells into nude mice subcutaneously. Mice were divided into treated group and control group randomly,The 125I seeds were implanted into the tumors according to the treatment plan defined by the computer three dimensional treatment planning system (TPS) in treated group,with a prescription dose of 120 Gy. The control group was given the implantation with cold seeds. The expression of VEGF and MVD which signed with CD34 were detected by immunohistochemistry at the 15th day and the 30th day after 125I seeds implantation.
Results:The expression of MVD of control group and treated group after 15 days and 30days were (12.7±0.68) piece/0.72mm2、(13.5±0.97)piece /0.72mm2、(7.6±0.63)piece /0.72mm2 and 3.9±0.87piece/0.72mm2;The expression of VEGF of control group after 15 days and 30days,the positive cell were 6、6,and The expression of VEGF of treated group after 15 days and 30days,the positive cell were 3、2. The expressions of VEGF and MVD in control group were lower than the treated group at the 15th day and the 30th day (P<0.05),but there was no statistically significant differences in same group at two time(P>0.05).
Conclusions:The expressions of VEGF in tumor are suppressed,and the 125I seeds implantation has the anti-tumor capillaries production function which can inhibit the formation and growth of microvessel.
引文
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5 Pellizzon AC,Salvajoli JV,Maia MA,et al. Late urinary morbidity with high dose prostate brathytherapy as a boost to conventional extemal beam radiation therapy for local and locally advanced prostste cancer .J Urol,2004,171 (3): 1105~1108
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12 Jansen N,Deneufbourg JM,Nickers P,et al.Adjuvant stereotactic permanent seed breast implant:a boost series in view of partial breast irradiation. Int J Radiat Oncol Biol Phys,2007,67(4):1052~1058
1 Datta K,Weinfeld M,Neumann RD,et al. Neumann RD Determination and analysis of site-specific 125I decay -induced DNA double-strand break end-group structures. Radiat Res. 2007,167(2):152~166
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3 Ohashi T,Yorozu A,Toya K,et al.Rectal morbidity following I-125 prostate brachytherapy in relation to dosimetry.Jpn J Clin Oncol. 2007,37(2):121~126
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1 Guedea F,Ellison T,Venselaar J,et al. Overview of brachytherapy resources in Europe:a survey of patterns of care study for brachytherapy in Europe. Radiother Oncol,2007,82(1):50~54
2 Feinendegen LE,Pollycove M,Neumann RD,et al. Wholebody responses to low-level radiation exposure : new concepts in mammalian radiobiology . Exp Hematol,2007,35(4 Suppl 1):37~46
3 Sudprasert W, Navasumrit P, Ruchirawat M,et al. Effects of low-dose gamma radiation on DNA damage ,chromosomal aberration and expression of repair genes in human blood cells. Int J Hyg Environ Health,2006,209(6):503~511
4 Anglesio S,Calamia E,Fiandra C,et al .Prostate brachy therapy with iodine-125 seeds:radiation protection issues. Tumori,2005,91(4):335~338
5 Pellizzon AC,Salvajoli JV,Maia MA,et al. Late urinary morbidity with high dose prostate brathytherapy as a boost to conventional extemal beam radiation therapy for local and locally advanced prostste cancer .J Urol,2004,171 (3): 1105~1108
6 Stone NN,Stock RG,et al. Long-term urinary,sexual, and rectal morbidity in patients treated with iodine-125 prostate brachytherapy followed up for a minimum of 5 years. Urology,2007,69(2):338~342
7 Bottomley D,Ash D,Al-Qaisieh B,et al. Side effects of permanent 125I prostate seed implants in 667 patients treated in Leeds. Radiother Oncol,2007,82(1):46~49
8 Cattani F,Vavassori A,Polo A,et al.Radiation exposure after permanent prostate brachytherapy .Radiother Oncol, 2006,79(1):65~69
9 Michalski J,Mutic S,Eichlinq J,et al. Radiation exposure to family and household members after prostate brachy therapy. Int J Radiat Oncol Biol Phys,2003,56(3):764~768
10 Julow J,Viola A,Balint K,et al. Image fusion-guided stereotactic iodine-125 interstitial irradiation of inoperable and recurrent gliomas. Prog Neurol Surg,2007,20:303~311
11 Kopp J,Strnad V,Bach AD,et al.Vacuum application incre- -ases therapeutic safety and allows intensified local radiat- -ion treatment of malignant soft-tissue tumors. Strahlenther Onkol,2005,181(2):124~130
12 Jansen N,Deneufbourg JM,Nickers P,et al.Adjuvant stereotactic permanent seed breast implant:a boost series in view of partial breast irradiation. Int J Radiat Oncol Biol Phys,2007,67(4):1052~1058
1 Datta K,Weinfeld M,Neumann RD,et al. Neumann RD Determination and analysis of site-specific 125I decay -induced DNA double-strand break end-group structures. Radiat Res. 2007,167(2):152~166
2 Elmroth K, Stenerl?w B.Influence of chromatin structureon induction of double-strand breaks in mammalian cells irradiated with DNA-incorporated 125I. Radiat Res. 2007,168 (2):175~182
3 Ohashi T,Yorozu A,Toya K,et al.Rectal morbidity following I-125 prostate brachytherapy in relation to dosimetry.Jpn J Clin Oncol. 2007,37(2):121~126
4 Stone NN,Stock RG,White I,et al. Long-term urinary, sexual,and rectal morbidity in patients treated with iodine-125 prostate brachytherapy followed up for a minimum of 5 years. Urology. 2007,69(2):338~342
5 Shakespeare D , Mitchell DM , Carey BM , et al. Recto-urethral fistula following brachytherapy for localized prostate cancer. Colorectal Dis. 2007,9 (4) :328~331
6 Peters CA,Cesaretti JA,Stone NN,et al.Low-dose rate prostate brachytherapy is well tolerated in patients with a history of inflammatory bowel disease. Int J Radiat Oncol Biol Phys. 2006,66(2):424~429
7 Mishra MV,Shirazi R,Barrett WL. Incidence and clinical course of hemorrhagic radiation proctitis after iodine-125 prostate brachytherapy. Clin Genitourin Cancer. 2007,5(6): 397~ 400
8 Zhang FJ, Wu PH, Zhao M,et al.CT guided radioactive seed 125I implantation in treatment of pancreatic cancer. Zhonghua Yi Xue Za Zhi. 2006,86(4):223~227
9 Zhang FJ,Li CX,Wu PH,et al. Radioactive seed 125I implantation in treating recurrence and metastasis after livertransplantation in hepatoma. Zhonghua Yi Xue Za Zhi. 2007,87(14):956~969
10 Julow J,Viola A,Bálint K,et al.Image fusion-guided stere- -otactic iodine-125 interstitial irradiation of inoperable and recurrent gliomas. Prog Neurol Surg. 2007,20:303~311
11 Ellis RJ,Zhou H,Kaminsky DA,et al.Rectal morbidity after permanent prostate brachytherapy with dose escalation to biologic target volumes identified by SPECT/CT fusion. Brachytherapy. 2007,6(2),149~156
12 Kishi K,Takifuji K,Shirai S,et al.Brachytherapy technique for abdominal wall metastases of colorectal cancer : ultrasound-guided insertion of applicator needle and a skin preservation method. Acta Radiol. 2006,47(2):157~161