改良法兔VX2肝移植瘤模型建立及综合治疗的实验研究
摘要
肝癌是我国最常见的恶性肿瘤之一,发病率居第三位。早期肝癌最有效的治疗方法是手术切除。但由于其发病隐匿、就诊较晚及合并肝硬化致肝功能差等原因,手术切除率仅20%-30%。对不能手术切除的中晚期肝癌患者采用微创治疗,仍可取得较好疗效。随着现代物理学技术向医学领域的延伸以及现代影像技术、微电子学、计算机信息处理等在医学领域的应用,微创治疗已成为中晚期肝癌治疗中不可缺少的重要组成部分。肝癌常用的微创治疗可以分成两大类：一类是血管内微创治疗,包括肝动脉灌注化疗(transcatheter arterial infusion, TAI)、肝动脉栓塞(transcatheter arterial embolization,TAE)和肝动脉化疗栓塞(1ranscatheter arterial chemoembolization,TACE);另一类是非血管性微创治疗,包括经皮化学消融和经皮物理消融,前者常用的有经皮穿刺无水乙醇注射(percutaneous ethanol injection therapy, PEI)、经皮穿刺乙酸注射(percutaneous acetic acid injection therapy, PAI),后者包括经皮穿刺微波凝固(percutaneous microwave coagulation therapy,PMCT)、经皮穿刺靶向氩氦刀冷冻消融(percutaneous targeted argon-helium cryoablation, PAHCA)、经皮穿刺射频消融(percutaneous radio-frequency ablation,RFA)、经皮穿刺激光间质热疗(percutaneous laser-induced thermo therapy, LITT)及高强度聚焦超声(high-intensity focused ultrasound,HIFU)等。其中微波凝固、氩氦刀冷冻消融和射频消融在临床上被广泛应用。这三种微创治疗都属于经皮物理消融技术,即采用冷或热效应来杀灭肿瘤细胞,达到“一次性损毁”的治疗效果。所谓“一次性损毁”是指使用该项技术治疗肝癌时能一次性毁灭、杀死其治疗范围内的肿瘤细胞。各种微创技术治疗肝癌各有其优缺点,临床疗效各有千秋。TACE联合PMCT治疗肝癌的效果目前国内外尚无相关实验对比研究的报道。兔VX2肝癌模型是少数建立在大动物身上的肝癌模型,比较适合于肝癌的微创治疗实验研究。其瘤源VX2肿瘤细胞株起源于Shope病毒诱发的兔乳头状瘤衍生的鳞癌,经过72次移植传代后正式建立株,命名为VX2,是目前最为理想的肝癌实验模型之一,被广泛应用于肝癌肿瘤学、肿瘤治疗学、放射生物学、抗癌药物药代动力学及肿瘤影像学等实验研究。本实验研究的目的在于采用数字减影血管造影(digital subtraction angiography,DSA)设备导引下使用Angiotech SKATER穿刺针经皮穿刺接种瘤组织块于肝脏制作兔VX2肝移植瘤模型,并使用经动脉化疗栓塞、微波凝固和经动脉化疗栓塞+微波凝固三种微创治疗技术进行分组治疗,通过对比各组CT测量肿瘤体积、外周血CD3+、CD4+细胞分布、肿瘤组织坏死率比较各自的治疗效果,为临床上正确地选择肝癌综合治疗技术提供理论依据和实验依据。
本研究内容分为两个部分。
第一部分改良法兔VX2肝移植瘤模型的建立
目的：探讨DSA设备导引下经皮穿刺瘤组织块接种法制作兔VX2肝移植瘤模型的可行性
方法：新西兰大白兔50只,DSA设备导引下采用Angiotech SKATER穿刺针经皮穿刺接种瘤组织块于肝脏,14天后行CT平扫评价肿瘤接种成功率,测量肿瘤体积并随机处死10只实验兔进行病理分析。结果：DSA设备导引下经皮穿刺瘤组织块接种法制作兔VX2肝移植瘤模型成功率为100%。
结论：1采用Angiotech SKATER穿刺针经皮穿刺瘤组织块接种法建立兔VX2肝移植瘤模型具有方法简单、成功率高、动物损伤小等特点,能为肝癌临床治疗研究提供成熟的大型实验动物模型。
2兔VX2肝移植瘤为富血管性肿瘤,其供血动脉主要为肝动脉,类似于人类原发性肝癌。病理学上肿瘤为巨块型实体瘤、侵润性生长,血供丰富,类似于巨块型肝癌。
3应用DSA作为穿刺导向设备,尤其是应用C臂CT的特殊功能,可使穿刺定位更加准确,造模成功率高,表明该方法安全可靠
第二部分经导管肝动脉化疗栓塞、经皮微波凝固、经导管肝动脉化疗栓塞+经皮微波凝固对兔VX2肝移植瘤治疗效果对比研究
目的：对比TACE、PMCT、TACE+PMCT三种方法治疗兔VX2肝移植瘤的效果。
方法：取制作成功的肝移植瘤模型30只,随机分为TACE组(A组)、PMCT组(B组)和TACE+PMCT组(C组),每组10只,治疗后第14天对比各组CT测量肿瘤体积、外周血CD3'.CD4.细胞分布、肿瘤组织坏死率。
结果：治疗后14天,C组的肿瘤体积为(0.624±0.031)cm3,明显小于A组(0.799±0.057)cm.和B组(0.858±0.112)cm3,(P<0.05)；C组外周血CD3+细胞百分数为(66.30±1.36)%,明显高于A组(53.34±2.12)%和B组(60.68±1.06)%,(P<0.05)；C组外周血CD4+细胞百分数为(48.19±1.43)%,也明显高于A组(40.21±1.07)%和B组(44.03±0.08)%, (P<0.05)；C组肿瘤组织坏死率明显高于A组和B组, (P<0.05)。
结论：1 TACE.PMCT均可使兔VX2肿瘤产生治疗效果,但单独使用两种治疗后肿瘤仍有残余生存。TACE+PMCT综合治疗是一种安全有效地治疗方法,且优于单一方法的治疗效果,为临床肝癌的综合治疗提供了依据。
2本实验结果进一步证实了PMCT或TACE+PMCT治疗有增强机体免疫功能的作用,且后者对免疫功能的增强作用优于前者。
Liver cancer is one of the most common malignant tumors and has rank in third in our country. Operation is the most effective treatment in liver cancer in early stage.Due to its occult onset, the late visit to doctors combined with cirrhosis leading to bad Liver function, the rate of the surgical operation is only 20%-30%.For unsecetable patients with medium and latter stage liver cancer, microinvasive treatment still can get the good curative effect.Therefore, microinvsive therapy has become an indispensable and important method in the treatment of the later period liver cancer. Frequently the microinvasive treatment to the liver cancer have two main typerone is angio-microinvasive treatment,ineluding the transcatheter arterial infusion(TAI), transcatheter artery embolization (TAE) and transcatheter arterial chemoembolization (TACE).Another is noneangio-microinvasive treatment, including percutaneous chemoablation and percutaneous physicoablation, the former includes percutaneous ethanol injection (PEI) and percutaneous acetic acid injection(PAI), the latter includes percutaneous microwave coagulation therapy(PMCT), percutaneous targeted argon-helium cryoablation(PAHCA), percutaneous radio-frequency ablation(RFA), percutaneous laser-induced thermo therapy(LITT) and high intensity focused ultrasound(HIFU).Among them, PMCT, PAHCA and RFA are widely applied in the clinical.The three kinds of microinvasive therapy belong to percutenous physicoablation techniques, which can destroy or kill tumor cell by cold or hot effect and attain destruction in one time therapeutic outcome.Destruction in one time is defined that the technique can destroy and kill tumor cell in the treatment scope in one time.But for these microinvasive therapy methods, which has the most excellent clinical curative effect is not clear.Currently there is no related experiment contrast research in domestic and international on the therapy effect of TACE combined PMCT on liver cancer.The model of rabbit VX2 liver cancer which was esta-
blished on the big animal is suitable for the experimental study of liver cancer microinvasive treatment.VX2 tumor cell strain is originated from the squamous carcinoma that is derived from the rabbit's papilloma induceing by Shope virus.Through seventy-two times transplantion and passage, VX2 tumor cells formally produce strain. At present, it is one of the best ideal liver cancer experiment models.lt is widely applied in empirical study such as liver oncology, tumor therapeutics, radio-
biology, pharmacokinetics of anticancer drugs and tumor imageology.The purpose of this study is to establish a transplanted model of rabbit VX2 liver tumor using percutaneous puncture tumor tissue pieces inoculation through Angiotech SKATER puncture needle guided by the equipment of digital subtraction angiography(DSA),then treat them by TACE,PMCTand TACE+PMCT seperately, compare the therapy effect through the volume of the tumor, the distribution of CD3+、CD4+ cell in peripheral blood and the necrosis rate of tumor.The study was divided into two parts.
Part 1 The retrofit method of building transplanted model of rabbit liver VX2 tumor
Objective To evaluate the method of establishing a transplanted model of rabbit VX2 liver tumor using percutaneous puncture tumor tissue pieces inoculation guided by the equipment of digital subtraction angiography (DSA). Methods A total of 50 New Zealand white rabbits, VX2 tumor masses were implanted into the liver through Angiotech SKATER percutaneous puncture needle guided by the equipment of DSA. Fourteen days later, using routine scan of CT histopathology to indicate the success rate of the animal model and the condition of tumor.
Results The success rate of percutaneous puncture tumor tissue pieces inoculation to establish rabbit VX2 liver tumor model was 100%.
Conclusion 1 The method of percutaneous puncture tumor tissue pieces inoculation using Angiotech SKATER percutaneous puncture needle to establish rabbit VX2 liver transplanted model is simple, it has high success rate and has little damage to the animal.It is possible to gain a reliable mature transplanted tumor animal model for the study of liver carcinoma therapy.
2 The rabbit VX2 liver transplanted model has abundant bloodsupply, the supply artery was the hepatic artery, similar to human liver cancer. Histopathology indicated that the tumor growth was infiltrated, it has the similar biological features of huge tumor.
3 Guided by the equipment of DSA, especially use the function of C-arm Angiographic CT can allocation exactly, it has high success rate and safe.
Part 2 The threpy effect of TACE,PMCT and TACE+PMCT on transplanted model of rabbit liver VX2 tumor
Objective The rabbit liver transplanted VX2 tumor was treated by trans-catheter arterial chemoembolization (TACE),percutaneous microwave coagulation therapy(PMCT) and TACE+PMCT, then compare the therapy effect.
Methods A total of 30 New Zealand white rabbits with liver transplanted VX2 tumor were randomly divided into three groups,10 for each group.Treated by TACE(group A),PMCT(group B)and TACE+PMCT(group C) seperately. Fourteen days later,compare the volume of the tumor, the distribution of CD3+、CD4+ cell in peripheral blood and the necrosis rate of tumor between each group.
Results Fourteen days after the treatment,the volume of the tumor of group C was (0.624±0.031)cm3,it has significant difference with group A (0.799±0.057)cm3 and group B (0.858±0.112)cm3, (P<0.05).The percentage of CD3+cell in peripheral blood of group C was (66.30±1.36)%, it has significant difference with group A (53.34±2.12)% and group B (60.68±1.06)%, (P<0.05). The percentage of CD4+ cell in peripheral blood of group C was(48.19±1.43)%,it also has significant difference with group A(40.21±1.07)% and group B(44.03±0.08)%, (P<0.05).The necrosis rate of tumor in group C has significant difference with group A and group B (P< 0.05)
Conclusion 1 TACE and PMCT all have therapy effect on rabbit VX2 tumor, but there was many survival tumor cells after singlehanded TACE therapy or singlehanded PMCT therapy and the therapy effect of TACE+PMCT was better than the singlehanded TACE or singlehanded PMCT,it provided evidence to the combined therapy method application in liver cancer clinical therapy.
2 The study confirmed that the PMCT or TACE+PMCT therapy can enhance the immunity, the TACE+PMCT has more advantages.
本研究内容分为两个部分。
第一部分改良法兔VX2肝移植瘤模型的建立
目的：探讨DSA设备导引下经皮穿刺瘤组织块接种法制作兔VX2肝移植瘤模型的可行性
方法：新西兰大白兔50只,DSA设备导引下采用Angiotech SKATER穿刺针经皮穿刺接种瘤组织块于肝脏,14天后行CT平扫评价肿瘤接种成功率,测量肿瘤体积并随机处死10只实验兔进行病理分析。结果：DSA设备导引下经皮穿刺瘤组织块接种法制作兔VX2肝移植瘤模型成功率为100%。
结论：1采用Angiotech SKATER穿刺针经皮穿刺瘤组织块接种法建立兔VX2肝移植瘤模型具有方法简单、成功率高、动物损伤小等特点,能为肝癌临床治疗研究提供成熟的大型实验动物模型。
2兔VX2肝移植瘤为富血管性肿瘤,其供血动脉主要为肝动脉,类似于人类原发性肝癌。病理学上肿瘤为巨块型实体瘤、侵润性生长,血供丰富,类似于巨块型肝癌。
3应用DSA作为穿刺导向设备,尤其是应用C臂CT的特殊功能,可使穿刺定位更加准确,造模成功率高,表明该方法安全可靠
第二部分经导管肝动脉化疗栓塞、经皮微波凝固、经导管肝动脉化疗栓塞+经皮微波凝固对兔VX2肝移植瘤治疗效果对比研究
目的：对比TACE、PMCT、TACE+PMCT三种方法治疗兔VX2肝移植瘤的效果。
方法：取制作成功的肝移植瘤模型30只,随机分为TACE组(A组)、PMCT组(B组)和TACE+PMCT组(C组),每组10只,治疗后第14天对比各组CT测量肿瘤体积、外周血CD3'.CD4.细胞分布、肿瘤组织坏死率。
结果：治疗后14天,C组的肿瘤体积为(0.624±0.031)cm3,明显小于A组(0.799±0.057)cm.和B组(0.858±0.112)cm3,(P<0.05)；C组外周血CD3+细胞百分数为(66.30±1.36)%,明显高于A组(53.34±2.12)%和B组(60.68±1.06)%,(P<0.05)；C组外周血CD4+细胞百分数为(48.19±1.43)%,也明显高于A组(40.21±1.07)%和B组(44.03±0.08)%, (P<0.05)；C组肿瘤组织坏死率明显高于A组和B组, (P<0.05)。
结论：1 TACE.PMCT均可使兔VX2肿瘤产生治疗效果,但单独使用两种治疗后肿瘤仍有残余生存。TACE+PMCT综合治疗是一种安全有效地治疗方法,且优于单一方法的治疗效果,为临床肝癌的综合治疗提供了依据。
2本实验结果进一步证实了PMCT或TACE+PMCT治疗有增强机体免疫功能的作用,且后者对免疫功能的增强作用优于前者。
Liver cancer is one of the most common malignant tumors and has rank in third in our country. Operation is the most effective treatment in liver cancer in early stage.Due to its occult onset, the late visit to doctors combined with cirrhosis leading to bad Liver function, the rate of the surgical operation is only 20%-30%.For unsecetable patients with medium and latter stage liver cancer, microinvasive treatment still can get the good curative effect.Therefore, microinvsive therapy has become an indispensable and important method in the treatment of the later period liver cancer. Frequently the microinvasive treatment to the liver cancer have two main typerone is angio-microinvasive treatment,ineluding the transcatheter arterial infusion(TAI), transcatheter artery embolization (TAE) and transcatheter arterial chemoembolization (TACE).Another is noneangio-microinvasive treatment, including percutaneous chemoablation and percutaneous physicoablation, the former includes percutaneous ethanol injection (PEI) and percutaneous acetic acid injection(PAI), the latter includes percutaneous microwave coagulation therapy(PMCT), percutaneous targeted argon-helium cryoablation(PAHCA), percutaneous radio-frequency ablation(RFA), percutaneous laser-induced thermo therapy(LITT) and high intensity focused ultrasound(HIFU).Among them, PMCT, PAHCA and RFA are widely applied in the clinical.The three kinds of microinvasive therapy belong to percutenous physicoablation techniques, which can destroy or kill tumor cell by cold or hot effect and attain destruction in one time therapeutic outcome.Destruction in one time is defined that the technique can destroy and kill tumor cell in the treatment scope in one time.But for these microinvasive therapy methods, which has the most excellent clinical curative effect is not clear.Currently there is no related experiment contrast research in domestic and international on the therapy effect of TACE combined PMCT on liver cancer.The model of rabbit VX2 liver cancer which was esta-
blished on the big animal is suitable for the experimental study of liver cancer microinvasive treatment.VX2 tumor cell strain is originated from the squamous carcinoma that is derived from the rabbit's papilloma induceing by Shope virus.Through seventy-two times transplantion and passage, VX2 tumor cells formally produce strain. At present, it is one of the best ideal liver cancer experiment models.lt is widely applied in empirical study such as liver oncology, tumor therapeutics, radio-
biology, pharmacokinetics of anticancer drugs and tumor imageology.The purpose of this study is to establish a transplanted model of rabbit VX2 liver tumor using percutaneous puncture tumor tissue pieces inoculation through Angiotech SKATER puncture needle guided by the equipment of digital subtraction angiography(DSA),then treat them by TACE,PMCTand TACE+PMCT seperately, compare the therapy effect through the volume of the tumor, the distribution of CD3+、CD4+ cell in peripheral blood and the necrosis rate of tumor.The study was divided into two parts.
Part 1 The retrofit method of building transplanted model of rabbit liver VX2 tumor
Objective To evaluate the method of establishing a transplanted model of rabbit VX2 liver tumor using percutaneous puncture tumor tissue pieces inoculation guided by the equipment of digital subtraction angiography (DSA). Methods A total of 50 New Zealand white rabbits, VX2 tumor masses were implanted into the liver through Angiotech SKATER percutaneous puncture needle guided by the equipment of DSA. Fourteen days later, using routine scan of CT histopathology to indicate the success rate of the animal model and the condition of tumor.
Results The success rate of percutaneous puncture tumor tissue pieces inoculation to establish rabbit VX2 liver tumor model was 100%.
Conclusion 1 The method of percutaneous puncture tumor tissue pieces inoculation using Angiotech SKATER percutaneous puncture needle to establish rabbit VX2 liver transplanted model is simple, it has high success rate and has little damage to the animal.It is possible to gain a reliable mature transplanted tumor animal model for the study of liver carcinoma therapy.
2 The rabbit VX2 liver transplanted model has abundant bloodsupply, the supply artery was the hepatic artery, similar to human liver cancer. Histopathology indicated that the tumor growth was infiltrated, it has the similar biological features of huge tumor.
3 Guided by the equipment of DSA, especially use the function of C-arm Angiographic CT can allocation exactly, it has high success rate and safe.
Part 2 The threpy effect of TACE,PMCT and TACE+PMCT on transplanted model of rabbit liver VX2 tumor
Objective The rabbit liver transplanted VX2 tumor was treated by trans-catheter arterial chemoembolization (TACE),percutaneous microwave coagulation therapy(PMCT) and TACE+PMCT, then compare the therapy effect.
Methods A total of 30 New Zealand white rabbits with liver transplanted VX2 tumor were randomly divided into three groups,10 for each group.Treated by TACE(group A),PMCT(group B)and TACE+PMCT(group C) seperately. Fourteen days later,compare the volume of the tumor, the distribution of CD3+、CD4+ cell in peripheral blood and the necrosis rate of tumor between each group.
Results Fourteen days after the treatment,the volume of the tumor of group C was (0.624±0.031)cm3,it has significant difference with group A (0.799±0.057)cm3 and group B (0.858±0.112)cm3, (P<0.05).The percentage of CD3+cell in peripheral blood of group C was (66.30±1.36)%, it has significant difference with group A (53.34±2.12)% and group B (60.68±1.06)%, (P<0.05). The percentage of CD4+ cell in peripheral blood of group C was(48.19±1.43)%,it also has significant difference with group A(40.21±1.07)% and group B(44.03±0.08)%, (P<0.05).The necrosis rate of tumor in group C has significant difference with group A and group B (P< 0.05)
Conclusion 1 TACE and PMCT all have therapy effect on rabbit VX2 tumor, but there was many survival tumor cells after singlehanded TACE therapy or singlehanded PMCT therapy and the therapy effect of TACE+PMCT was better than the singlehanded TACE or singlehanded PMCT,it provided evidence to the combined therapy method application in liver cancer clinical therapy.
2 The study confirmed that the PMCT or TACE+PMCT therapy can enhance the immunity, the TACE+PMCT has more advantages.
引文
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