CA4P联合十全大补汤/磁热疗对小鼠H22肝癌移植瘤的实验研究
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摘要
目的1.观察小分子血管破坏药物Combretastatin A4Phosphate (CA4P)与十全大补汤合用对小鼠H22肝癌移植瘤生长的抑制作用,并初步探讨其作用机制。2.观察CA4P联合磁热疗对小鼠H22肝癌移植瘤生长的抑制作用。
方法1.建立小鼠H22肝癌移植瘤模型,将成瘤小鼠随机分成7组：Ⅰ组：CA4P单药组,Ⅱ组：十全大补汤低剂量组,Ⅲ组：十全大补汤高剂量组,Ⅳ组：CA4P+十全大补汤低剂量组,Ⅴ组：CA4P+十全大补汤高剂量组,Ⅵ组：空白对照组。用药期间每3天测量移植瘤长短经,计算移植瘤体积,绘制肿瘤生长曲线,用药28天后颈椎脱臼法处死小鼠,剥离皮下移植瘤称重,计算抑瘤率,评价联合用药效应；HE染色,镜下观察移植瘤组织形态变化；MRI检测肿瘤坏死率；计算免疫脏器指数,流式细胞检测小鼠外周血中CD3+、CD4+、CD8+细胞比率,ELISA试剂盒检测外周血中IL-6、IFN-γ水平,观察联合用药对荷瘤鼠免疫功能的影响。2.建立小鼠H22肝癌移植瘤模型,将小鼠随机分成4组：NS对照组(NS),磁流体热疗组(MFH), CA4P单药组(CA), CA4P联合磁热疗组(CMFH)。用药期间每3天测量移植瘤长短经,计算移植瘤体积,绘制肿瘤生长曲线,用药14天后颈椎脱臼法处死小鼠,剥离皮下移植瘤称重,计算抑瘤率,评价联合用药效应；HE染色,镜下观察移植瘤组织形态变化。
结果1.(1)CA4P联合十全大补汤对移植瘤增长无明显抑制作用,CA4P单药组、十全大补汤低剂量组、十全大补汤高剂量组、CA4P+低剂量组、CA4P+高剂量组各组抑瘤率分别为：4.43%、11.61%、20.46%、2.22%、6.62%。(2)各给药组移植瘤肿瘤坏死率明显增高,十全大补汤低、高剂量联合CA4P较CA4P单药组肿瘤坏死面积增大。(3)各给药组对荷瘤鼠免疫脏器指数无影响,CA4P联合十全大补汤可升高荷瘤鼠外周血CD3+、CD4+、CD8+细胞比率(P<0.05),CA4P可使小鼠血清中IL-6、IFN-γ含量明显升高(P<0.01),联合十全大补汤抑制该调节作用。
2.CA4P、磁热疗可抑制移植瘤生长,CA4P联合磁热疗组抑瘤作用明显增强(P<0.01),CA、MFH、CMFH各组抑瘤率分别为：42.3%、63.3%、82.54%。HE染色示各治疗组肿瘤坏死区增大,CMFH组肿瘤坏死最为明显。
结论1.(1)CA4P联合十全大补汤可促进移植瘤组织坏死,但对移植瘤增长无明显抑制作用；(2)CA4P联合十全大补汤可促进荷瘤鼠T细胞增殖活化,十全大补汤可拮抗CA4P促进细胞因子分泌的作用。
2.CA4P联合磁热疗可明显抑制小鼠H22肝癌移植瘤增长。
Objective1.To investigate the effect of a Low-molecular-weight vascular-disrupting agent Combretastatin A4phosphate (CA4P) combination with Shiquandabu Decoction on growth of H22hepatoma xenograft mice and its mechanism.2.To investigate the effect of CA4P combination with Magnetic fluid Hyperthermia(MFH) on growth of H22hepatoma xenograft mice.
Methods1.The liver cancer xenograft mode in mice was established H22cell.Seventy eight mice with liver cancer xenograft were randomly divided into six groups:I CA4P group; II Shiquandabu Decoction low-dose group; III Shiquandabu Decoction high-dose group; IV CA4P+Shiquandabu Decoction low-dose group; V CA4P+Shiquandabu Decoction high-dose group; VIcontrol group.The lenghth and width of xenograft were measured by vernier caliper at every three days during the therapy time.The volume of the xenograft was calculated,and xenograft grouth curves were ploted out.After28days,the tumor necrosis ratio was measured by MRI,the weight of primary subcutaneous xenograft and the inhibitory rate of weight of xenograft were examined after all mice sacrificed.Recipe blood from vein of eyeball centrifuging.The T cell subsets in peripheral blood were detected by FCM.The contents of IL-6and IFN-y of blood serum were detected by ELISA.The pathology form of xenograft were observed under microscop.2.The hepatoma-xenograft mice were constructed as moder,divided into four groups randomly:control group(NS),CA4P group(CA), Magnetic fluid Hyperthermia group(MFH) and CA4P+MFH group (CMFH). The lenghth and width of xenograft were measured by vernier caliper at every three days during the therapy time.The volume of the xenograft was calculated,and xenograft grouth curves were ploted out.The weight of primary subcutaneous xenograft and the inhibitory rate of weight of xenograft were examined at14days after the last hyperthermia after all mice sacrificed. The pathology form of xenograft were observed under microscop.
Results1.(1)Comparing the tumor growth of all groups with that of control group,it hadn't remarkable difference(P>0.05). The inhibitory rate of weight of subcutaneous xenograft in CA4P group,Shiquandabu Decoction low-dose group,Shiquandabu Decoction high-dose group,CA4P+low-dose group,CA4P+high-dose group,control group were respectively:4.43%、11.61%、20.46%、2.22%、6.62%.(2) In every treatment group the tumor necrosis ratio was increased, CA4P combination with Shiquandabu Decoction showed larger necrosis areas than CA4P group.(3) CA4P combination with Shiquandabu Decoction can increase CD3+、 CD4+、 CD8+T cell ratio in peripheral blood. CA4P can promote markedly production of IL-6and IFN-y, Shiquandabu Decoction can produce protective effect.
2.In every treatment group xenograft growth was suppressed significantly.CA4P plus MFH group showed enhancement efficacy in anti-tumor growth(P<0.01).The inhibitory rate of weight of subcutaneous xenograft were respectively423%、63.3%、82.54%。 Pathological examination showed much larger necrosis areas in every treatment group.CA4P plus MFH showed the most obvious changes.
Conclusions1.(1) CA4P combination with Shiquandabu Decoction can aggravate tissue necrosis in the xenograft,however,it can not inhibit the xenograft growth.(2) CA4P combination with Shiquandabu Decoction can promote the proliferation and activation of T cells, CA4P can significantly promote cytokines production, Shiquandabu Decoction exerts a protective action against this effect.
2. CA4P combination with MFH can significantly inhibit the growth of H22hepatoma-xenograft in mice.
方法1.建立小鼠H22肝癌移植瘤模型,将成瘤小鼠随机分成7组：Ⅰ组：CA4P单药组,Ⅱ组：十全大补汤低剂量组,Ⅲ组：十全大补汤高剂量组,Ⅳ组：CA4P+十全大补汤低剂量组,Ⅴ组：CA4P+十全大补汤高剂量组,Ⅵ组：空白对照组。用药期间每3天测量移植瘤长短经,计算移植瘤体积,绘制肿瘤生长曲线,用药28天后颈椎脱臼法处死小鼠,剥离皮下移植瘤称重,计算抑瘤率,评价联合用药效应；HE染色,镜下观察移植瘤组织形态变化；MRI检测肿瘤坏死率；计算免疫脏器指数,流式细胞检测小鼠外周血中CD3+、CD4+、CD8+细胞比率,ELISA试剂盒检测外周血中IL-6、IFN-γ水平,观察联合用药对荷瘤鼠免疫功能的影响。2.建立小鼠H22肝癌移植瘤模型,将小鼠随机分成4组：NS对照组(NS),磁流体热疗组(MFH), CA4P单药组(CA), CA4P联合磁热疗组(CMFH)。用药期间每3天测量移植瘤长短经,计算移植瘤体积,绘制肿瘤生长曲线,用药14天后颈椎脱臼法处死小鼠,剥离皮下移植瘤称重,计算抑瘤率,评价联合用药效应；HE染色,镜下观察移植瘤组织形态变化。
结果1.(1)CA4P联合十全大补汤对移植瘤增长无明显抑制作用,CA4P单药组、十全大补汤低剂量组、十全大补汤高剂量组、CA4P+低剂量组、CA4P+高剂量组各组抑瘤率分别为：4.43%、11.61%、20.46%、2.22%、6.62%。(2)各给药组移植瘤肿瘤坏死率明显增高,十全大补汤低、高剂量联合CA4P较CA4P单药组肿瘤坏死面积增大。(3)各给药组对荷瘤鼠免疫脏器指数无影响,CA4P联合十全大补汤可升高荷瘤鼠外周血CD3+、CD4+、CD8+细胞比率(P<0.05),CA4P可使小鼠血清中IL-6、IFN-γ含量明显升高(P<0.01),联合十全大补汤抑制该调节作用。
2.CA4P、磁热疗可抑制移植瘤生长,CA4P联合磁热疗组抑瘤作用明显增强(P<0.01),CA、MFH、CMFH各组抑瘤率分别为：42.3%、63.3%、82.54%。HE染色示各治疗组肿瘤坏死区增大,CMFH组肿瘤坏死最为明显。
结论1.(1)CA4P联合十全大补汤可促进移植瘤组织坏死,但对移植瘤增长无明显抑制作用；(2)CA4P联合十全大补汤可促进荷瘤鼠T细胞增殖活化,十全大补汤可拮抗CA4P促进细胞因子分泌的作用。
2.CA4P联合磁热疗可明显抑制小鼠H22肝癌移植瘤增长。
Objective1.To investigate the effect of a Low-molecular-weight vascular-disrupting agent Combretastatin A4phosphate (CA4P) combination with Shiquandabu Decoction on growth of H22hepatoma xenograft mice and its mechanism.2.To investigate the effect of CA4P combination with Magnetic fluid Hyperthermia(MFH) on growth of H22hepatoma xenograft mice.
Methods1.The liver cancer xenograft mode in mice was established H22cell.Seventy eight mice with liver cancer xenograft were randomly divided into six groups:I CA4P group; II Shiquandabu Decoction low-dose group; III Shiquandabu Decoction high-dose group; IV CA4P+Shiquandabu Decoction low-dose group; V CA4P+Shiquandabu Decoction high-dose group; VIcontrol group.The lenghth and width of xenograft were measured by vernier caliper at every three days during the therapy time.The volume of the xenograft was calculated,and xenograft grouth curves were ploted out.After28days,the tumor necrosis ratio was measured by MRI,the weight of primary subcutaneous xenograft and the inhibitory rate of weight of xenograft were examined after all mice sacrificed.Recipe blood from vein of eyeball centrifuging.The T cell subsets in peripheral blood were detected by FCM.The contents of IL-6and IFN-y of blood serum were detected by ELISA.The pathology form of xenograft were observed under microscop.2.The hepatoma-xenograft mice were constructed as moder,divided into four groups randomly:control group(NS),CA4P group(CA), Magnetic fluid Hyperthermia group(MFH) and CA4P+MFH group (CMFH). The lenghth and width of xenograft were measured by vernier caliper at every three days during the therapy time.The volume of the xenograft was calculated,and xenograft grouth curves were ploted out.The weight of primary subcutaneous xenograft and the inhibitory rate of weight of xenograft were examined at14days after the last hyperthermia after all mice sacrificed. The pathology form of xenograft were observed under microscop.
Results1.(1)Comparing the tumor growth of all groups with that of control group,it hadn't remarkable difference(P>0.05). The inhibitory rate of weight of subcutaneous xenograft in CA4P group,Shiquandabu Decoction low-dose group,Shiquandabu Decoction high-dose group,CA4P+low-dose group,CA4P+high-dose group,control group were respectively:4.43%、11.61%、20.46%、2.22%、6.62%.(2) In every treatment group the tumor necrosis ratio was increased, CA4P combination with Shiquandabu Decoction showed larger necrosis areas than CA4P group.(3) CA4P combination with Shiquandabu Decoction can increase CD3+、 CD4+、 CD8+T cell ratio in peripheral blood. CA4P can promote markedly production of IL-6and IFN-y, Shiquandabu Decoction can produce protective effect.
2.In every treatment group xenograft growth was suppressed significantly.CA4P plus MFH group showed enhancement efficacy in anti-tumor growth(P<0.01).The inhibitory rate of weight of subcutaneous xenograft were respectively423%、63.3%、82.54%。 Pathological examination showed much larger necrosis areas in every treatment group.CA4P plus MFH showed the most obvious changes.
Conclusions1.(1) CA4P combination with Shiquandabu Decoction can aggravate tissue necrosis in the xenograft,however,it can not inhibit the xenograft growth.(2) CA4P combination with Shiquandabu Decoction can promote the proliferation and activation of T cells, CA4P can significantly promote cytokines production, Shiquandabu Decoction exerts a protective action against this effect.
2. CA4P combination with MFH can significantly inhibit the growth of H22hepatoma-xenograft in mice.
引文
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[1]张永军,包素珍,张爱琴等.十全大补汤促进小鼠与瘤共存的实验研究[J].中华中医药学刊.2009,27(6)：1308·1309.
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[5]Budhu A,Forg UesM,Ye QH,et al.Predietion of venous metastases,reeurrenee,and Prognosis in hePatoeellular eareinoma based on a Unique immune response signature of the liver mieroenvironment[J].CaneerCell,2006,10(2):99-111.
[6]孙昕,陈振东,段力.恶性肿瘤患者血清TNF-a和IL-6浓度的测定[J].实用癌症杂志.2001,16(6)：615-616.
[7]Tomimatsu,Lchikura T,Mochlzuki H.Significant correlation between expression of interleukin-la and liver metastasis in gastric carcinoma[J].Cancer,2001,91(7):1272-1276.
[8]Shao X,Liu C.Influence of IFN- α and IFN- γ on lymphangiogenesis[J].Interferon Cytokine Res,2006,26(8):568-574.
[9]袁宇宁,熊树民.多发性骨髓瘤患者血清中IL-6和TNF-α水平测定及意义fJl.实川癌症杂志,2000,15(3)：306-307.
[10]杨子彬,李戈,李善华,等IFN-γ、Bct-2、MMP-9及STIM-1在肿瘤患者中的表达及其相关性[J].广东医学.2011,32(18)：2451-2452.
[11]Whitmire JK,Tan JT,Whitton JL.Interferon-γ acts directly on CD8+ T cells to increase their abundance during virus infection.J Exp Med.2005,201(7):1053-1059.
[12]Strehl B,Seifert U,Kruger E,et al. Interferon-γ,the functional plasticity of the ubiquitin-proteasome system,and MHC class I antigen processing.Innunol Rev,2005,207:19-30
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[14]Tekauta TM,Zhu k,Grenet J,et al.Evaluation of IFN-γ effects on apoptosis and gene expression in neuroblastoma-preclinical studies.Biochim Biophys Acta,2006,1763(10):1000-1010.
[15]Saban MR,Memet S,Jackson DG,et al.Visualization of lymphatic vessels through NF-kappaB activity[J].Blood, 2004,104(10):3228-3230.
[16]Nielsen T, Murata R, Maxwell RJ, Stedkilde-Jorgensen H, Ostergaard L, Ley CD, Kristjansen PE, Horsman MR, Non-invasive imaging of combretastatin activity in two tumor models Association with invasive estimates. Acta Oncologica (Stockholm, Sweden) [Acta Oncol], 2010 49 (7):906-913.
[17]CS Parkins, AL Holder, SA Hilll, DJ Chaplin,GM Tozer. Determinants of anti-vascular action by combretastatin A-4 phosphate:role of nitric oxide. British Journal of Cancer (2000) 83(6), 811-816.
[18]Tsuchiya M, Kono H, Matsuda M, et al. Protective effect of Juzen-taiho-to on hepatocarcinogenesis is mediated through the inhibition of Kupffer cell-induced oxidative stress. Int J Cancer,2008, 123 (11): 2503-2511.
[19]郜明,张伟伟,吴家明等.十全大补汤对体外血管生成的影响[J].南京中医药大学学报,2008,24(2)：101-103,146.
[20]宋红,包素珍,郑小伟,等.血管内皮细胞生长因子在Lewis肺癌组织中表达的意义及十全大补汤对其干预作用[J].中华中医药杂志,2008,23(8)：684-687.
[21]Kamiyama H, Takano S, Ishikawa, et al. Anti-angiogenic and immunomodulatory effect of the herbal medicine "Juzen-taiho-to"on malignant glioma. Biol Pharm Bull, 2005,28 (11):2111-2116.
[1]夏启胜,刘轩,李红艳等.热籽感应加温治疗肿瘤实验与临床研究进展[J].中华物理医学与康复杂志,2005,27：380-382.
[2]Landeghem FK,Maier-Hauff K,Jordan A,et al.Postmortem studies in glioblastoma patients treatd with thermotherapy using magbetic nanopaticles[J].Biomaterials,2009,30(1):52-57.
[3]Johannsen M,Gneveckow U,Thiesen B,et al.Thermotherapy of Prostate cancer using magnetic nanoPartieles: feasibility,imaging,and three-dimensional temperature distribution [J]. EuroPean Urology,2007,52(6):1653-1662.
[4]Wildiers H,Ahmed B,Guetens G.,et al. Combretastatin A-4 phosphate enhances CPT-11 activity independently of the administration sequence.European Journal of Cancer, Jan2004,40(2):284.
[5]Grosios K,Loadman PM,Swaine DJ,et al. Combination chemotherapy with combretastatin A-4 phosphate and 5-fluorouracil in an experimental murine colon adenocarcinoma. Combination chemotherapy with combretastatin A-4 phosphate and 5-fluorouracil in an experimental murinecolon adenocarcinoma.Anticancer Research [Anticancer Res] 2000,20 (1A):229-233.
[6]Edley RB,Hill SA,Boxer GM,et al. Eradication of colorectal xenografts by combined radioimmunotherapy and combretastatin a-4 3-O-phosphate. Cancer Res 2001;61:4716-4722
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[8]王桂华,王晓文,夏启胜等.Fe3O4磁纳米介导磁感应治疗W istar大鼠W alker-256肿瘤[J].中国微创外科杂志,2009,9(3)：237-239.
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[1]张永军,包素珍,张爱琴等.十全大补汤促进小鼠与瘤共存的实验研究[J].中华中医药学刊.2009,27(6)：1308·1309.
[2]Dawen Zhao,Edmond Richer,Peter P. Antich, and Ralph P. Mason. Antivascular effectsof combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI.[J] FASEB Journal,2008,22(7):2445-2451.
[3]Bhardwaj N.Harnessing the immune system to treat cancer.J Clin Invest.2007,117(5):1130-1136.
[4]任秀红,刘莉,刘平平,等.恶性肿瘤患者T细胞亚群变化及其与肿瘤分期的关系[J].第三军医大学学报.2006,28(18)：1906-1908.
[5]Budhu A,Forg UesM,Ye QH,et al.Predietion of venous metastases,reeurrenee,and Prognosis in hePatoeellular eareinoma based on a Unique immune response signature of the liver mieroenvironment[J].CaneerCell,2006,10(2):99-111.
[6]孙昕,陈振东,段力.恶性肿瘤患者血清TNF-a和IL-6浓度的测定[J].实用癌症杂志.2001,16(6)：615-616.
[7]Tomimatsu,Lchikura T,Mochlzuki H.Significant correlation between expression of interleukin-la and liver metastasis in gastric carcinoma[J].Cancer,2001,91(7):1272-1276.
[8]Shao X,Liu C.Influence of IFN- α and IFN- γ on lymphangiogenesis[J].Interferon Cytokine Res,2006,26(8):568-574.
[9]袁宇宁,熊树民.多发性骨髓瘤患者血清中IL-6和TNF-α水平测定及意义fJl.实川癌症杂志,2000,15(3)：306-307.
[10]杨子彬,李戈,李善华,等IFN-γ、Bct-2、MMP-9及STIM-1在肿瘤患者中的表达及其相关性[J].广东医学.2011,32(18)：2451-2452.
[11]Whitmire JK,Tan JT,Whitton JL.Interferon-γ acts directly on CD8+ T cells to increase their abundance during virus infection.J Exp Med.2005,201(7):1053-1059.
[12]Strehl B,Seifert U,Kruger E,et al. Interferon-γ,the functional plasticity of the ubiquitin-proteasome system,and MHC class I antigen processing.Innunol Rev,2005,207:19-30
[13]Schroder K,Sweet MJ,Hume DA,et al.Signal integration between IFN-γ and TLR signaling pathway in macrophage.Immunobiology,2006,211(6-8):511-524.
[14]Tekauta TM,Zhu k,Grenet J,et al.Evaluation of IFN-γ effects on apoptosis and gene expression in neuroblastoma-preclinical studies.Biochim Biophys Acta,2006,1763(10):1000-1010.
[15]Saban MR,Memet S,Jackson DG,et al.Visualization of lymphatic vessels through NF-kappaB activity[J].Blood, 2004,104(10):3228-3230.
[16]Nielsen T, Murata R, Maxwell RJ, Stedkilde-Jorgensen H, Ostergaard L, Ley CD, Kristjansen PE, Horsman MR, Non-invasive imaging of combretastatin activity in two tumor models Association with invasive estimates. Acta Oncologica (Stockholm, Sweden) [Acta Oncol], 2010 49 (7):906-913.
[17]CS Parkins, AL Holder, SA Hilll, DJ Chaplin,GM Tozer. Determinants of anti-vascular action by combretastatin A-4 phosphate:role of nitric oxide. British Journal of Cancer (2000) 83(6), 811-816.
[18]Tsuchiya M, Kono H, Matsuda M, et al. Protective effect of Juzen-taiho-to on hepatocarcinogenesis is mediated through the inhibition of Kupffer cell-induced oxidative stress. Int J Cancer,2008, 123 (11): 2503-2511.
[19]郜明,张伟伟,吴家明等.十全大补汤对体外血管生成的影响[J].南京中医药大学学报,2008,24(2)：101-103,146.
[20]宋红,包素珍,郑小伟,等.血管内皮细胞生长因子在Lewis肺癌组织中表达的意义及十全大补汤对其干预作用[J].中华中医药杂志,2008,23(8)：684-687.
[21]Kamiyama H, Takano S, Ishikawa, et al. Anti-angiogenic and immunomodulatory effect of the herbal medicine "Juzen-taiho-to"on malignant glioma. Biol Pharm Bull, 2005,28 (11):2111-2116.
[1]夏启胜,刘轩,李红艳等.热籽感应加温治疗肿瘤实验与临床研究进展[J].中华物理医学与康复杂志,2005,27：380-382.
[2]Landeghem FK,Maier-Hauff K,Jordan A,et al.Postmortem studies in glioblastoma patients treatd with thermotherapy using magbetic nanopaticles[J].Biomaterials,2009,30(1):52-57.
[3]Johannsen M,Gneveckow U,Thiesen B,et al.Thermotherapy of Prostate cancer using magnetic nanoPartieles: feasibility,imaging,and three-dimensional temperature distribution [J]. EuroPean Urology,2007,52(6):1653-1662.
[4]Wildiers H,Ahmed B,Guetens G.,et al. Combretastatin A-4 phosphate enhances CPT-11 activity independently of the administration sequence.European Journal of Cancer, Jan2004,40(2):284.
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