异臭椿烷对S_（180）细胞小鼠皮下移植瘤的作用研究
|
摘要
目的:探讨不同剂量异臭椿烷对S_(180)肉瘤细胞小鼠皮下移植瘤的抑瘤作用。
方法:建立S_(180)细胞小鼠皮下移植瘤动物模型,随机分为三组:空白对照组,阳性对照组和实验组。空白对照组给予纯食用油;阳性对照组给以环磷酰胺(25mg/kg);实验组根据异臭椿烷用药剂量分为低剂量组(0.1mg/ml)、中剂量组(0.5mg/ml)、高剂量组(1.0mg/ml)。所有小鼠均连续给药5天后间隔两天为一疗程,共两疗程。停药后24小时处死小鼠,称取瘤重,计算抑瘤率;脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(TUNEL)测定肿瘤组织凋亡指数(AI);通过免疫组织化学方法观察肿瘤组织中Caspase-3与Bcl-2基因蛋白表达情况。
结果:异臭椿烷能有效抑制肿瘤的发生发展,并且表现出明显的剂量依赖性,其中高剂量组及环磷酰胺组抑瘤率分别为40.0%,52.2%,与空白对照组比较均有统计学意义(P＜0.01),但高剂量组与环磷酰胺组抑瘤率比较差异无统计学意义(P＞0.01);中剂量和低剂量组抑瘤率分别为29.1%、24.7%,两者比较并无明显差异;异臭椿烷可以诱导肿瘤细胞凋亡,高、中、低三组凋亡指数分别为:11.04%、9.12%、8.85%;三者组间两两比较可以得出高剂量组凋亡指数与中、低剂量组指数差异具有统计学意义。中剂量组与低剂量组之间指数比较差异并无统计学意义;异臭椿烷可明显增高Caspase-3活性(阳:阴=18:3),同时显著抑制Bcl-2活性(阳:阴=13:8),尤以高剂量组变化最为显著。
结论:异臭椿烷在体内可通过增加Caspase-3的活性和降低Bcl-2活性来诱导肿瘤细胞凋亡进而发挥抗肿瘤作用。
Objective:To explore the anti-tumor effect of Isomalabaricane triterpenes on trsnsplant subcutaneous sarcoma in S_(180) mice.
Methods:The subcutaneous transplnantable tumor model of S_(180) sarcoma in KM mice were established and divided at random into five groups:(0.1,0.5,1.0mg/ml) Isomalabaricane triterpenes, blank group(edible oil)and CTX(25mg / kg)group,each of which was composed of nine KM mice and received medicine(oil) in the following five days,interval for two days and continue five days again.The mouse was killed by dislocation of cervical spine surgery 24 hours after medication.The inhibition rate(TIR) was calculated to evaluate the anti-tumor effect by checking tumors'weight.The apoptotic index(AI) was determinated by the terminal deoxynucleotidyl transferase-mediated nick end labeling method(TUNEL).The Caspase-3 with the Bcl-2 gene protein expression in tumor tissue was determinated by the Immunohistochemical method.
Results:Isomalabaricane triterpenes can inhibit tumor occurrence and development effectively,with a dose-dependent manner,the high-dose group's and Cyclophosphamide group' s inhibition rate are 40.6%and 58.2%,respecting compared with blank control group,there were statistically significant (P＜0.01).However,high-dose group and the cyclophosphamide group compared with each other the inhibition rate were no significant difference(P＞0.01);Low-dose group's and intermediate dose group's inhibition rates were 29.1%and 24.7%,There is no significant difference between the two groups.Isomalabaricane triterpenes could induce tumor cell apoptosis,high,middle and low dose groups'apoptotic index were 11.04%、9.12%and 8.85%.Comparison of the three groups can be seen among high-dose group's apoptotic index are more statistically significant than the middle dose group's and low-dose group's.Isomalabaricane triterpenes could increased Caspase-3 gene activity. At the same time,inhibiting the activity of Bcl-2 gene significantly,especially in the high dose group
Conclusion:Isomalabaricane triterpenes can inhibit the S_(180) sarcoma cell s growth.By increasing the activity of Caspase-3 and reduction of Bcl-2 activity induced apoptosis in tumor cells.
方法:建立S_(180)细胞小鼠皮下移植瘤动物模型,随机分为三组:空白对照组,阳性对照组和实验组。空白对照组给予纯食用油;阳性对照组给以环磷酰胺(25mg/kg);实验组根据异臭椿烷用药剂量分为低剂量组(0.1mg/ml)、中剂量组(0.5mg/ml)、高剂量组(1.0mg/ml)。所有小鼠均连续给药5天后间隔两天为一疗程,共两疗程。停药后24小时处死小鼠,称取瘤重,计算抑瘤率;脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(TUNEL)测定肿瘤组织凋亡指数(AI);通过免疫组织化学方法观察肿瘤组织中Caspase-3与Bcl-2基因蛋白表达情况。
结果:异臭椿烷能有效抑制肿瘤的发生发展,并且表现出明显的剂量依赖性,其中高剂量组及环磷酰胺组抑瘤率分别为40.0%,52.2%,与空白对照组比较均有统计学意义(P＜0.01),但高剂量组与环磷酰胺组抑瘤率比较差异无统计学意义(P＞0.01);中剂量和低剂量组抑瘤率分别为29.1%、24.7%,两者比较并无明显差异;异臭椿烷可以诱导肿瘤细胞凋亡,高、中、低三组凋亡指数分别为:11.04%、9.12%、8.85%;三者组间两两比较可以得出高剂量组凋亡指数与中、低剂量组指数差异具有统计学意义。中剂量组与低剂量组之间指数比较差异并无统计学意义;异臭椿烷可明显增高Caspase-3活性(阳:阴=18:3),同时显著抑制Bcl-2活性(阳:阴=13:8),尤以高剂量组变化最为显著。
结论:异臭椿烷在体内可通过增加Caspase-3的活性和降低Bcl-2活性来诱导肿瘤细胞凋亡进而发挥抗肿瘤作用。
Objective:To explore the anti-tumor effect of Isomalabaricane triterpenes on trsnsplant subcutaneous sarcoma in S_(180) mice.
Methods:The subcutaneous transplnantable tumor model of S_(180) sarcoma in KM mice were established and divided at random into five groups:(0.1,0.5,1.0mg/ml) Isomalabaricane triterpenes, blank group(edible oil)and CTX(25mg / kg)group,each of which was composed of nine KM mice and received medicine(oil) in the following five days,interval for two days and continue five days again.The mouse was killed by dislocation of cervical spine surgery 24 hours after medication.The inhibition rate(TIR) was calculated to evaluate the anti-tumor effect by checking tumors'weight.The apoptotic index(AI) was determinated by the terminal deoxynucleotidyl transferase-mediated nick end labeling method(TUNEL).The Caspase-3 with the Bcl-2 gene protein expression in tumor tissue was determinated by the Immunohistochemical method.
Results:Isomalabaricane triterpenes can inhibit tumor occurrence and development effectively,with a dose-dependent manner,the high-dose group's and Cyclophosphamide group' s inhibition rate are 40.6%and 58.2%,respecting compared with blank control group,there were statistically significant (P＜0.01).However,high-dose group and the cyclophosphamide group compared with each other the inhibition rate were no significant difference(P＞0.01);Low-dose group's and intermediate dose group's inhibition rates were 29.1%and 24.7%,There is no significant difference between the two groups.Isomalabaricane triterpenes could induce tumor cell apoptosis,high,middle and low dose groups'apoptotic index were 11.04%、9.12%and 8.85%.Comparison of the three groups can be seen among high-dose group's apoptotic index are more statistically significant than the middle dose group's and low-dose group's.Isomalabaricane triterpenes could increased Caspase-3 gene activity. At the same time,inhibiting the activity of Bcl-2 gene significantly,especially in the high dose group
Conclusion:Isomalabaricane triterpenes can inhibit the S_(180) sarcoma cell s growth.By increasing the activity of Caspase-3 and reduction of Bcl-2 activity induced apoptosis in tumor cells.
引文
[1].邓松之(Deng sz).海洋臭椿类三萜(malabaricane triterpenes)的研究进展[J].中国海洋药物(Chin J Mar Drugs),2004,23(1):37-41.
[2].林文翰.海洋异臭椿类三萜化学结构与生物活性的关系[J].中国天然药物(Chin J Nat Med),2005,3(3):74-76.
[3].Miller LJ,Marx J.Apoptosis.Scicence,1998,281(5381):1301-1304
[4].Swanton E,Savory P,Cosulich S,et al.Bcl-2 regulates a Caspase-3 / caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18(10):1778.
[5].Iseki K,Tatsuata M,Uehara H,et al.Inhibition of angiogenesis as a mechanism for Inhibition by 1 α-hydroxy vitam in D3 and 1,25-dihydroxy vitam in D3 of colon carcinogenesis induced by azoxymethane in Wistar rat[J].Int[J]Cancer,1999,81(5):730.
[6].Haldar S,Negrini M,Monne M,et al.Down-regulation of Bcl-2 by p53 in breast cancer cells[J].Cancer Res,1994,54:2095.
[7].Femade-Alnemri T,Litwack G,Alnemri ES,et al.CPP32,anovel human apoptotic protein with homology to caenrohabditis elegans cell death protein Ced-3 and mammalian interletlkin-1beta-converting enzyme.J Bid Chem,1994,269:30761
[8].Nicholson DW,Ali A,Thomberry NA,et al.Identiifcation and inhibition of the ICE / CED-3pmteas enecessary for mammalian apoptosis[J].Nature,1995,376(6535):3743.
[9].Saikumar P,Dong Z,Mikhailov V,et al.Apoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489.506.
[10].Poter AG,Janicke RU.Emerging roles of Caspase-3 in apoptosis[J].CellDeath Difer,1999,6(2):99.104.
[11].Grutter MG.Caspase:key players in programmed cell death[J].Current Opinion in structural biology,2000,10(6):649-655
[12].Maier JK,Lahoua Z,Gendmn NH,et al.The neuronal apoptosis inhibitor protein is a direct in hibitor of Caspases-3 and Caspases-7[J].J Neuro Sci,2002,22(6):2035-2043.
[13].Wang J,Zheng L,Lobito A,et al.Inheritde humana Caspase-10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoinmaune lymphopm liferative syndorme type Ⅱ[J].Cell,1999,98(1):47-58
[14].Brenner C.Kroemer G.The mitochondrion:decisive for cell death control? Signaling pathway in apoptosis.Hawood academic pub-lishers.1999,207-216.
[15].Ashkenazi A.Dixit VM.Death receptors:signaling and modulation.Science,1998.281(5381): 1305～1308.
[16].Depraetere V.Golstein P.Dismantling in cell death;molecular mechanisms and relationship to caspase activation.Scand J Immunol,1998,47(6):523～531.
[17].Saikumar P,Dong Z,Mikhailov V,et al.Apoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489～506.
[18].Tsujimoto Y,et al.Cloning of the chromosome breakpoint of neoplastic B cell swiththet(14;18)chromosome transilocation.Science,1984,226:1097.
[19].Vauxt DL,Cory S,Adram JM.Bcl-2 gene promotes haemoietic cell survival and cooperates with c-myc to immortalize pre-B cells[J].Nature,1988,335(6 189):440
[20].Folkman J.Angiogenesis and aopptosis[J].Semin Cancer Biol,2003,13(2):159.
[21].Steller H.mechanisms and genes of cellular suicide.Science,1995,267:1445～14481
[22].Sermadiras S,Dumas M,Joly B,et al.Expression of Bcl-2 and Bax in cultured normal human kerationcytes and melanocytes:relation ship to differentiation and melanogenesis.[J].Dermatol 5/o.l997,137:883～889
[23].Folkman J.Angiogenesis and aopptosis[J].Semin Cancer Biol,2003,13(2):159
[24].Swanton E,Savory P,Cosulich S,et al.Bcl-2 regulates a Caspase-3 / caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18(10):1778.
[25].Swanton E,Savory P,Cosulich S,et al.Bcl-2 regulates a Caspase-3 / caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18(10):1778.
[26].Hoshi T,Sasano H,Noritaka Y,et al.Immunohisto chemistry of caspase-3 / CPP32 in human stomach and its correlation with cell proliferation and apoptosis.Anticancer Res,1998,18:4347.
[27].Gavrieal Y,Sherman Y.Identification of programmed cell death in situvia specific labeling of nuclear DNA fragmenation[J]-JCellBiol,1992,119(2):493-501
1.Shah MA,Schwartz GK.Treatment of metastatic esophagus and gastric cancer.Semin Oncol 2004;31:574-587
2.韩锐.抗癌药物研究与实验技术[M].北京:北京医科大学中国协和医科大学联合出版社,1997.299.
3.徐建国,包可杰.甲基胆蒽诱发大小鼠胃癌的实验观察.白求恩医科大学学报,1992,18(5):466
4.覃国忠,严瑞琪,覃柳亮,等.黄曲霉毒素诱发大鼠前胃肿瘤的观察.广西医学院学报,1990,7(4):5
5.孟振行.MNNG诱发动物实验性腺胃癌机理的研究进展.国外医学·消化系疾病分册,1997,17(3):136
6.朱建思,苏琦,许金华,等.甲基硝基亚硝基肌对裸鼠异种移植人胚胃粘膜的影响(J).衡阳医学院学报,2000.28(2):124-127.
7.Watenable T,Tada M,Nagai H,et al.Helieobacter pylori,infection induces gastric cancer in mongolian gerbils[J].1998.115(3):642-648.
8.Drazek ES,Dubois A,Holmes RK.Characterization and pre-sumptive identification of Helicobacter pylori isolates from rhesus monkeys(J).Clin Microbiol,1994,32(7):1799-1804.
9.刘芳莉,李钰,高凌寒,等.RAB5A基因表达改变对人肺腺癌细胞系GLC-82和SPC.al 的分化和侵袋特性影响[J].遗传学报,2002,29(12):1043-1407.
10.Katz MH,Takimoto S,Spivack D,et al.An imageable highly metastatic orthotopic red fluorescent protein model of pancreatic cancer[J].Clin Exp Metastasis,2004,21(1):7-12.
11.Katz MH,Bouvet M,Takimoto S,et al.Survival efficacy of adjuvant cytosine-analogue CS-682in a fluorescent orthotopic model of human pancreatic cancer[J].CancerRes,2004,64(5):1828-1833.
12.Yamaguchi K,Ura H,Yasoshima T,et al Lver established metastatic model for human gastric cancer by orthotopic tumor cell implantation[J].World J Surg,2001,25(2):131-137.
13.Furukawa T,Fu X,Kubota T,et al.Nude mouse metastatic models of human stomach CanCer constructed using orthotopic implantation of histologically intact tissue[J].Cancer Res,1993,53(5):1204-1208.
14.Steel GG Courtenay VD Rostom AY et al.Improved immune suppression techniques for the xenografting of human tumous.[J]Cancer,1978;37:224
15.Pathaka S,Nemeth MA,Mlutnai AS.Human tumor xenografts in nude mice are not always of human origin:A warning signal[J].Cancer.1998;83:1891-1893.
16.张煜和,祝金泉,王崇文,等.改良Steel法建立人胃癌动物模型[J].实用肿瘤杂志,1998,13(5):291-293
17.周本杰,陈蔚文,王建华,等胃癌动物模型研究现状与评价[J].广州中医药大学学报,1998,15(2):156-159
18.Hinrichs S H,Fontes J D,Bills N D,et al.Transgenic models of human cancer.Princess Takamatsu Symp,1991,22:259
[1].Haldar S,Negrini M,Monne M,et al.Down-regulation of Bcl-2 by p53 in breast cancer cells[J].CancerRes,1994,54:2095.
[2].Miller LJ,Marx J.Apoptosis.Scicence,1998,281(5381):1301-1304
[3].Haldar S,Negrini M,Monne M,et al.Down-regulation of Bcl-2 by p53 in breast cancer cells [J].CancerRes,1994,54:2095.
[4].Yan JY,Shai SH,Ledoux S,Ellis HM,Horvitz R.The C.elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-Iβ converting enzyme[J].Cell,1993,75:641-652.
[5].Wilson J,Thomson JB,Kim E,Black M.Structurenad mechanism of interleukin-Iβ converting enzyme[J].Nature,1994,370:270-275.
[6].Emad S,Alnemri,David J,Livingstone,Donald W Nicholson.Humna ICE / CED-3 protease nomencalture[J].Cell,1996,87:171-176.
[7].熊世勤,来锡华..Csapase激活与调控的分子机制[J].生物化学与生物物理进展,2002,27(10):33-36
[8].Thornberry NA,Lazebnik Y.Caspase enemies within[J].Science,1998,281:1312.
[9].Wang J,Lenardo MJ.Roles of caspases in apoptosis,development and cytokine maturation revealed byhomozygous gene deficiencise[J].Cell,2000.113(Pt5):753-757.
[10].Femade-Alnemri T,Litwack G,Alnemri ES,et al.CPP32,anovel human apoptotic protein with homology to caenrohabditis elegans cell death protein Ced-3 and mammalian interletlkin-1beta-converting enzyme[J].Bid Chem,1994,269:30761.
[11].Nicholson DW,Ali A,Thomberry NA,et al.Identiifcation and inhibition of the ICE / CED-3pmteas enecessary for mammalian apoptosis[J].Nature,1995,376(6535):3743.
[12].Saikumar P,Dong Z,Mikhailov V,et al.Apoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489-506.
[13].Poter AG,Janicke RU.Emerging roles of Caspase-3 in apoptosis/J].Cell Death Difer,1999,6(2):99-104.
[14].Grutter MG.Caspase:key players in programmed cell death[J].Current Opinion in structural biology,2000,10(6):649-655
[15].Fantuzzi G.Puren AJ,Harding MW,et al.Interleukin-18 egulation of interferon gamma production and cell proliferation asshown in interleukin-lbeta-converting enzyme(caspase-1)-deficient mice[J].Blood,1998,91(6):2118-2125.
[16].Ghayur T,Banerjee S.Hugunin 1V1,et al.Caspase-1 processesIFN-game.-inducing factor and regulates LPSinduced IFN-gamma production[J].Nature,1997,386(6625):619-623
[17].Faucheu C,DiuA,Chan AW,et al.A noevl human protease similar to the interleukin-1 be ta convertign enzyme induces apoptosisintramsf-ted cells[J].EMBOJ,1995,14(9):1914-1922.
[18].BergeronL,PerezGI,MacdonaldG,et al.Defects in regulation of apoptosis in caspase-2deficient mice[J].GenesDev,1998,12(9):1304-1314.
[19].Honarpour N,Du C,Richardson JA,et al.Adult Apaf-1 deficient Mice exhibit male in fertility[J].DewBiol,2000,218(2):248-258.
[20].Hakem R,Hakem A,Duncan GS,et al.Differential requirement for caspase-9 in apoptotic pathways in vivo[J].Cell.1998,94(3):339-352
[21].Srinivasula SM,Femnades-Alnemri T,Zangrilli J,et al.TheCed-3/interleukin-1 beta ocnverting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32[J].Biol Chem,1996,271(43):27099-27106.
[22].Maier JK,Lahoua Z,Gendmn NH,et al.The neuronal apoptosis inhibitor protein is a direct in hibitor of Caspases-3 and Caspases-7[J].Neuro Sci,2002,22(6):2035-2043.
[23].Wang J,Zheng L,Lobito A,et al.Inheritde humana Caspase-10 mutations underlie defcetive lymphocyte and dendritic cell apoptosis in autoinmaune lymphopm liferative syndorme type Ⅱ[J].Cell.1999,98(1):47-58
[24].Brenner C.Kroemer G.The mitochondrion:decisive for cell death control? Signaling pathway in apoptosis.Hawood academic pub-lishers.1999,207-216.
[25].Ashkenazi A.Dixit VM.Death receptors:signaling and modulation.Science,1998.281(5381):1305-1308.
[26].Depraetere V.Golstein P.Dismantling in cell death;molecular mechanisms and relationship to caspase activation.[J]Immunol,1998,47(6):523-531.
[27].Saikumar P,Dong Z,Mikhailov V,et al.Apoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489-506.
[28].Budihardjo I,Oliver H,LuRer M,et al.Biochemical pathways of caspase activation during apoptosis[J].Annu Rev Cell Dev Biol,1999,15:(269-290)
[29].Poter AG,Janicke RU.Emerging roles of Caspase-3 in apoptosis[J].Cell Death Difer,1999,6(2):99-104.
[30].Tsujimoto Y,et al.Cloning of the chromosome breakpoint of neoplastic B cell swiththet(14;18)chromosome transilocation.Science,1984,226:1097.
[31].Vauxt DL,Cory S,Adram JM.Bcl-2 gene promotes haemoietic cell survival and cooperates with c-myc to immortalize pre-B cells[J].Nature,1988,335(6 189):440
[32].Folkman J.Angiogenesis and aopptosis[J].Semin Cancer Biol,2003,13(2):159.
[33].Steller H.mechanisms and genes of cellular suicide.Science,1995,267:1445-1448
[34].Sermadiras S,Dumas M,Joly B,et al.Expression of Bcl-2 and Bax in cultured normal human kerationcytes and melanocytes:relation ship to differentiation and melanogenesis.[J].Dermatol Bio.1997,137:883-889
[35].Folkman J.Angiogenesis and aopptosis[J].Semin Cancer Biol,2003,13(2):159
[36].Swanton E,Savory P,Cosulich S,et al.Bcl-2 regulates a Caspase-3/caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18(10):1778.
[37].Pant G,Orourke K,Dixit VM.Caspas-9,Bcl-xl,and Apaf-1 from a ternary complex[J].Bio chem,1996,273(10):5481.
[38].Gavrieal Y,Sherman Y.Identification of programmed cell death in situvia specific labeling of nuclear DNA fragmenation[J].J Cell Biol,1992,119(2):493-501
[39].Higaki K,Ynao H,Kojiro M.Fesantigen expression and its relationship with aopptosis in human hepatocellular carcinoma and noncancerous tissues[J].AmJ Pathol,1996,149(2):429-437.
[40].Petito CK,Oberts B.Effect of postmortem of DNA digonudesanes[J].Neuropathol,1995,54(6):761-765.
[2].林文翰.海洋异臭椿类三萜化学结构与生物活性的关系[J].中国天然药物(Chin J Nat Med),2005,3(3):74-76.
[3].Miller LJ,Marx J.Apoptosis.Scicence,1998,281(5381):1301-1304
[4].Swanton E,Savory P,Cosulich S,et al.Bcl-2 regulates a Caspase-3 / caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18(10):1778.
[5].Iseki K,Tatsuata M,Uehara H,et al.Inhibition of angiogenesis as a mechanism for Inhibition by 1 α-hydroxy vitam in D3 and 1,25-dihydroxy vitam in D3 of colon carcinogenesis induced by azoxymethane in Wistar rat[J].Int[J]Cancer,1999,81(5):730.
[6].Haldar S,Negrini M,Monne M,et al.Down-regulation of Bcl-2 by p53 in breast cancer cells[J].Cancer Res,1994,54:2095.
[7].Femade-Alnemri T,Litwack G,Alnemri ES,et al.CPP32,anovel human apoptotic protein with homology to caenrohabditis elegans cell death protein Ced-3 and mammalian interletlkin-1beta-converting enzyme.J Bid Chem,1994,269:30761
[8].Nicholson DW,Ali A,Thomberry NA,et al.Identiifcation and inhibition of the ICE / CED-3pmteas enecessary for mammalian apoptosis[J].Nature,1995,376(6535):3743.
[9].Saikumar P,Dong Z,Mikhailov V,et al.Apoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489.506.
[10].Poter AG,Janicke RU.Emerging roles of Caspase-3 in apoptosis[J].CellDeath Difer,1999,6(2):99.104.
[11].Grutter MG.Caspase:key players in programmed cell death[J].Current Opinion in structural biology,2000,10(6):649-655
[12].Maier JK,Lahoua Z,Gendmn NH,et al.The neuronal apoptosis inhibitor protein is a direct in hibitor of Caspases-3 and Caspases-7[J].J Neuro Sci,2002,22(6):2035-2043.
[13].Wang J,Zheng L,Lobito A,et al.Inheritde humana Caspase-10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoinmaune lymphopm liferative syndorme type Ⅱ[J].Cell,1999,98(1):47-58
[14].Brenner C.Kroemer G.The mitochondrion:decisive for cell death control? Signaling pathway in apoptosis.Hawood academic pub-lishers.1999,207-216.
[15].Ashkenazi A.Dixit VM.Death receptors:signaling and modulation.Science,1998.281(5381): 1305～1308.
[16].Depraetere V.Golstein P.Dismantling in cell death;molecular mechanisms and relationship to caspase activation.Scand J Immunol,1998,47(6):523～531.
[17].Saikumar P,Dong Z,Mikhailov V,et al.Apoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489～506.
[18].Tsujimoto Y,et al.Cloning of the chromosome breakpoint of neoplastic B cell swiththet(14;18)chromosome transilocation.Science,1984,226:1097.
[19].Vauxt DL,Cory S,Adram JM.Bcl-2 gene promotes haemoietic cell survival and cooperates with c-myc to immortalize pre-B cells[J].Nature,1988,335(6 189):440
[20].Folkman J.Angiogenesis and aopptosis[J].Semin Cancer Biol,2003,13(2):159.
[21].Steller H.mechanisms and genes of cellular suicide.Science,1995,267:1445～14481
[22].Sermadiras S,Dumas M,Joly B,et al.Expression of Bcl-2 and Bax in cultured normal human kerationcytes and melanocytes:relation ship to differentiation and melanogenesis.[J].Dermatol 5/o.l997,137:883～889
[23].Folkman J.Angiogenesis and aopptosis[J].Semin Cancer Biol,2003,13(2):159
[24].Swanton E,Savory P,Cosulich S,et al.Bcl-2 regulates a Caspase-3 / caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18(10):1778.
[25].Swanton E,Savory P,Cosulich S,et al.Bcl-2 regulates a Caspase-3 / caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18(10):1778.
[26].Hoshi T,Sasano H,Noritaka Y,et al.Immunohisto chemistry of caspase-3 / CPP32 in human stomach and its correlation with cell proliferation and apoptosis.Anticancer Res,1998,18:4347.
[27].Gavrieal Y,Sherman Y.Identification of programmed cell death in situvia specific labeling of nuclear DNA fragmenation[J]-JCellBiol,1992,119(2):493-501
1.Shah MA,Schwartz GK.Treatment of metastatic esophagus and gastric cancer.Semin Oncol 2004;31:574-587
2.韩锐.抗癌药物研究与实验技术[M].北京:北京医科大学中国协和医科大学联合出版社,1997.299.
3.徐建国,包可杰.甲基胆蒽诱发大小鼠胃癌的实验观察.白求恩医科大学学报,1992,18(5):466
4.覃国忠,严瑞琪,覃柳亮,等.黄曲霉毒素诱发大鼠前胃肿瘤的观察.广西医学院学报,1990,7(4):5
5.孟振行.MNNG诱发动物实验性腺胃癌机理的研究进展.国外医学·消化系疾病分册,1997,17(3):136
6.朱建思,苏琦,许金华,等.甲基硝基亚硝基肌对裸鼠异种移植人胚胃粘膜的影响(J).衡阳医学院学报,2000.28(2):124-127.
7.Watenable T,Tada M,Nagai H,et al.Helieobacter pylori,infection induces gastric cancer in mongolian gerbils[J].1998.115(3):642-648.
8.Drazek ES,Dubois A,Holmes RK.Characterization and pre-sumptive identification of Helicobacter pylori isolates from rhesus monkeys(J).Clin Microbiol,1994,32(7):1799-1804.
9.刘芳莉,李钰,高凌寒,等.RAB5A基因表达改变对人肺腺癌细胞系GLC-82和SPC.al 的分化和侵袋特性影响[J].遗传学报,2002,29(12):1043-1407.
10.Katz MH,Takimoto S,Spivack D,et al.An imageable highly metastatic orthotopic red fluorescent protein model of pancreatic cancer[J].Clin Exp Metastasis,2004,21(1):7-12.
11.Katz MH,Bouvet M,Takimoto S,et al.Survival efficacy of adjuvant cytosine-analogue CS-682in a fluorescent orthotopic model of human pancreatic cancer[J].CancerRes,2004,64(5):1828-1833.
12.Yamaguchi K,Ura H,Yasoshima T,et al Lver established metastatic model for human gastric cancer by orthotopic tumor cell implantation[J].World J Surg,2001,25(2):131-137.
13.Furukawa T,Fu X,Kubota T,et al.Nude mouse metastatic models of human stomach CanCer constructed using orthotopic implantation of histologically intact tissue[J].Cancer Res,1993,53(5):1204-1208.
14.Steel GG Courtenay VD Rostom AY et al.Improved immune suppression techniques for the xenografting of human tumous.[J]Cancer,1978;37:224
15.Pathaka S,Nemeth MA,Mlutnai AS.Human tumor xenografts in nude mice are not always of human origin:A warning signal[J].Cancer.1998;83:1891-1893.
16.张煜和,祝金泉,王崇文,等.改良Steel法建立人胃癌动物模型[J].实用肿瘤杂志,1998,13(5):291-293
17.周本杰,陈蔚文,王建华,等胃癌动物模型研究现状与评价[J].广州中医药大学学报,1998,15(2):156-159
18.Hinrichs S H,Fontes J D,Bills N D,et al.Transgenic models of human cancer.Princess Takamatsu Symp,1991,22:259
[1].Haldar S,Negrini M,Monne M,et al.Down-regulation of Bcl-2 by p53 in breast cancer cells[J].CancerRes,1994,54:2095.
[2].Miller LJ,Marx J.Apoptosis.Scicence,1998,281(5381):1301-1304
[3].Haldar S,Negrini M,Monne M,et al.Down-regulation of Bcl-2 by p53 in breast cancer cells [J].CancerRes,1994,54:2095.
[4].Yan JY,Shai SH,Ledoux S,Ellis HM,Horvitz R.The C.elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-Iβ converting enzyme[J].Cell,1993,75:641-652.
[5].Wilson J,Thomson JB,Kim E,Black M.Structurenad mechanism of interleukin-Iβ converting enzyme[J].Nature,1994,370:270-275.
[6].Emad S,Alnemri,David J,Livingstone,Donald W Nicholson.Humna ICE / CED-3 protease nomencalture[J].Cell,1996,87:171-176.
[7].熊世勤,来锡华..Csapase激活与调控的分子机制[J].生物化学与生物物理进展,2002,27(10):33-36
[8].Thornberry NA,Lazebnik Y.Caspase enemies within[J].Science,1998,281:1312.
[9].Wang J,Lenardo MJ.Roles of caspases in apoptosis,development and cytokine maturation revealed byhomozygous gene deficiencise[J].Cell,2000.113(Pt5):753-757.
[10].Femade-Alnemri T,Litwack G,Alnemri ES,et al.CPP32,anovel human apoptotic protein with homology to caenrohabditis elegans cell death protein Ced-3 and mammalian interletlkin-1beta-converting enzyme[J].Bid Chem,1994,269:30761.
[11].Nicholson DW,Ali A,Thomberry NA,et al.Identiifcation and inhibition of the ICE / CED-3pmteas enecessary for mammalian apoptosis[J].Nature,1995,376(6535):3743.
[12].Saikumar P,Dong Z,Mikhailov V,et al.Apoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489-506.
[13].Poter AG,Janicke RU.Emerging roles of Caspase-3 in apoptosis/J].Cell Death Difer,1999,6(2):99-104.
[14].Grutter MG.Caspase:key players in programmed cell death[J].Current Opinion in structural biology,2000,10(6):649-655
[15].Fantuzzi G.Puren AJ,Harding MW,et al.Interleukin-18 egulation of interferon gamma production and cell proliferation asshown in interleukin-lbeta-converting enzyme(caspase-1)-deficient mice[J].Blood,1998,91(6):2118-2125.
[16].Ghayur T,Banerjee S.Hugunin 1V1,et al.Caspase-1 processesIFN-game.-inducing factor and regulates LPSinduced IFN-gamma production[J].Nature,1997,386(6625):619-623
[17].Faucheu C,DiuA,Chan AW,et al.A noevl human protease similar to the interleukin-1 be ta convertign enzyme induces apoptosisintramsf-ted cells[J].EMBOJ,1995,14(9):1914-1922.
[18].BergeronL,PerezGI,MacdonaldG,et al.Defects in regulation of apoptosis in caspase-2deficient mice[J].GenesDev,1998,12(9):1304-1314.
[19].Honarpour N,Du C,Richardson JA,et al.Adult Apaf-1 deficient Mice exhibit male in fertility[J].DewBiol,2000,218(2):248-258.
[20].Hakem R,Hakem A,Duncan GS,et al.Differential requirement for caspase-9 in apoptotic pathways in vivo[J].Cell.1998,94(3):339-352
[21].Srinivasula SM,Femnades-Alnemri T,Zangrilli J,et al.TheCed-3/interleukin-1 beta ocnverting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32[J].Biol Chem,1996,271(43):27099-27106.
[22].Maier JK,Lahoua Z,Gendmn NH,et al.The neuronal apoptosis inhibitor protein is a direct in hibitor of Caspases-3 and Caspases-7[J].Neuro Sci,2002,22(6):2035-2043.
[23].Wang J,Zheng L,Lobito A,et al.Inheritde humana Caspase-10 mutations underlie defcetive lymphocyte and dendritic cell apoptosis in autoinmaune lymphopm liferative syndorme type Ⅱ[J].Cell.1999,98(1):47-58
[24].Brenner C.Kroemer G.The mitochondrion:decisive for cell death control? Signaling pathway in apoptosis.Hawood academic pub-lishers.1999,207-216.
[25].Ashkenazi A.Dixit VM.Death receptors:signaling and modulation.Science,1998.281(5381):1305-1308.
[26].Depraetere V.Golstein P.Dismantling in cell death;molecular mechanisms and relationship to caspase activation.[J]Immunol,1998,47(6):523-531.
[27].Saikumar P,Dong Z,Mikhailov V,et al.Apoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489-506.
[28].Budihardjo I,Oliver H,LuRer M,et al.Biochemical pathways of caspase activation during apoptosis[J].Annu Rev Cell Dev Biol,1999,15:(269-290)
[29].Poter AG,Janicke RU.Emerging roles of Caspase-3 in apoptosis[J].Cell Death Difer,1999,6(2):99-104.
[30].Tsujimoto Y,et al.Cloning of the chromosome breakpoint of neoplastic B cell swiththet(14;18)chromosome transilocation.Science,1984,226:1097.
[31].Vauxt DL,Cory S,Adram JM.Bcl-2 gene promotes haemoietic cell survival and cooperates with c-myc to immortalize pre-B cells[J].Nature,1988,335(6 189):440
[32].Folkman J.Angiogenesis and aopptosis[J].Semin Cancer Biol,2003,13(2):159.
[33].Steller H.mechanisms and genes of cellular suicide.Science,1995,267:1445-1448
[34].Sermadiras S,Dumas M,Joly B,et al.Expression of Bcl-2 and Bax in cultured normal human kerationcytes and melanocytes:relation ship to differentiation and melanogenesis.[J].Dermatol Bio.1997,137:883-889
[35].Folkman J.Angiogenesis and aopptosis[J].Semin Cancer Biol,2003,13(2):159
[36].Swanton E,Savory P,Cosulich S,et al.Bcl-2 regulates a Caspase-3/caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18(10):1778.
[37].Pant G,Orourke K,Dixit VM.Caspas-9,Bcl-xl,and Apaf-1 from a ternary complex[J].Bio chem,1996,273(10):5481.
[38].Gavrieal Y,Sherman Y.Identification of programmed cell death in situvia specific labeling of nuclear DNA fragmenation[J].J Cell Biol,1992,119(2):493-501
[39].Higaki K,Ynao H,Kojiro M.Fesantigen expression and its relationship with aopptosis in human hepatocellular carcinoma and noncancerous tissues[J].AmJ Pathol,1996,149(2):429-437.
[40].Petito CK,Oberts B.Effect of postmortem of DNA digonudesanes[J].Neuropathol,1995,54(6):761-765.