千金藤素对化疗药物减毒增效及抗肿瘤转移作用研究
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摘要
肿瘤是严重危害人类健康的疾病之一，目前治疗癌症的手段主要是手术切除、放疗或化疗。对于较早期未扩散或转移的癌灶，采用手术切除或放疗较为成功，但对于发现时已处于晚期的肿瘤患者则不甚理想；而且放、化疗在杀死癌细胞的同时，对增殖旺盛的正常细胞也有一定影响，导致呕吐、腹泻、脱发和骨髓抑制等不良反应，严重影响了患者的生存质量。本课题分别从体内实验和体外实验两个方面，研究了千金藤素联合化疗药物对肿瘤的抑制作用，并探讨了其提高机体免疫力、诱导肿瘤细胞凋亡、阻止肿瘤细胞侵袭等的可能机制。
通过口服千金藤素来明确其是否对肿瘤生长具有抑制作用：进行联合化疗药物的抑瘤实验，明确千金藤素是否对化疗药具有增效作用；检测白细胞、红细胞及血清ALT和BUN等的水平、骨髓有核细胞的数目，明确千金藤素对荷瘤化疗小鼠的一般药理学指标；分析千金藤素对脾脏、胸腺指数及白细胞的DNA的影响，明确千金藤素是否具有增强免疫的作用；然后，分别采用粘附分析实验、划痕实验、人工基底膜体外重建实验、明胶酶谱分析等方法观察千金藤素对人纤维肉瘤细胞HT1080等体外侵袭过程的影响；采用吖啶橙染色和流式细胞技术检测千金藤素对肿瘤细胞凋亡的诱导作用；采用集落形成法测定千金藤素对肿瘤细胞恶性程度的影响。
实验结果表明：1．千金藤素能够剂量依赖性地抑制小鼠移植实体瘤的生长，并对化疗药物有增效减毒作用。千金藤素明显延长荷瘤(S180)小鼠的生存期，腹腔注射千金藤素(20mg／kg体重)可使U14瘤重抑制率达30.8％(P＜0.01)；可使B16-F10瘤重抑制率达35.8％(P＜0.01)。与模型组比较，小鼠生存时间延长42.6％(P＜0.01)。千金藤素与CTX联合应用时，抑瘤活性明显提高(p＜0.01)。中、高剂量千金藤素(10、20mg／kg)与CTX联用组的抑瘤率(分别为44.9％和62.5％)要高于CTX单用组(p＜0.05，p＜0.01)。中、高剂量千金藤素与CTX联用后与单独使用CTX比较，可使化疗荷瘤小鼠外周红细胞明显增多(P＜0.01)，分别提高3.7％和8.3％，可使小鼠外周血红蛋白值明显升高(P＜0.01)，分别提高7.3％和9.1％。千金藤素与CTX联用后，治疗组较正常组，白细胞下降幅度较少，与CTX组相比差异显著(P＜0.01)；单独使用CTX组的荷瘤小鼠血清ALT水平显著高于正常组(P＜0.01)，千金藤素与CTX联用后，与CTX单用组相比差异显著(P＜0.01)；千金藤素与CTX联用后，与CTX单用组相比较，小鼠骨髓有核细胞数目显著(P＜0.01)增多；千金藤素与CTX联用后，小鼠脾淋巴细胞转化率显著(P＜0.01)升高。小鼠接种U14瘤株，千金藤素与CTX联用后，荷瘤小鼠的脾脏指数、胸腺指数有明显的提升(P＜0.01)；千金藤素能够剂量依赖性地预防环磷酰胺所致DNA损伤。以上结果说明千金藤素对CTX抑瘤能够产生一定的增效减毒作用。
2．千金藤素单独作用能够浓度依赖性地抑制人纤维肉瘤细胞HT-1080、肝癌细胞SMMC7721、Hela细胞等肿瘤细胞增殖(2～40μM)，药物对上述肿瘤细胞的IC50值分别为12.37±1.64μM，12.58±1.05μM，11.83±1.33μM(处理48 hr)；而且千金藤素能够诱导肝癌细胞凋亡。经AO／EB染色后，计数凋亡细胞，4μM千金藤素处理48小时SMMC7721细胞。细胞凋亡率可达24.7％(P＜0.01)。
3．千金藤素能够抑制肿瘤细胞浸润和转移。与对照组比较，4μM药物预处理48小时后，HT1080细胞的侵袭能力显著降低(p＜0.01)。而且能够剂量依赖性地显著抑制肿瘤细胞与基底膜的粘附，减弱肿瘤细胞的运动能力和侵袭力，降低基质金属蛋白酶2(MMP-2)的活性和表达量，上调金属蛋白酶组织抑制剂2(TIMP-2)的表达。
4．千金藤素低浓度、长时间作用降低肿瘤恶性程度，千金藤素4μM长时间处理SMMC7721细胞株。经过50代的处理，克隆形成率逐渐降低，细胞倍增时间逐渐增加。
结论：千金藤素能够剂量依赖性地抑制小鼠移植实体瘤的生长，延长荷瘤小鼠的生存时间，与化疗药物环磷酰胺联用，具有一定的增效减毒作用。千金藤素抑制肿瘤生长和肿瘤细胞凋亡的作用机制与其抑制肿瘤细胞降解基底膜、增强免疫力、降低细胞恶性程度等紧密相关。千金藤素有望研究开发成为一种新型的抗肿瘤药物。
Objective: Cancer is one of the diseases that mostly harmful to human health in theworld. The main means of cancer treatment is surgical resection, radiotherapy orchemotherapy. Surgical resection or radiotherapy is more successful for the early tumorpatients with no invasion and metastasis, but it is not ideal for patients with late tumors;Moreover, radiotherapy and chemotherapy also have a certain impact on the exuberantproliferation of normal cells while killing cancer cells, as a result, in vomiting, diarrhea,hair loss and bone marrow suppression and other adverse reactions, it seriouslyinfluenced the patients' life quality. In this study, effect of cepharanthine joint applicationwith chemotherapy drugs on inhibition of tumor were studied, and the possiblemechanism of cepharanthine raising organism immunity, inducing apoptosis of tumorcell and preventing invasion of tumor cell were approached in vivo and in vitro.
Methods: The effects of cepharanthine on inhibition of tumor growth was studied byoral administration cepharanthine; It was identified whether cepharanthine has thesynergies on chemotherapy drug through the inhibit-tumor experiment of cepharanthinejoint application with chemotherapy drugs; The general pharmacology indicators ofcepharanthine on chemotherapy bearing-tumor mice was identified by detecting the levelof WBC, erythrocyte, serum ALT and BUN, etc. and the number of bone marrow cells; Itwas identified whether cepharanthine has synergistic effects on immune system throughanalyzing the effect of cepharanthine on spleen index, thymus index and the impact ofleukocyte DNA; Then, the effect of cepharanthine on invasion process in vitro of humanHT1080 fibrosarcoma cells was observed through adhesion analysis assay, scarificationassay, artificial reconstruction of the basement membrane experiment gelatinase spectrumanalysis, Western blotting and so on in vitro; Induction of cepharanthine on tumor-cellapoptosis was detected using acridine orange staining and flow cytometry; Impact ofcepharanthine on the malignancy extent of tumor cells was detected applyingcolony-forming.
Results: The results show that: 1. Cepharanthine could dose-dependently inhibit thegrowth of transplanted solid tumors of mice, significantly extended life span ofbearing-tumor (S180), intraperitoneal injection of cepharatnhine (20 mg / kg body weight)could make inhibitory rate of U14 tumor weight reach 30.8% (P＜0.01); and inhibitoryrate of B16-F10 tumor weight reach 35.8% (P＜0.01). Compared with model group, lifespan of mice was extended at 42.6% (P＜0.01). When cepharanthine and CTX-jointapplied, antitumor activity was significantly increased (p＜0.01). Medium and high dosecepharanthine and CTX-joint application tumor inhibition rates (44.9% and 62.5 %) ishigher than that of CTX group (p＜0.05, p＜0.01); Medium and high dose cepharanthinecombined with CTX comparison to single CTX group, the peripheral red blood cells inmice could significantly increased (P＜0.01), 3.7% and 8.3% respectively. The peripheralhemoglobin in mice could significantly increased (P＜0.01), 7.3% and 9.1% respectively.Cepharanthine combined with CTX comparison to the normal group, the descentamplitude of white blood cells were less, but the difference was significant comparison toCTX group (P＜0.01); The mice spleen lymphocyte transformation rate were significantly(P＜0.01) increased compared with CTX group after cepharanthine combined with CTX,U14 tumor cell lines inoculation of mice, spleen index and thymus index oftumor-beating mice were significantly increased after cepharanthine combined with CTX(P＜0.01).Cepharanthine could dose-dependently prevent DNA damage induced bycyclophosphamide. The results indicated that cepharanthine has some attenuationsynergistic effect on anti-tumor of CTX.
2. Cepharanthine could concentration-dependently inhibit tumor cell proliferation (2～40μM) to people fibrosarcoma cells HT-1080, hepatoma carcinoma cell SMMC7721, Helacells and so on. IC50 values of drugs on the tumor cells were 12.37±1.64μM, 12.58±1.05μM, 11.83±1.33μM respectively (treated for 48 hr); Moreover cepharanthinecould induce apoptosis of hepatoma carcinoma cell. Apoptotic cell was counted after theAO / EB stained, when SMMC7721 cells were dealed with 4μM cepharanthine for 48hours, the apoptosis rate can reach 24.7% (P＜0.01).
3. Cepharanthine could inhibit tumor cell invasion and migration. Compared with thecontrol group, 4μM drug pretreatment 48 hours later, the invasiveness of HT1080 cellswas significantly decreased (p＜0.01). Moreover cepharanthine could dose-dependently inhibit the adhesion of tumor cell and basement membrane remarkably, weaken the motorability and invasiveness of tumor cell, reduce activity and expression quantity of MMP-2,up-regulate the expression of TIMP-2.
4. Cepharanthine could lower malignancy extent with low concentration and longprocessing time, SMMC7721 cells was treated using cepharanthine 4μM for a long time,after treatment of 50 generations, the colony formation rate was decreased gradually, andcell doubling time was increased gradually.
Conclusion: Cepharanthine could dose-dependently inhibit the growth of transplantedsolid tumors of mice, extended life span of bearing-tumor. It could play a certain synergiaand attenuation when combined with the chemotherapy drug cyclophosphamide. Themechanisms of cepharanthine inhibition tumor growth and tumor apoptosis is closelyrelated to its effect of inhibition tumor cell degradation basement membrane.Cepharanthine is expected to study and develop as a new type of anticancer drug.
通过口服千金藤素来明确其是否对肿瘤生长具有抑制作用：进行联合化疗药物的抑瘤实验，明确千金藤素是否对化疗药具有增效作用；检测白细胞、红细胞及血清ALT和BUN等的水平、骨髓有核细胞的数目，明确千金藤素对荷瘤化疗小鼠的一般药理学指标；分析千金藤素对脾脏、胸腺指数及白细胞的DNA的影响，明确千金藤素是否具有增强免疫的作用；然后，分别采用粘附分析实验、划痕实验、人工基底膜体外重建实验、明胶酶谱分析等方法观察千金藤素对人纤维肉瘤细胞HT1080等体外侵袭过程的影响；采用吖啶橙染色和流式细胞技术检测千金藤素对肿瘤细胞凋亡的诱导作用；采用集落形成法测定千金藤素对肿瘤细胞恶性程度的影响。
实验结果表明：1．千金藤素能够剂量依赖性地抑制小鼠移植实体瘤的生长，并对化疗药物有增效减毒作用。千金藤素明显延长荷瘤(S180)小鼠的生存期，腹腔注射千金藤素(20mg／kg体重)可使U14瘤重抑制率达30.8％(P＜0.01)；可使B16-F10瘤重抑制率达35.8％(P＜0.01)。与模型组比较，小鼠生存时间延长42.6％(P＜0.01)。千金藤素与CTX联合应用时，抑瘤活性明显提高(p＜0.01)。中、高剂量千金藤素(10、20mg／kg)与CTX联用组的抑瘤率(分别为44.9％和62.5％)要高于CTX单用组(p＜0.05，p＜0.01)。中、高剂量千金藤素与CTX联用后与单独使用CTX比较，可使化疗荷瘤小鼠外周红细胞明显增多(P＜0.01)，分别提高3.7％和8.3％，可使小鼠外周血红蛋白值明显升高(P＜0.01)，分别提高7.3％和9.1％。千金藤素与CTX联用后，治疗组较正常组，白细胞下降幅度较少，与CTX组相比差异显著(P＜0.01)；单独使用CTX组的荷瘤小鼠血清ALT水平显著高于正常组(P＜0.01)，千金藤素与CTX联用后，与CTX单用组相比差异显著(P＜0.01)；千金藤素与CTX联用后，与CTX单用组相比较，小鼠骨髓有核细胞数目显著(P＜0.01)增多；千金藤素与CTX联用后，小鼠脾淋巴细胞转化率显著(P＜0.01)升高。小鼠接种U14瘤株，千金藤素与CTX联用后，荷瘤小鼠的脾脏指数、胸腺指数有明显的提升(P＜0.01)；千金藤素能够剂量依赖性地预防环磷酰胺所致DNA损伤。以上结果说明千金藤素对CTX抑瘤能够产生一定的增效减毒作用。
2．千金藤素单独作用能够浓度依赖性地抑制人纤维肉瘤细胞HT-1080、肝癌细胞SMMC7721、Hela细胞等肿瘤细胞增殖(2～40μM)，药物对上述肿瘤细胞的IC50值分别为12.37±1.64μM，12.58±1.05μM，11.83±1.33μM(处理48 hr)；而且千金藤素能够诱导肝癌细胞凋亡。经AO／EB染色后，计数凋亡细胞，4μM千金藤素处理48小时SMMC7721细胞。细胞凋亡率可达24.7％(P＜0.01)。
3．千金藤素能够抑制肿瘤细胞浸润和转移。与对照组比较，4μM药物预处理48小时后，HT1080细胞的侵袭能力显著降低(p＜0.01)。而且能够剂量依赖性地显著抑制肿瘤细胞与基底膜的粘附，减弱肿瘤细胞的运动能力和侵袭力，降低基质金属蛋白酶2(MMP-2)的活性和表达量，上调金属蛋白酶组织抑制剂2(TIMP-2)的表达。
4．千金藤素低浓度、长时间作用降低肿瘤恶性程度，千金藤素4μM长时间处理SMMC7721细胞株。经过50代的处理，克隆形成率逐渐降低，细胞倍增时间逐渐增加。
结论：千金藤素能够剂量依赖性地抑制小鼠移植实体瘤的生长，延长荷瘤小鼠的生存时间，与化疗药物环磷酰胺联用，具有一定的增效减毒作用。千金藤素抑制肿瘤生长和肿瘤细胞凋亡的作用机制与其抑制肿瘤细胞降解基底膜、增强免疫力、降低细胞恶性程度等紧密相关。千金藤素有望研究开发成为一种新型的抗肿瘤药物。
Objective: Cancer is one of the diseases that mostly harmful to human health in theworld. The main means of cancer treatment is surgical resection, radiotherapy orchemotherapy. Surgical resection or radiotherapy is more successful for the early tumorpatients with no invasion and metastasis, but it is not ideal for patients with late tumors;Moreover, radiotherapy and chemotherapy also have a certain impact on the exuberantproliferation of normal cells while killing cancer cells, as a result, in vomiting, diarrhea,hair loss and bone marrow suppression and other adverse reactions, it seriouslyinfluenced the patients' life quality. In this study, effect of cepharanthine joint applicationwith chemotherapy drugs on inhibition of tumor were studied, and the possiblemechanism of cepharanthine raising organism immunity, inducing apoptosis of tumorcell and preventing invasion of tumor cell were approached in vivo and in vitro.
Methods: The effects of cepharanthine on inhibition of tumor growth was studied byoral administration cepharanthine; It was identified whether cepharanthine has thesynergies on chemotherapy drug through the inhibit-tumor experiment of cepharanthinejoint application with chemotherapy drugs; The general pharmacology indicators ofcepharanthine on chemotherapy bearing-tumor mice was identified by detecting the levelof WBC, erythrocyte, serum ALT and BUN, etc. and the number of bone marrow cells; Itwas identified whether cepharanthine has synergistic effects on immune system throughanalyzing the effect of cepharanthine on spleen index, thymus index and the impact ofleukocyte DNA; Then, the effect of cepharanthine on invasion process in vitro of humanHT1080 fibrosarcoma cells was observed through adhesion analysis assay, scarificationassay, artificial reconstruction of the basement membrane experiment gelatinase spectrumanalysis, Western blotting and so on in vitro; Induction of cepharanthine on tumor-cellapoptosis was detected using acridine orange staining and flow cytometry; Impact ofcepharanthine on the malignancy extent of tumor cells was detected applyingcolony-forming.
Results: The results show that: 1. Cepharanthine could dose-dependently inhibit thegrowth of transplanted solid tumors of mice, significantly extended life span ofbearing-tumor (S180), intraperitoneal injection of cepharatnhine (20 mg / kg body weight)could make inhibitory rate of U14 tumor weight reach 30.8% (P＜0.01); and inhibitoryrate of B16-F10 tumor weight reach 35.8% (P＜0.01). Compared with model group, lifespan of mice was extended at 42.6% (P＜0.01). When cepharanthine and CTX-jointapplied, antitumor activity was significantly increased (p＜0.01). Medium and high dosecepharanthine and CTX-joint application tumor inhibition rates (44.9% and 62.5 %) ishigher than that of CTX group (p＜0.05, p＜0.01); Medium and high dose cepharanthinecombined with CTX comparison to single CTX group, the peripheral red blood cells inmice could significantly increased (P＜0.01), 3.7% and 8.3% respectively. The peripheralhemoglobin in mice could significantly increased (P＜0.01), 7.3% and 9.1% respectively.Cepharanthine combined with CTX comparison to the normal group, the descentamplitude of white blood cells were less, but the difference was significant comparison toCTX group (P＜0.01); The mice spleen lymphocyte transformation rate were significantly(P＜0.01) increased compared with CTX group after cepharanthine combined with CTX,U14 tumor cell lines inoculation of mice, spleen index and thymus index oftumor-beating mice were significantly increased after cepharanthine combined with CTX(P＜0.01).Cepharanthine could dose-dependently prevent DNA damage induced bycyclophosphamide. The results indicated that cepharanthine has some attenuationsynergistic effect on anti-tumor of CTX.
2. Cepharanthine could concentration-dependently inhibit tumor cell proliferation (2～40μM) to people fibrosarcoma cells HT-1080, hepatoma carcinoma cell SMMC7721, Helacells and so on. IC50 values of drugs on the tumor cells were 12.37±1.64μM, 12.58±1.05μM, 11.83±1.33μM respectively (treated for 48 hr); Moreover cepharanthinecould induce apoptosis of hepatoma carcinoma cell. Apoptotic cell was counted after theAO / EB stained, when SMMC7721 cells were dealed with 4μM cepharanthine for 48hours, the apoptosis rate can reach 24.7% (P＜0.01).
3. Cepharanthine could inhibit tumor cell invasion and migration. Compared with thecontrol group, 4μM drug pretreatment 48 hours later, the invasiveness of HT1080 cellswas significantly decreased (p＜0.01). Moreover cepharanthine could dose-dependently inhibit the adhesion of tumor cell and basement membrane remarkably, weaken the motorability and invasiveness of tumor cell, reduce activity and expression quantity of MMP-2,up-regulate the expression of TIMP-2.
4. Cepharanthine could lower malignancy extent with low concentration and longprocessing time, SMMC7721 cells was treated using cepharanthine 4μM for a long time,after treatment of 50 generations, the colony formation rate was decreased gradually, andcell doubling time was increased gradually.
Conclusion: Cepharanthine could dose-dependently inhibit the growth of transplantedsolid tumors of mice, extended life span of bearing-tumor. It could play a certain synergiaand attenuation when combined with the chemotherapy drug cyclophosphamide. Themechanisms of cepharanthine inhibition tumor growth and tumor apoptosis is closelyrelated to its effect of inhibition tumor cell degradation basement membrane.Cepharanthine is expected to study and develop as a new type of anticancer drug.
引文
[1] 孙靖中，邹雄主编．肿瘤分子生物学．第1版．北京：人民卫生出版社，1998．2
[2] 李学文，张齐峰主编．常见恶性肿瘤．第1版．北京：科学技术文献出版社，1998．1
[3] 董志伟主编．临床肿瘤学．北京：人民卫生出版社，2002．3
[4] The Role of an 80 kDa Fragment of E-cadherin in the Metastatic Progression of Prostate Cancer, C Lin, Cancer Res, Dec 2003, 9:6447-6452
[5] E-Cadherin Phosphorylation by Protein Kinase D1/Protein Kinase Cμ is Associated with Altered Cellular Aggregation and Motility in Prostate Cancer, Cancer Res, 2005, 65:483-492
[6] Meyer T, Hart IR.Mechanisms of tumor metastasis. Eur J Cancer, 1998, 34(2):214-221
[7] Woodhouse EC, Chuaqui RF, Liotta LA. General mechanisms ofmetastasis. Cancer, 1997, 80(8 suppt): 1529-1537
[8] Sava G, Bergamo A. Drug control of solid tumor metastasis: a critical view. Anticancer Res, 1999, 19(2A): 1117-1124
[9] Meier F, Satyamoorthy K, Nesbit M, et al. Molecular events in melanoma development and progression. Front Biosci, 1998,3:1005-1010
[10] Nathanson SD. Insights into the mechanisms of lymph node metastasis.Cancer,2003; 98(2):413-423
[11] Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol, 2002, 3(3):207-214
[12] Mook OR, Frederiks WM, Van Noorden CJ. The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta,2004, 1705(2):69-89
[13] Bjorklund M, Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta,2005,1755(1):37-69
[14] Turpeenniemi-Hujanen T. Gelatinases (MMP-2 and -9) and their natural inhibitors as prognostic indicators in solid cancers. Biochimie,2005, 87(3-4):287-297
[15] Itoh Y, Nagase H. Matrix metalloproteinases in cancer.Essays Biocbem, 2002, 38:21-36
[16] Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res, 2003, 92(8):827-839
[17] Zucker S, Hymowitz M, Conner C, Zarrabi HM, Hurewitz AN, Matrisian L, Boyd D, Nicolson G, Montana S. Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Ann N Y Acad Sci, 1999, 878:212-227
[18] Morrison CJ, Butler GS, Bigg HF, Roberts CR, Soloway PD, Overall CM. Cellular activation of MMP-2 (gelatinase A) by MT2-MMP occurs via a TIMP-2-independent pathway. J Biol Chem, 2001,276(50):47402-47410
[19] Maeta H, Ohgi S, Terada T. Protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinase 1 and 2 in papillary thyroid carcinomas. Virchows Arch, 2001, 438(2):121-128
[20] Nagel H, Laskawi R, Wahlers A, Hemmerlein B.Expression of matrix metalloproteinases MMP-2, MMP-9 and their tissue inhibitors TIMP-1, -2, and -3 in benign and malignant tumours of the salivary gland. Histopathology, 2004, 44(3):222-231
[21] Khasigov PZ, Podobed OV, Gracheva TS, Salbiev KD, Grachev SV, Berezov TT. Role of matrix metalloproteinases and their inhibitors in tumor invasion and metastasis, Biochemistry, 2003, 68(7):711-717
[22] Giannelli G, Antonaci S. Gelatinases and their inhibitors in tumor metastasis: from biological research to medical applications. Histol Histopathol,2002, 17(1):339-345
[23] Anne Ahtikoski. Synthesis and degradation of muscle collagen during immobilization, glucocorticoid treatment and in neuromuscular diseases. Oulu university press, 2003,24-25
[24] Kerrigan JJ, Mansell JP, Sandy JR. Matrix turnover. J Orthod,2000,27(3):227-233
[25] Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics [J].British Journal of Cancer, 1972, 26:239
[26] 夏凤琴，李延钩．细胞凋亡[J]．国外医学-老年病学分册，1996，17(3)：123-125
[27] Wyllie AH. Apoptosis: mechanisms and roles in pathology [J].British Journal of Cancer, 1993, 67:205
[28] Vaux DL, Korsmeyer SJ. Cell death in development. Cell,1999,96:245-254
[29] Franko J, Pomfy M, Prnsbova T. Apoptosis and cell death (mechanisms, pharmacology and promise for the future). Acta Medica (Hradec Kralove),2000,43(2):63-68
[30] Boutonnat J, Barbier M, Muirhead K, et al. Response of chemosensitive and chemoresistant leukemic cell lines to drug therapy: simultaneous assessment of proliferation, apoptosis, and necrosis. Cytometry, 2000, 42(1):50-60
[31] Kamb A, Gruis NA, Weaver FT, et al. A cell cycle regulator potentially in genesis of many tumor types [J].Seience, 1994, 264:436
[32] Thornberry NA, Rano TA, Peterson EP, et al. Acombinational aPProach defines specificies of members of the easpase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem, 1997,272:17907-17911
[33] 姚林，王广谱．细胞凋亡与癌的发生[J]．卫生毒理学杂志，1996，10(3)：161-162
[34] Steven WH.To die or not to die: an overview of apoptosis and its role in disease[J].JAMA-Journal of the American Medical Association, 1998,279:300-307
[35] Fisher DE. Apoptosis in cancer therapy crossing the threshold[J].Cell, 1994,78:539-542
[36] 苏长青，龚西渝．细胞凋亡的形态特点及生物学意义．临床与实验病理学杂志，1996，12：346-348
[37] Majno G Joris I. Apoptosis, oncosis, and necrosis, An overview of cell death. Am J Pathol, 1995,146:3-15
[38] 彭黎明．吞噬细胞对凋亡细胞的识别与吞噬．中华病理学杂志，1999，28：304-306
[39] Nagata S. Apoptotic DNA fragmentation. Exp Cell Res, 2000,10:12-18
[40] 贺俊崎，范慕贞，房青．二氟甲基鸟氨酸及反义bcl-2协同HL-60细胞凋亡[J]．中华肿瘤杂志，2000，22(2)：105-108
[41] Sachs L, Lotem J.Control of programmed cell death in normal and leukemic cells: new implications for therapy[J].Blood, 1993,82:15-21
[42] Roberts JR, Allison DC, Donehower RC, etal.DeveloPment of PolyPloidization in taxol-resistant Human leukemia cell in vitro.Cancer Res, 1990,50(3):710-716
[43] Fang M,Zhang HQ,Xu SB.Apoptosis resistance and its reversal in harringtonine resistant cell line[J].Aeta Pharmacology Sinica, 1994,29:891
[44] Ormerod MG, Neill C, Robertson D, et al. Cis-diamminedichloroplatinum(Ⅱ)-induced cell death through apoptosis in sensitive and resistant human ovarian carcinoma cell lines [J]. Cancer Chemotherapy Pharmacology, 1996, 37:463-467
[45] Meyn RE,Stephens LC,Hunter NR, et al.Induction of apoptosis in murine tumors by cyclophosphaminde[J].Cancer Chemotherapy Pharmacology, 1994,33:410-419
[46] KeerJF, Winierford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy.Cancer,1994,73(8):2013-2026
[47] Yamamoto M, Maehara Y, Sakaguchi Y, et al.Transformin growth factor-beta 1 induces apoptosis in gastric cancer cells through a p53-independent pathway [J]. Cancer, 1996, 77(suppl 8): 1628-1633
[48] Gorczyea W, Gong JP, Darzynkiewicz Z.Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assay[J].CancerResearch, 1993,53:1945-1949
[49] Nieoletti I,Migliorati G,Pagliacci MC.A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry[J].Journal of Immunology Methods, 1991,139:271-278
[50] Vermes I, Haanen C,Steffens-Nakken H, et al.A novel assay for apoptosis.Flow cytimetric detection of phosphatidylserine expression on early apoptosis cells using fluorescein labeled Annexin V [J].Journal of Immunology Methods,1995,184:39
[51] 韩锐．抗癌药物研究与实验技术[M]．北京：中国协和医科大学联合出版社，1997．
[52] 吴振．紫草素诱导肿瘤细胞凋亡作用机制的研究．2004．
[53] 杨镇．肿瘤免疫学．武汉：湖北科学技术出版社，1998．1-9
[54] 杨镇．肿瘤免疫学[M]．武汉：湖北科学技术出版社，1998．31
[55] 刘重贞．结直肠癌患者肿瘤血管形成的临床病理意义初探．临床消化病杂志，2000，11(4)：175
[56] Anan K, Morisaki T, Kataon M, et al.Vascular endothelialgrowth factoraad platelet derived growth factor are potentialangiogenic and metastaticfactors in human breast cancer.Surgery, 1996,119(3):333
[57] 韩锐．抗癌药物与实验技术[M]．第1版．北京：北京医科大学和中国协和医科大学联合出版社，1997．116-146
[58] Kohno H,Tanaka T, Kawabata K, et al. Silymarin, a naturally occurring polyphenolie antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats.Int J Cancer, 2002,101(5):461-468
[59] Devasena T, Rajasekaran KN, MenonVP. Bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione(a curcumin analog) ameliorates DMH-induced hepatic oxidative stress during colon carcinogenesis.Pharmacol Res, 2002,46(1):39-45
[60] Murakami A, Takahashi D,Kinoshita T, et al. Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the alpha, beta-unsaturated carbonyl group is a prerequisite.Carcinogenesis, 2002,23(5):795-802
[61] Giardiello FM,Yang VW, Hylind LM, et al. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med,2002,346(14): 1054-1059
[62] 韩红梅，杨贵贞．人参三醇型皂试调整骨髓受抑模型鼠的免疫功能．中国免疫学杂志，1991，7(5)：312-316
[63] Takara K, Sakaeda T, okumura K.An update on overcoming MDRI-mediated multidrug resistance in cancer chernotherapy.Curr Pharm Des.2006,12(3):273-286
[64] Pusztai L, Siddik ZH, Mills GB, Bast RC Jr. Physiologic and Pathologic drugresistance in ovarian carcinoma-a hypothesis based on a clonal Porgression model.Acta Oncol. 1998,37(7-8):629-640
[65] Beck WT.The cell biology of multiple drug resistance.Biochem Pharmacol. 1987,36(18):2879-2887
[66] Lee JJ, Swain SM.Development of novel chemotherapeutic agents to evade the mechanisms of multidrug resistance(MDR).Sernin Oncol.2005,32(6 Suppl 7):S22-26
[67] BecK WT, The cell biology of multiple drug resistance [J]. Biochem Pharmacol, 1987,36(18):2879-2887
[68] Rhoads CD.Nitrogen mustards in treatment of neoplastic disease.JAMA. 1946,21:656-677
[69] Bush JA, Li G.Cancer chemoresistanee:therelationship Bewteen P53 and multidrug transporters.Int J Caneer.2002,98(3):323-330
[70] Bergman AM, Pinedo HM, Talianidis I, et al. Increased sensitivity to gemcitabine of P-glycopmtein and multidrug resisfence-associated protein-overexpressing human cancer cell lines[J].Br J Cancer,2003,88(12): 1963-1970
[71] Paumi CM, Wright M, Townsend AJ, et al. Multidrug resisfence protein MRPI and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-delta(12,14)prostaglandin J2 in MCF7 breast cancer cells[J].Biochemistry,2003,42(18):5429-5437
[72] Scheffer GL, SchroeijersAB, Izquierdo MA, et al. Lung resistance-related protein/major vaults in multidrug-resistant cancer[J]. Current Opinion Oneology, 2000, 12(6): 550-556
[73] 余慎初主编．中国药学史纲．第1版．昆明：云南科学技术出版社，1987．11
[74] 薛愚主编．中国药学史料．北京：人民卫生出版社，1984．3
[75] 青彬主编．肿瘤药理学与化学治疗学．河南：河南医科大学出版社，2002．5
[76] 丁健等．端粒酶活性调节的分子机制．生理科学进展，2001，32(3)：220-224
[77] Sanding V, Brand K, Herwing s,etal.Adenovirally transferred P16IN-K/CDK2 and P53 genes cooperate to induce apoptotic tumor cell death.NatMed, 1997,3(3):313-319
[78] 纪云晶，肖白，王宗惠等．轻稀土元素抗癌作用机理研究[J]．卫生毒理学杂志，1996，10(4)：223-227
[79] 李连达，靖雨珍，李映欧．中西医结合研究与开发中药新药[J]．中药药理与临床研究进展，1996，4：14-17
[80] 韩玉英，丰平，文朝阳．抗癌中草药研究进展．北京中医杂志，2003，22(2)：45
[81] 邵梦杨，王守章，郭秀梅．中西医结合临床肿瘤内科学．天津：天津科技翻译出版公司，1994．616
[82] 丘华兴等．中国科学院《中国植物志》编辑委员会编著．中国植物志．北京：科技出版社，1996．41
[83] 方圣鼎，陈嬿等．千金藤属生物碱的研究Ⅱ黄叶地不容中的生物碱．中草药．1981，12(02)：1-3
[84] Noriaki K, Jun T. aporphine glycosides from Stephania cepharantha seeds. Journal of Natural Products,2000,63 (04): 477-479
[85] Nakaoji K, Tanahashi T, Tanahashi T. Bisbenzylisoquinoline alkaloids from Stephania cepharantha and their effects on prolieration of cultured cells from the murine hair apparatus. Planta Medica, 1997,63(05): 425-428
[86] 崔俊屹．千金藤素的药理作用概述[J]．中草药，1995，(09)：502
[87] Okamoto M, Ono M, Baba M. Suppression of cytokine production and neural cell death by the anti-inflammatory alkaloid cepharanthine: a potential agent against HIV-1 encephalopathy. Biochem Pharmacol, 2001,62(6):747-753
[88] Sun Ya-feng, Tang Fang-ming, Zhang Guang-yi, Jin Guo-zhang. Effect of 1-Stepholidine on CaM KⅡ Activity in Brain Ischemic Injured Mongolian Gerbils Striatum and Hippocampus.The Chinese Academic Medical Magazine of Organisms,2003, (01):43-46
[89] 孟海燕，邸秀珍，毕国华，赵永岐，杨征．左旋四氢巴马汀和左旋千金藤啶碱对吗啡处理大鼠相关脑区神经胶质纤维酸性蛋白的影响．中国新药杂志，2007，(2)：24-26
[90] Kogure K, Goto S, Abe K, Ohiwa C, Akasu M, Terada H. Potent antiperoxidation activity of the bisbenzylisoquinoline alkaloid cepharanthine: the amine moiety is responsible for its pH-dependent radical scavenge activity. Biochim Biophys Acta, 1999,1426(1): 133-142
[91] 崔俊屹．千金藤素的药理作用概述[J]．中草药，1995，(09)：502
[92] Okamoto M, Ono M, Baba M. Potent inhibition of HIV type 1 replication by an antiinflammatory alkaloid, cepharanthine, in chronically infected monocytic cells. AIDS Res Hum Retroviruses, 1998,14(14):1239-1245
[93] Ohno N, Kreitman RJ, Saito T, Masamoto I, Uozumi K, Hanada S, Takeuchi S, Furukawa T, Sumizawa T, Arima T, Akiyama S. Augmentation of the activity of an immunotoxin, anti-Tac(Fv)-PFAOKDEL, in T cell lines infected with human T cell leukemia virus type-Ⅰ. Leuk Lymphoma, 2002,43(4):885-888
[94] Baba M, Okamoto M, Kashiwaba N, Ono M. Anti-HIV-1 activity and structure-activity relationship of cepharanoline derivatives in chronically infected cells. Antivir Chem Chemother, 2001,12(5):307-312
[95] Maruyama H, Kikuchi S, Kawaguchi K, Hasunuma R, Ono M, Ohbu M, Kumazawa Y. Suppression of lethal toxicity of endotoxin by biscoclaurine alkaloid cepbaranthine. Shock, 2000,13(2):160-165
[96] Okamoto M, Okamoto T, Baba M. Inhibition of human immunodeficiency virus type 1 replication by combination of transcription inhibitor K-12 and other antiretroviral agents in acutely and chronically infected cells. Antimicrob Agents Chemother, 1999,43(3):492-497
[97] Ikeda R, Che XF, Yamaguchi T, Ushiyama M, Zheng CL, Okumura H, Takeda Y, Shibayama Y, Nakamura K, Jeung HC, Furukawa T, Sumizawa T, Haraguchi M, Akiyama S, Yamada K. Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells. Cancer Sci, 2005,96(6):372-376
[98] Nomoto S, Irnada H, Ohguri T, Yahara K, Kato F, Morioka T, Korogi Y. Effect of Cepharanthine in preventing radiation induced normal tissue damage in prostate cancer. Gan To Kagaku Ryoho, 2004,31(7): 1063-1066
[99] Imada H, Nomoto S, Ohguri T, Yahara K, Kato F, Morioka T, Korogi Y. Effect of Cepharanthine to prevent radiation induced xerostomia in head and neck cancer. Gan To Kagaku Ryoho, 2004,31(7): 1041-1045
[100] Furusawa S, Wu J. The effects of biscoclaurine alkaloid cepharanthine on mammalian cells: implications for cancer, shock, and inflammatory diseases. Life Sci, 2007,80(12): 1073-1079
[101] Azuma M, Ashida Y, Tamatani T, Motegi K, Takamaru N, Ishimaru N, Hayashi Y, Sato M. Cepharanthine, a biscoclaurine alkaloid, prevents destruction of acinar tissues in murine Sj(o|¨)gren's syndrome. J Rheumatol, 2006,33(5):912-920
[102] Hayama M, Inoue R, Akiba S, Sato T. Inhibitory effect of cepharanthine on fibronectin production in growth factor-stimulated rat mesangial cells. Eur J Pharmacol, 2000,390(1-2):37-42
[103] Oyaizu H, Adachi Y, Yasumizu R, Ono M, Ikebukuro K, Fukuhara S, Ikehara S. Protection of T cells from radiation-induced apoptosis by Cepharanthine. Int Immunopharmacol, 2001, 1(12):2091-2099
[104] 李金陵，程爱明，荆宇红，赵国新，孟林敏．千金藤对免疫功能的作用[J]．中国冶金工业医学杂志，2002，(01)：5-6
[105] Tamez PA, Lantvit D, Lim E, Pezzuto JM. Chemosensitizing action of cepharanthine against drug-resistant human malaria, Plasmodium falciparum. J Ethnopharmacol,2005, 98(1-2): 137-142
[106] Haruki K, Bray PG, Ono M, Ward SA. Potent enhancement of the sensitivity of Plasmodium falciparum to chloroquine by the bisbenzylisoquinoline alkaloid cepharanthine. Antimicrob Agents Chernother, 2000,44(10):2706-2708
[107] Nagano M, Kanno T, Fujita H, Muranaka S, Fujiwara T, Utsumi K. Cepharanthine, an anti-inflammatory drug, suppresses mitochondrial membrane permeability transition. Physiol Chem Phys Med NMR, 2003,35(2):131-143
[108] 王庆端，江金花，孙文欣，夏薇．千金藤素抗炎镇痛作用的实验研究[J]．中国药学杂志，1999，(09)：594-597
[109] Murakami K, Cox RA, Hawkins HK, Schmalstieg FC, McGuire RW, Jodoin JM, Traber LD, Traber DL. Cepharanthine, an alkaloid from Stephania cepharantha, inhibits increased pulmonary vascular permeability in an ovine model of sepsis. Shock, 2003,20(1):46-51
[110] Murakami K, Okajima K, Uchilm M. The prevention of lipopolysaecharide-induced pulmonary vascular injury by pretreatment with cepharanthine in rats. Am J Respir Crit Care Med, 2000,161(1):57-63
[111] Mukai M, Che XF, Furukawa T, Sumizawa T, Aoki S, Ren XQ, Haraguchi M, Sugimoto Y, Kobayashi M, Takamatsu H, Akiyama S.Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells. Cancer Sci, 2003,94(6):557-563
[112] Sakaguchi S, Furusawa S, Wu J, Nagata K. Preventive effects of a biscoclaurine alkaloid, cepharanthine, on endotoxin or tumor necrosis factor-alpha-induced septic shock symptoms: involvement of from cell death in L929 cells and nitric oxide production in raw 264.7 cells. Int Immunopharmacol, 2007,7(2): 191-197
[113] Sogawa N, Sogawa CA, Abuku EI, Inoue T, Oda N, Kishi K, Furuta H. Opposing pharmacological actions of cepharanthine on lipopolysaccharide-induced histidine decarboxylase activity in mice spleens. Life Sci, 2001,68(12): 1395-1403
[114] Sato T, Morita I, Fujita H, Ono M, Kimishima A, Tomiyama J, Murota S. Pharmacological characterization of cepharanthin in chronic idiopathic thrombocytopenic purpura. Platelets, 2001,12(3): 156-162
[115] Ebina T, Ono M. Antitumor effect of the plant alkaloid preparation, cepharanthine Gan To Kagaku Ryoho,2001,28(2):211-215
[116] Furuyama H, Koga Y, Hamasaki K, Kuroki F, Itami N, Ishikawa Y. Effective treatment of cyclic thrombocytopenia with cepharanthine. Pediatr Int, 1999,41(5):584-585
[117] Nomura S, Matsuzaki T, Yamaoka M, Ozaki Y, Nagahama M, Yoshimura C, Kagawa H, Nakayama S, Fukuhara S. Genetic analysis of HLA- and HPA-typing in idiopathic(autoimmune) thrombocytopenic purpura patients treated with cepharanthine. Autoimmunity, 1999,30(2):99-105
[118] Harada K, Bando T, Yoshida H, Sato M. Characteristics of antitumour activity of cepharanthine against a human adenosquamous cell carcinoma cell line. Oral Oncol, 2001,37(8):643-651
[119] Kono K. Takahashi JA, Ueba T, Mori H, Hashimoto N, Fukumoto M. Effects of combination chemotherapy with iscoclaurine-derived alkaloid (Cepharanthine) and nimustine hydrochloride on malignant glioma cell lines. J Neurooncol, 2002,56(2): 101-108
[120] 郭青龙，雷治海．复方千金藤口服液对实验性肿瘤的治疗及对化疗减毒作用研究[J]．中国药师，2000，(05)：267-268
[121] Ono M, Tanaka N. Positive interaction of bisbenzylisoquinoline alkaloid, cepharanthine, with vinca alkaloid agents against human tumors. In Vivo, 1997,11(3):233-241.
[122] Ebina T, Ono M. Antitumor effect of the plant alkaloid preparation, cepharanthine Gan To Kagaku Ryoho,2001, 28(2):211-215
[123] Harada K, Supriatno, Yamamoto S, Kawaguchi S, Yoshida H, Sato M Cepharanthine exerts antitumor activity on oral squamous cell carcinoma cell lines by induction of p27Kip1. Anticancer Res, 2003,23(2B): 1441-1448
[124] Wu J, Suzuki H, Zhou YW, Liu W, Yoshihara M, Kato M, Akhand AA, Hayakawa A, Takeuchi K, Hossain K, Kurosawa M, Nakashima I. Cepharanthine activates caspases and induces apoptosis in Jurkat and K562 human leukemia cell lines. J Cell Biochem, 2001, 82(2):200-214
[125] Sogawa N, Sogawa CA, Abuku EI, Inoue T, Oda N, Kishi K, Furuta H. Opposing pharmacological actions of cepharanthine on lipopolysaccharide-induced histidine decarboxylase activity in mice spleens. Life Sci, 2001,68(12): 1395-1403
[126] Wang Y, Kuroda M, Gao XS, Akaki S, Asaumi J, Okumura Y, Shibuya K, Kawasaki S, Joja I, Kato H, Himei K, Dendo S, Kanazawa S, Hiraki Y.Cepharanthine enhances in vitro and in vivo thermosensitivity of a mouse fibrosarcoma, FSa-Ⅱ, based on increased apoptosis. Int J Mol Med, 2004,13(3):405-411
[127] Biswas KK, Tancharoen S, Sarker KP, Kawahara K, Hashiguchi T, Maruyama I. Cepharanthine triggers apoptosis in a human hepatocellular carcinoma cell line (HUH-7) through the activation of JNK1/2 and the downregulation of Akt. FEBS Lett, 2006, 580(2):703-710
[128] Furusawa S, Wu J, Fujimura T, Nakano S, Nemoto S, Takayanagi M, Sasaki K, Takayanagi Y. Cepharanthine inhibits proliferation of cancer cells by inducing apoptosis. Methods Find Exp Clin Pharmacol, 1998,20(2):87-97
[129] Wu J, Suzuki H, Akhand AA, Zhou YW, Hossain K, Nakashima I. Modes of activation of mitogen-activated protein kinases and their roles in cepharanthine-induced apoptosis in human leukemia cells. Cell Signal, 2002,14(6): 509-515
[130] Shiraishi N, Akiyama S, Nakagawa M, et al. Effect of bisbenzylisoquinoline (biscoclaurine) alkaloids on multidrug resistance in KB human cancer cells[J]. Cancer Res, 1987, 47(9): 2413-2416
[131] Hotta T, Tanimura H, Yarnaue H, Iwahashi M, Tani M, Tsunoda T, Tamai M, Noguchi K, Mizobata S, Arii K, Terasawa H. Modulation of multidrug resistance by cepharanthine in fresh human gastrointestinal tumor cells. Oneology, 1997,54(2): 153-157
[132] Hotta T, Tanimura H, Yamaue H, Iwahashi M, Tani M, Tsunoda T, Noguchi K, Mizobata S, Terasawa H. Synergistic effects of tamoxifen and cepharanthine for circumventing the multidrug resistance. Cancer Lett, 1996,107(1): 117-123
[133] Sumizawa T, Chen ZS, Chuman Y, Seto K, Furukawa T, Haraguchi M, Tani A, Shudo N, Akiyama SI. Reversal of multidrug resistance-associated protein-mediated drug resistance by the pyridine analog PAK-104P. Mol Pharmacol, 1997, 51(3):399-405
[134] Kitazono M, Okumura H, Ikeda R, Sumizawa T, Furukawa T, Nagayama S, Seto K, Aikou T, Akiyama S. Reversal of LRP-associated drug resistance in colon carcinoma SW-620 cells. Int J Cancer, 2001,91(1):126-131
[135] Nakajima A, Yamamoto Y, Taura K, Hata K, Fukumoto M, Uchinami H, Yonezawa K, Yamaoka Y. Beneficial effect of cepharanthine on overcoming drug-resistance of hepatocellular carcinoma. Int J Oncol, 2004,24(3):635-645
[136] Ikeda R, Che XF, Yamaguchi T, Ushiyama M, Zheng CL, Okumura H, Takeda Y, Shibayama Y, Nakamura K, Jeung HC, Furukawa T, Sumizawa T, Haraguchi M, Akiyama S, Yamada K. Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells. Cancer Sci, 2005, 96(6):372-376
[137] Aogi K, Nishiyama M, Kim R, Hirabayashi N, Toge T, Mizutani A, Okada K, Sumiyoshi H, Fujiwara Y, Yamakido M, Kusano T, Andoh T. Overcoming CPT-11 resistance by using a biscoclaurine alkaloid, cepharanthine, to modulate plasma tram-membrane potential. Int J Cancer, 1997,72(2):295-300
[138] Katsui K, Kuroda M, Wang Y, Komatsu M, Himei K, Takemoto M, Akaki S, Asaumi J, Kanazawa S, Hiraki Y. Cepharanthine enhances adriamycin sensitivity by synergistically accelerating apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR. Int J Oncol, 2004,25(1):47-56
[139] Okada K, Sakusabe N,. Kobayashi A, Hoshi N, Sato K. Prevention of lung metastasis by intra-tumoral injection of Cepharanthine and staphylococcal enterotoxin B in transplantable rat osteosarcoma. Jpn J Cancer Res, 1999,90(9):928-933
[140] 徐伟娟，蒋学华，张若琪．千金藤素在大鼠肠道内的吸收动力学[J]，华西药学杂志，2007，22(4)：416-418
[141] 黄丽春，张爱莲，陈家玉，李红．千金藤素在大鼠体内的吸收分布及排泄[J]．工业卫生与职业病，1998，(03)：177-178
[142] 黄丽春．千金藤素的LD_(50)及蓄积毒性实验．工业卫生与职业病，1998，(02)：100
[143] 张均田主编．现代药理实验方法．北京医科大学中国协和医科大学联合出版社，北京：1998．930
[144] 胡志力，温守功，于人江，朱燕．灵芝菌合剂抗肿瘤及增效减毒作用研究．山东中医药大学学报，2003，27：466-468
[145] Franke D, Philippi A, Tores F, Hager J, Ziegler A, K(o|¨)nig IR.On confidence intervals for genotype relative risks and attributable risks from case parent trio designs for eandidate-gene studies. Hum Hered, 2005;60(2):81-8
[146] 徐叔云，卞如濂，陈修主编．药理实验方法学．第3版．北京：人民卫生出版社，1982．1757
[147] 叶应妩，王毓三．全国临床检验操作规程．东南大学出版社，1991．64
[148] Wick W, Wagner S, Kerkau S, Dichgans J, Tonn JC, Weller M. BCL-2 promotes migration and invasiveness of human glioma cells. FEBS Lett, 1998, 440(3):419-424
[149] Malinda KM, Nomizu M, Chung M, Delgado M, Kuratomi Y, Yamada Y, Kleinman IIK, Ponce ML. Identification of laminin alphal and betal chain peptides active for endothelial cell adhesion, tube formation, and aortic sprouting. FASEB J, 1999,13(1):53-62
[150] Fishman DA, Kearns A, Chilukuri K, Bafetti LM, O'Toole EA, Georgacopoulos J, Ravosa MJ, Stack MS. Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type Ⅰ collagen. Invasion Metastasis, 1998,18(1):15-26
[151] Lalu, M.M., C. Csonka, Z. Giricz, T. Csont, R. Schulz & P. Ferdinandy: Preconditioning decreases ischemia/reperfusion-induced release and activation of matrix metalloproteinase-2. Biochem. Biophys. Res. Commun,2002,296:937-941
[152] Fishman DA, Liu YY, Ellerbroek SM, Sharon Stack M. Lysophosphatidic Acid Promotes Matrix Metalloproteinase (MMP) Activation and MMP-dependent Invasion in Ovarian Cancer Cells. Cancer Research,2001,61:3194-3199
[153] Ribble D, Goldstein NB, Norris DA, Shellman YG. A simple technique for quantifying apoptosis in 96-well plates. BMC Biotechnol, 2005, 5:12.
[154] Telford WG, King LE, Fraker PJ.Comparative evaluation of several DNA binding dyes in the detection of apoptosis-associated chromatin degradation by flow cytometry. Cytometry, 1992,13(2):137-143
[155] 姚林，王广谱．细胞凋亡与癌的发生[J]．卫生毒理学杂志，1996，10(3)：161-162
[156] Steven WH. To die or not to die: an overview of apoptosis and its role in disease[J].JAMA-Journal of the American Medical Association, 1998,279:300-307
[157] 陈意生．肿瘤分子细胞生物学．北京：人民军医出版社，2002．50-71
[158] Nelson AR,Rothenberg ML,Rothenberg ML.Matrix metalloproteinase biologic activity and clinical implications. Journal of Clinical Oncology, 2000,18(05): 1135-1149
[159] Curran S.Matrix metalloproteinases in tumor invasion and metastasis. Journal of Pathology, 1999,189(03)300-308
[160] Ara T,Inoue M, Inoue MD.etermination of imbalance between MMP-2 and TIMP-2 in human neuroblastoma by reverse-tranciption polymerase chain reaction and its correlation with tumor progression. Journal of Pediatric Surgery, 2000,35(03): 432-437
[161] Baker AH. Geoge SJ. Geoge SJ. Divergent effects of tissue inhibitor of metalloproteinase-1,-2 or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro TIMP-3 promotes apoptosis. Journal of Clinical Investigation, 1998, 101 (06): 1478-1487
[162] Ozdemir E, Okuno H, Okuno H. Role of matrix metalloproteinase-9 in the basement memebrane destruction of superficial urothelial carcinomas. Journal Of Urology, 1999,161 (04): 1359
[163] Sier CF, Verheijen JH. Verheijen JHEnhanced urinary gelainase activities (matrix metailoproteinase-2 and 9) are associated with early-stage bladder carcinoma: a cmparison with clinically used tumor markers. Clinical Cancer Research, 2000,6(06): 2333-2340
[164] Hoyhtya M, Hujanen E, Turpeenniemi-Hujanen T, Thorgeirsson U, Liotta LA, Tryggvason K. Modulation of type-Ⅳ collagenase activity and invasive behavior of metastatic human melanoma (A2058) cells in vitro by monoclonal antibodies to type-Ⅳ collagenase. Int J Cancer, 1990, 46(2):282-286
[165] DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE, Taylor SM. Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res,1992,52(3):701-708
[166] 张覃沐主编．抗肿瘤药物的药理与临床应用．第1版．郑州：河南医科大学出版社，1999．69
[167] 张志义，孙燕主编．恶性肿瘤化学治疗学．第1版．上海：上海科学技术出版社，1981．25-33
[168] 徐叔云，卞如镰，陈修主编．药理实验方法学．第1版．北京：人民卫生出版社，1982．1123
[169] 孟胜．克服化疗骨髓毒性的新尝试-反转录病毒介导的耐药基因转染．国外医学肿瘤学分册，1998，25(1)：16
[170] Qgawa M. Differation and proliferation of hematopois setm celltic. Blood, 1993,81(11):288498
[171] Droshkind K. Regulation of hemopoiesis by bone marrow stromal cells and their Produces. Annul REV Immmunol, 1990,8(2): 111-116
[172] 王炯，杨贵．“秘灵王”对骨随受抑模型鼠的免疫调整作用．中国免疫学杂志，1997，13(6)：36095
[173] 潘敏求，黎月恒，孙兆泉，等．癌复康片减低肿瘤化疗反应的临床和实验研究．中国中西医结合外科杂志，1999，5(4)：226-230
[174] Strom TB. The Parallel, time-dependent, bimodal change in LymPhocyte cholinergicbinding activity and cholinergic influence upon lymphocyte mediated cytotoxicity after lymphocyte activation. J Immunol, 1991,127:705-709
[175] Jackson JC. Influence of serotonin on the immune resoonse. Immunology,1985,54:505-507
[176] 杰拉尔德：P墨菲主编．黎介寿主译．肿瘤学手册．第1版．上海：上海科学技术出版社，1998．123
[177] 张均田主编．现代药理实验方法．第1版．北京：北京医科大学中国协和医科大学联合出版社，1998．701
[178] 柏洁，蔡定芳．中医药对放化疗免疫抑制的影响．中国中西医结合杂志，1999，19(2)：124
[179] 吴敏毓，刘恭植主编．医学免疫学．第3版．合肥：中国科学技术大学出版社，1999．137-150
[180] 燕敏，林言蔑，尹浩然等．围手术期静脉营养对胃癌患者免疫功能的影响．中华外科杂志，1990，28(12)：739
[181] 方建明，毕爱华．IL-2与肿瘤．国际免疫学杂志，1988，(01)：137-140
[182] 郑斯祥，王学民．肿瘤IL-2／LAK疗法研究进展．河北医药，1993，(05)：53-56
[183] Gao Y, Yang W, Pan M, et al. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med, 2003, 198(3): 433-442
[184] Kato Y, Tanaka Y, Miyagawa F, et al. Targeting of tumor cells for human gamma delta T cells by nonpeptide antigens. J Immunol, 2001, 167(9): 5092-5098
[185] Wilhelm M, Kunzmann V, Eckstein S, et al. Gamma delta T cells for immune therapy of patients with lymphoid malignancies. Blood, 2003, 102(1): 200-206
[186] Casetti R, Perretta G, Taglioni A, et al. Drug-induced expansion and differentiation of V gamma 9V delta 2 T cells in vivo: the role of exogenous IL-2. J Immunol, 2005, 175(3): 1593-1598
[187] Conti L, Casetti R, Candone M, et al. Reciprocal activating interaction between dendritic cells and parnidronate-stimulated gamma delta T cells: role of CD86 and inflammatory cytokines. J Immunol, 2005, 174(1): 252-260
[188] Kabelitz D, Wesch D, Pitters E, et al. Characterization of tumor reactivity of human V gamma 9V delta 2 gamma delta T cells in vitro and in SCID mice in vivo. J Immunol, 2004, 173(11): 6767-6776
[189] 孙达春，李小亮，张爱华，等．血小板活化对恶性肿瘤转移和预后影响的临床研究．中华血液学杂志，2002，23(9)：484-485
[190] Kim YJ, Borsing L, Varki NM, et al. P-selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci, 1998, 95:9325-9330
[191] 余耀，周信达，刘银坤．血小板粘附分子与肿瘤转移的研究进展．国外医学输血及血液分册，2000，23：5-7
[192] Kato Y, Fujita N, Yano H, et al. Suppression of experimental lun colonization of mouse colon adenocarcinoma 26 in vivo by an anti-idiotype monoclonal antibody recognizing a platelet surface molecule.Cancer Res, 1997,57(14):3040-3043
[193] Thurin M, Kieber-Emrnons T.SA-Lea and tumor metastasis: the old prediction and recent findings. Hybrid Hybridomics, 2002,21(2): 111-116
[2] 李学文，张齐峰主编．常见恶性肿瘤．第1版．北京：科学技术文献出版社，1998．1
[3] 董志伟主编．临床肿瘤学．北京：人民卫生出版社，2002．3
[4] The Role of an 80 kDa Fragment of E-cadherin in the Metastatic Progression of Prostate Cancer, C Lin, Cancer Res, Dec 2003, 9:6447-6452
[5] E-Cadherin Phosphorylation by Protein Kinase D1/Protein Kinase Cμ is Associated with Altered Cellular Aggregation and Motility in Prostate Cancer, Cancer Res, 2005, 65:483-492
[6] Meyer T, Hart IR.Mechanisms of tumor metastasis. Eur J Cancer, 1998, 34(2):214-221
[7] Woodhouse EC, Chuaqui RF, Liotta LA. General mechanisms ofmetastasis. Cancer, 1997, 80(8 suppt): 1529-1537
[8] Sava G, Bergamo A. Drug control of solid tumor metastasis: a critical view. Anticancer Res, 1999, 19(2A): 1117-1124
[9] Meier F, Satyamoorthy K, Nesbit M, et al. Molecular events in melanoma development and progression. Front Biosci, 1998,3:1005-1010
[10] Nathanson SD. Insights into the mechanisms of lymph node metastasis.Cancer,2003; 98(2):413-423
[11] Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol, 2002, 3(3):207-214
[12] Mook OR, Frederiks WM, Van Noorden CJ. The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta,2004, 1705(2):69-89
[13] Bjorklund M, Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta,2005,1755(1):37-69
[14] Turpeenniemi-Hujanen T. Gelatinases (MMP-2 and -9) and their natural inhibitors as prognostic indicators in solid cancers. Biochimie,2005, 87(3-4):287-297
[15] Itoh Y, Nagase H. Matrix metalloproteinases in cancer.Essays Biocbem, 2002, 38:21-36
[16] Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res, 2003, 92(8):827-839
[17] Zucker S, Hymowitz M, Conner C, Zarrabi HM, Hurewitz AN, Matrisian L, Boyd D, Nicolson G, Montana S. Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Ann N Y Acad Sci, 1999, 878:212-227
[18] Morrison CJ, Butler GS, Bigg HF, Roberts CR, Soloway PD, Overall CM. Cellular activation of MMP-2 (gelatinase A) by MT2-MMP occurs via a TIMP-2-independent pathway. J Biol Chem, 2001,276(50):47402-47410
[19] Maeta H, Ohgi S, Terada T. Protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinase 1 and 2 in papillary thyroid carcinomas. Virchows Arch, 2001, 438(2):121-128
[20] Nagel H, Laskawi R, Wahlers A, Hemmerlein B.Expression of matrix metalloproteinases MMP-2, MMP-9 and their tissue inhibitors TIMP-1, -2, and -3 in benign and malignant tumours of the salivary gland. Histopathology, 2004, 44(3):222-231
[21] Khasigov PZ, Podobed OV, Gracheva TS, Salbiev KD, Grachev SV, Berezov TT. Role of matrix metalloproteinases and their inhibitors in tumor invasion and metastasis, Biochemistry, 2003, 68(7):711-717
[22] Giannelli G, Antonaci S. Gelatinases and their inhibitors in tumor metastasis: from biological research to medical applications. Histol Histopathol,2002, 17(1):339-345
[23] Anne Ahtikoski. Synthesis and degradation of muscle collagen during immobilization, glucocorticoid treatment and in neuromuscular diseases. Oulu university press, 2003,24-25
[24] Kerrigan JJ, Mansell JP, Sandy JR. Matrix turnover. J Orthod,2000,27(3):227-233
[25] Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics [J].British Journal of Cancer, 1972, 26:239
[26] 夏凤琴，李延钩．细胞凋亡[J]．国外医学-老年病学分册，1996，17(3)：123-125
[27] Wyllie AH. Apoptosis: mechanisms and roles in pathology [J].British Journal of Cancer, 1993, 67:205
[28] Vaux DL, Korsmeyer SJ. Cell death in development. Cell,1999,96:245-254
[29] Franko J, Pomfy M, Prnsbova T. Apoptosis and cell death (mechanisms, pharmacology and promise for the future). Acta Medica (Hradec Kralove),2000,43(2):63-68
[30] Boutonnat J, Barbier M, Muirhead K, et al. Response of chemosensitive and chemoresistant leukemic cell lines to drug therapy: simultaneous assessment of proliferation, apoptosis, and necrosis. Cytometry, 2000, 42(1):50-60
[31] Kamb A, Gruis NA, Weaver FT, et al. A cell cycle regulator potentially in genesis of many tumor types [J].Seience, 1994, 264:436
[32] Thornberry NA, Rano TA, Peterson EP, et al. Acombinational aPProach defines specificies of members of the easpase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem, 1997,272:17907-17911
[33] 姚林，王广谱．细胞凋亡与癌的发生[J]．卫生毒理学杂志，1996，10(3)：161-162
[34] Steven WH.To die or not to die: an overview of apoptosis and its role in disease[J].JAMA-Journal of the American Medical Association, 1998,279:300-307
[35] Fisher DE. Apoptosis in cancer therapy crossing the threshold[J].Cell, 1994,78:539-542
[36] 苏长青，龚西渝．细胞凋亡的形态特点及生物学意义．临床与实验病理学杂志，1996，12：346-348
[37] Majno G Joris I. Apoptosis, oncosis, and necrosis, An overview of cell death. Am J Pathol, 1995,146:3-15
[38] 彭黎明．吞噬细胞对凋亡细胞的识别与吞噬．中华病理学杂志，1999，28：304-306
[39] Nagata S. Apoptotic DNA fragmentation. Exp Cell Res, 2000,10:12-18
[40] 贺俊崎，范慕贞，房青．二氟甲基鸟氨酸及反义bcl-2协同HL-60细胞凋亡[J]．中华肿瘤杂志，2000，22(2)：105-108
[41] Sachs L, Lotem J.Control of programmed cell death in normal and leukemic cells: new implications for therapy[J].Blood, 1993,82:15-21
[42] Roberts JR, Allison DC, Donehower RC, etal.DeveloPment of PolyPloidization in taxol-resistant Human leukemia cell in vitro.Cancer Res, 1990,50(3):710-716
[43] Fang M,Zhang HQ,Xu SB.Apoptosis resistance and its reversal in harringtonine resistant cell line[J].Aeta Pharmacology Sinica, 1994,29:891
[44] Ormerod MG, Neill C, Robertson D, et al. Cis-diamminedichloroplatinum(Ⅱ)-induced cell death through apoptosis in sensitive and resistant human ovarian carcinoma cell lines [J]. Cancer Chemotherapy Pharmacology, 1996, 37:463-467
[45] Meyn RE,Stephens LC,Hunter NR, et al.Induction of apoptosis in murine tumors by cyclophosphaminde[J].Cancer Chemotherapy Pharmacology, 1994,33:410-419
[46] KeerJF, Winierford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy.Cancer,1994,73(8):2013-2026
[47] Yamamoto M, Maehara Y, Sakaguchi Y, et al.Transformin growth factor-beta 1 induces apoptosis in gastric cancer cells through a p53-independent pathway [J]. Cancer, 1996, 77(suppl 8): 1628-1633
[48] Gorczyea W, Gong JP, Darzynkiewicz Z.Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assay[J].CancerResearch, 1993,53:1945-1949
[49] Nieoletti I,Migliorati G,Pagliacci MC.A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry[J].Journal of Immunology Methods, 1991,139:271-278
[50] Vermes I, Haanen C,Steffens-Nakken H, et al.A novel assay for apoptosis.Flow cytimetric detection of phosphatidylserine expression on early apoptosis cells using fluorescein labeled Annexin V [J].Journal of Immunology Methods,1995,184:39
[51] 韩锐．抗癌药物研究与实验技术[M]．北京：中国协和医科大学联合出版社，1997．
[52] 吴振．紫草素诱导肿瘤细胞凋亡作用机制的研究．2004．
[53] 杨镇．肿瘤免疫学．武汉：湖北科学技术出版社，1998．1-9
[54] 杨镇．肿瘤免疫学[M]．武汉：湖北科学技术出版社，1998．31
[55] 刘重贞．结直肠癌患者肿瘤血管形成的临床病理意义初探．临床消化病杂志，2000，11(4)：175
[56] Anan K, Morisaki T, Kataon M, et al.Vascular endothelialgrowth factoraad platelet derived growth factor are potentialangiogenic and metastaticfactors in human breast cancer.Surgery, 1996,119(3):333
[57] 韩锐．抗癌药物与实验技术[M]．第1版．北京：北京医科大学和中国协和医科大学联合出版社，1997．116-146
[58] Kohno H,Tanaka T, Kawabata K, et al. Silymarin, a naturally occurring polyphenolie antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats.Int J Cancer, 2002,101(5):461-468
[59] Devasena T, Rajasekaran KN, MenonVP. Bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione(a curcumin analog) ameliorates DMH-induced hepatic oxidative stress during colon carcinogenesis.Pharmacol Res, 2002,46(1):39-45
[60] Murakami A, Takahashi D,Kinoshita T, et al. Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the alpha, beta-unsaturated carbonyl group is a prerequisite.Carcinogenesis, 2002,23(5):795-802
[61] Giardiello FM,Yang VW, Hylind LM, et al. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med,2002,346(14): 1054-1059
[62] 韩红梅，杨贵贞．人参三醇型皂试调整骨髓受抑模型鼠的免疫功能．中国免疫学杂志，1991，7(5)：312-316
[63] Takara K, Sakaeda T, okumura K.An update on overcoming MDRI-mediated multidrug resistance in cancer chernotherapy.Curr Pharm Des.2006,12(3):273-286
[64] Pusztai L, Siddik ZH, Mills GB, Bast RC Jr. Physiologic and Pathologic drugresistance in ovarian carcinoma-a hypothesis based on a clonal Porgression model.Acta Oncol. 1998,37(7-8):629-640
[65] Beck WT.The cell biology of multiple drug resistance.Biochem Pharmacol. 1987,36(18):2879-2887
[66] Lee JJ, Swain SM.Development of novel chemotherapeutic agents to evade the mechanisms of multidrug resistance(MDR).Sernin Oncol.2005,32(6 Suppl 7):S22-26
[67] BecK WT, The cell biology of multiple drug resistance [J]. Biochem Pharmacol, 1987,36(18):2879-2887
[68] Rhoads CD.Nitrogen mustards in treatment of neoplastic disease.JAMA. 1946,21:656-677
[69] Bush JA, Li G.Cancer chemoresistanee:therelationship Bewteen P53 and multidrug transporters.Int J Caneer.2002,98(3):323-330
[70] Bergman AM, Pinedo HM, Talianidis I, et al. Increased sensitivity to gemcitabine of P-glycopmtein and multidrug resisfence-associated protein-overexpressing human cancer cell lines[J].Br J Cancer,2003,88(12): 1963-1970
[71] Paumi CM, Wright M, Townsend AJ, et al. Multidrug resisfence protein MRPI and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-delta(12,14)prostaglandin J2 in MCF7 breast cancer cells[J].Biochemistry,2003,42(18):5429-5437
[72] Scheffer GL, SchroeijersAB, Izquierdo MA, et al. Lung resistance-related protein/major vaults in multidrug-resistant cancer[J]. Current Opinion Oneology, 2000, 12(6): 550-556
[73] 余慎初主编．中国药学史纲．第1版．昆明：云南科学技术出版社，1987．11
[74] 薛愚主编．中国药学史料．北京：人民卫生出版社，1984．3
[75] 青彬主编．肿瘤药理学与化学治疗学．河南：河南医科大学出版社，2002．5
[76] 丁健等．端粒酶活性调节的分子机制．生理科学进展，2001，32(3)：220-224
[77] Sanding V, Brand K, Herwing s,etal.Adenovirally transferred P16IN-K/CDK2 and P53 genes cooperate to induce apoptotic tumor cell death.NatMed, 1997,3(3):313-319
[78] 纪云晶，肖白，王宗惠等．轻稀土元素抗癌作用机理研究[J]．卫生毒理学杂志，1996，10(4)：223-227
[79] 李连达，靖雨珍，李映欧．中西医结合研究与开发中药新药[J]．中药药理与临床研究进展，1996，4：14-17
[80] 韩玉英，丰平，文朝阳．抗癌中草药研究进展．北京中医杂志，2003，22(2)：45
[81] 邵梦杨，王守章，郭秀梅．中西医结合临床肿瘤内科学．天津：天津科技翻译出版公司，1994．616
[82] 丘华兴等．中国科学院《中国植物志》编辑委员会编著．中国植物志．北京：科技出版社，1996．41
[83] 方圣鼎，陈嬿等．千金藤属生物碱的研究Ⅱ黄叶地不容中的生物碱．中草药．1981，12(02)：1-3
[84] Noriaki K, Jun T. aporphine glycosides from Stephania cepharantha seeds. Journal of Natural Products,2000,63 (04): 477-479
[85] Nakaoji K, Tanahashi T, Tanahashi T. Bisbenzylisoquinoline alkaloids from Stephania cepharantha and their effects on prolieration of cultured cells from the murine hair apparatus. Planta Medica, 1997,63(05): 425-428
[86] 崔俊屹．千金藤素的药理作用概述[J]．中草药，1995，(09)：502
[87] Okamoto M, Ono M, Baba M. Suppression of cytokine production and neural cell death by the anti-inflammatory alkaloid cepharanthine: a potential agent against HIV-1 encephalopathy. Biochem Pharmacol, 2001,62(6):747-753
[88] Sun Ya-feng, Tang Fang-ming, Zhang Guang-yi, Jin Guo-zhang. Effect of 1-Stepholidine on CaM KⅡ Activity in Brain Ischemic Injured Mongolian Gerbils Striatum and Hippocampus.The Chinese Academic Medical Magazine of Organisms,2003, (01):43-46
[89] 孟海燕，邸秀珍，毕国华，赵永岐，杨征．左旋四氢巴马汀和左旋千金藤啶碱对吗啡处理大鼠相关脑区神经胶质纤维酸性蛋白的影响．中国新药杂志，2007，(2)：24-26
[90] Kogure K, Goto S, Abe K, Ohiwa C, Akasu M, Terada H. Potent antiperoxidation activity of the bisbenzylisoquinoline alkaloid cepharanthine: the amine moiety is responsible for its pH-dependent radical scavenge activity. Biochim Biophys Acta, 1999,1426(1): 133-142
[91] 崔俊屹．千金藤素的药理作用概述[J]．中草药，1995，(09)：502
[92] Okamoto M, Ono M, Baba M. Potent inhibition of HIV type 1 replication by an antiinflammatory alkaloid, cepharanthine, in chronically infected monocytic cells. AIDS Res Hum Retroviruses, 1998,14(14):1239-1245
[93] Ohno N, Kreitman RJ, Saito T, Masamoto I, Uozumi K, Hanada S, Takeuchi S, Furukawa T, Sumizawa T, Arima T, Akiyama S. Augmentation of the activity of an immunotoxin, anti-Tac(Fv)-PFAOKDEL, in T cell lines infected with human T cell leukemia virus type-Ⅰ. Leuk Lymphoma, 2002,43(4):885-888
[94] Baba M, Okamoto M, Kashiwaba N, Ono M. Anti-HIV-1 activity and structure-activity relationship of cepharanoline derivatives in chronically infected cells. Antivir Chem Chemother, 2001,12(5):307-312
[95] Maruyama H, Kikuchi S, Kawaguchi K, Hasunuma R, Ono M, Ohbu M, Kumazawa Y. Suppression of lethal toxicity of endotoxin by biscoclaurine alkaloid cepbaranthine. Shock, 2000,13(2):160-165
[96] Okamoto M, Okamoto T, Baba M. Inhibition of human immunodeficiency virus type 1 replication by combination of transcription inhibitor K-12 and other antiretroviral agents in acutely and chronically infected cells. Antimicrob Agents Chemother, 1999,43(3):492-497
[97] Ikeda R, Che XF, Yamaguchi T, Ushiyama M, Zheng CL, Okumura H, Takeda Y, Shibayama Y, Nakamura K, Jeung HC, Furukawa T, Sumizawa T, Haraguchi M, Akiyama S, Yamada K. Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells. Cancer Sci, 2005,96(6):372-376
[98] Nomoto S, Irnada H, Ohguri T, Yahara K, Kato F, Morioka T, Korogi Y. Effect of Cepharanthine in preventing radiation induced normal tissue damage in prostate cancer. Gan To Kagaku Ryoho, 2004,31(7): 1063-1066
[99] Imada H, Nomoto S, Ohguri T, Yahara K, Kato F, Morioka T, Korogi Y. Effect of Cepharanthine to prevent radiation induced xerostomia in head and neck cancer. Gan To Kagaku Ryoho, 2004,31(7): 1041-1045
[100] Furusawa S, Wu J. The effects of biscoclaurine alkaloid cepharanthine on mammalian cells: implications for cancer, shock, and inflammatory diseases. Life Sci, 2007,80(12): 1073-1079
[101] Azuma M, Ashida Y, Tamatani T, Motegi K, Takamaru N, Ishimaru N, Hayashi Y, Sato M. Cepharanthine, a biscoclaurine alkaloid, prevents destruction of acinar tissues in murine Sj(o|¨)gren's syndrome. J Rheumatol, 2006,33(5):912-920
[102] Hayama M, Inoue R, Akiba S, Sato T. Inhibitory effect of cepharanthine on fibronectin production in growth factor-stimulated rat mesangial cells. Eur J Pharmacol, 2000,390(1-2):37-42
[103] Oyaizu H, Adachi Y, Yasumizu R, Ono M, Ikebukuro K, Fukuhara S, Ikehara S. Protection of T cells from radiation-induced apoptosis by Cepharanthine. Int Immunopharmacol, 2001, 1(12):2091-2099
[104] 李金陵，程爱明，荆宇红，赵国新，孟林敏．千金藤对免疫功能的作用[J]．中国冶金工业医学杂志，2002，(01)：5-6
[105] Tamez PA, Lantvit D, Lim E, Pezzuto JM. Chemosensitizing action of cepharanthine against drug-resistant human malaria, Plasmodium falciparum. J Ethnopharmacol,2005, 98(1-2): 137-142
[106] Haruki K, Bray PG, Ono M, Ward SA. Potent enhancement of the sensitivity of Plasmodium falciparum to chloroquine by the bisbenzylisoquinoline alkaloid cepharanthine. Antimicrob Agents Chernother, 2000,44(10):2706-2708
[107] Nagano M, Kanno T, Fujita H, Muranaka S, Fujiwara T, Utsumi K. Cepharanthine, an anti-inflammatory drug, suppresses mitochondrial membrane permeability transition. Physiol Chem Phys Med NMR, 2003,35(2):131-143
[108] 王庆端，江金花，孙文欣，夏薇．千金藤素抗炎镇痛作用的实验研究[J]．中国药学杂志，1999，(09)：594-597
[109] Murakami K, Cox RA, Hawkins HK, Schmalstieg FC, McGuire RW, Jodoin JM, Traber LD, Traber DL. Cepharanthine, an alkaloid from Stephania cepharantha, inhibits increased pulmonary vascular permeability in an ovine model of sepsis. Shock, 2003,20(1):46-51
[110] Murakami K, Okajima K, Uchilm M. The prevention of lipopolysaecharide-induced pulmonary vascular injury by pretreatment with cepharanthine in rats. Am J Respir Crit Care Med, 2000,161(1):57-63
[111] Mukai M, Che XF, Furukawa T, Sumizawa T, Aoki S, Ren XQ, Haraguchi M, Sugimoto Y, Kobayashi M, Takamatsu H, Akiyama S.Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells. Cancer Sci, 2003,94(6):557-563
[112] Sakaguchi S, Furusawa S, Wu J, Nagata K. Preventive effects of a biscoclaurine alkaloid, cepharanthine, on endotoxin or tumor necrosis factor-alpha-induced septic shock symptoms: involvement of from cell death in L929 cells and nitric oxide production in raw 264.7 cells. Int Immunopharmacol, 2007,7(2): 191-197
[113] Sogawa N, Sogawa CA, Abuku EI, Inoue T, Oda N, Kishi K, Furuta H. Opposing pharmacological actions of cepharanthine on lipopolysaccharide-induced histidine decarboxylase activity in mice spleens. Life Sci, 2001,68(12): 1395-1403
[114] Sato T, Morita I, Fujita H, Ono M, Kimishima A, Tomiyama J, Murota S. Pharmacological characterization of cepharanthin in chronic idiopathic thrombocytopenic purpura. Platelets, 2001,12(3): 156-162
[115] Ebina T, Ono M. Antitumor effect of the plant alkaloid preparation, cepharanthine Gan To Kagaku Ryoho,2001,28(2):211-215
[116] Furuyama H, Koga Y, Hamasaki K, Kuroki F, Itami N, Ishikawa Y. Effective treatment of cyclic thrombocytopenia with cepharanthine. Pediatr Int, 1999,41(5):584-585
[117] Nomura S, Matsuzaki T, Yamaoka M, Ozaki Y, Nagahama M, Yoshimura C, Kagawa H, Nakayama S, Fukuhara S. Genetic analysis of HLA- and HPA-typing in idiopathic(autoimmune) thrombocytopenic purpura patients treated with cepharanthine. Autoimmunity, 1999,30(2):99-105
[118] Harada K, Bando T, Yoshida H, Sato M. Characteristics of antitumour activity of cepharanthine against a human adenosquamous cell carcinoma cell line. Oral Oncol, 2001,37(8):643-651
[119] Kono K. Takahashi JA, Ueba T, Mori H, Hashimoto N, Fukumoto M. Effects of combination chemotherapy with iscoclaurine-derived alkaloid (Cepharanthine) and nimustine hydrochloride on malignant glioma cell lines. J Neurooncol, 2002,56(2): 101-108
[120] 郭青龙，雷治海．复方千金藤口服液对实验性肿瘤的治疗及对化疗减毒作用研究[J]．中国药师，2000，(05)：267-268
[121] Ono M, Tanaka N. Positive interaction of bisbenzylisoquinoline alkaloid, cepharanthine, with vinca alkaloid agents against human tumors. In Vivo, 1997,11(3):233-241.
[122] Ebina T, Ono M. Antitumor effect of the plant alkaloid preparation, cepharanthine Gan To Kagaku Ryoho,2001, 28(2):211-215
[123] Harada K, Supriatno, Yamamoto S, Kawaguchi S, Yoshida H, Sato M Cepharanthine exerts antitumor activity on oral squamous cell carcinoma cell lines by induction of p27Kip1. Anticancer Res, 2003,23(2B): 1441-1448
[124] Wu J, Suzuki H, Zhou YW, Liu W, Yoshihara M, Kato M, Akhand AA, Hayakawa A, Takeuchi K, Hossain K, Kurosawa M, Nakashima I. Cepharanthine activates caspases and induces apoptosis in Jurkat and K562 human leukemia cell lines. J Cell Biochem, 2001, 82(2):200-214
[125] Sogawa N, Sogawa CA, Abuku EI, Inoue T, Oda N, Kishi K, Furuta H. Opposing pharmacological actions of cepharanthine on lipopolysaccharide-induced histidine decarboxylase activity in mice spleens. Life Sci, 2001,68(12): 1395-1403
[126] Wang Y, Kuroda M, Gao XS, Akaki S, Asaumi J, Okumura Y, Shibuya K, Kawasaki S, Joja I, Kato H, Himei K, Dendo S, Kanazawa S, Hiraki Y.Cepharanthine enhances in vitro and in vivo thermosensitivity of a mouse fibrosarcoma, FSa-Ⅱ, based on increased apoptosis. Int J Mol Med, 2004,13(3):405-411
[127] Biswas KK, Tancharoen S, Sarker KP, Kawahara K, Hashiguchi T, Maruyama I. Cepharanthine triggers apoptosis in a human hepatocellular carcinoma cell line (HUH-7) through the activation of JNK1/2 and the downregulation of Akt. FEBS Lett, 2006, 580(2):703-710
[128] Furusawa S, Wu J, Fujimura T, Nakano S, Nemoto S, Takayanagi M, Sasaki K, Takayanagi Y. Cepharanthine inhibits proliferation of cancer cells by inducing apoptosis. Methods Find Exp Clin Pharmacol, 1998,20(2):87-97
[129] Wu J, Suzuki H, Akhand AA, Zhou YW, Hossain K, Nakashima I. Modes of activation of mitogen-activated protein kinases and their roles in cepharanthine-induced apoptosis in human leukemia cells. Cell Signal, 2002,14(6): 509-515
[130] Shiraishi N, Akiyama S, Nakagawa M, et al. Effect of bisbenzylisoquinoline (biscoclaurine) alkaloids on multidrug resistance in KB human cancer cells[J]. Cancer Res, 1987, 47(9): 2413-2416
[131] Hotta T, Tanimura H, Yarnaue H, Iwahashi M, Tani M, Tsunoda T, Tamai M, Noguchi K, Mizobata S, Arii K, Terasawa H. Modulation of multidrug resistance by cepharanthine in fresh human gastrointestinal tumor cells. Oneology, 1997,54(2): 153-157
[132] Hotta T, Tanimura H, Yamaue H, Iwahashi M, Tani M, Tsunoda T, Noguchi K, Mizobata S, Terasawa H. Synergistic effects of tamoxifen and cepharanthine for circumventing the multidrug resistance. Cancer Lett, 1996,107(1): 117-123
[133] Sumizawa T, Chen ZS, Chuman Y, Seto K, Furukawa T, Haraguchi M, Tani A, Shudo N, Akiyama SI. Reversal of multidrug resistance-associated protein-mediated drug resistance by the pyridine analog PAK-104P. Mol Pharmacol, 1997, 51(3):399-405
[134] Kitazono M, Okumura H, Ikeda R, Sumizawa T, Furukawa T, Nagayama S, Seto K, Aikou T, Akiyama S. Reversal of LRP-associated drug resistance in colon carcinoma SW-620 cells. Int J Cancer, 2001,91(1):126-131
[135] Nakajima A, Yamamoto Y, Taura K, Hata K, Fukumoto M, Uchinami H, Yonezawa K, Yamaoka Y. Beneficial effect of cepharanthine on overcoming drug-resistance of hepatocellular carcinoma. Int J Oncol, 2004,24(3):635-645
[136] Ikeda R, Che XF, Yamaguchi T, Ushiyama M, Zheng CL, Okumura H, Takeda Y, Shibayama Y, Nakamura K, Jeung HC, Furukawa T, Sumizawa T, Haraguchi M, Akiyama S, Yamada K. Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells. Cancer Sci, 2005, 96(6):372-376
[137] Aogi K, Nishiyama M, Kim R, Hirabayashi N, Toge T, Mizutani A, Okada K, Sumiyoshi H, Fujiwara Y, Yamakido M, Kusano T, Andoh T. Overcoming CPT-11 resistance by using a biscoclaurine alkaloid, cepharanthine, to modulate plasma tram-membrane potential. Int J Cancer, 1997,72(2):295-300
[138] Katsui K, Kuroda M, Wang Y, Komatsu M, Himei K, Takemoto M, Akaki S, Asaumi J, Kanazawa S, Hiraki Y. Cepharanthine enhances adriamycin sensitivity by synergistically accelerating apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR. Int J Oncol, 2004,25(1):47-56
[139] Okada K, Sakusabe N,. Kobayashi A, Hoshi N, Sato K. Prevention of lung metastasis by intra-tumoral injection of Cepharanthine and staphylococcal enterotoxin B in transplantable rat osteosarcoma. Jpn J Cancer Res, 1999,90(9):928-933
[140] 徐伟娟，蒋学华，张若琪．千金藤素在大鼠肠道内的吸收动力学[J]，华西药学杂志，2007，22(4)：416-418
[141] 黄丽春，张爱莲，陈家玉，李红．千金藤素在大鼠体内的吸收分布及排泄[J]．工业卫生与职业病，1998，(03)：177-178
[142] 黄丽春．千金藤素的LD_(50)及蓄积毒性实验．工业卫生与职业病，1998，(02)：100
[143] 张均田主编．现代药理实验方法．北京医科大学中国协和医科大学联合出版社，北京：1998．930
[144] 胡志力，温守功，于人江，朱燕．灵芝菌合剂抗肿瘤及增效减毒作用研究．山东中医药大学学报，2003，27：466-468
[145] Franke D, Philippi A, Tores F, Hager J, Ziegler A, K(o|¨)nig IR.On confidence intervals for genotype relative risks and attributable risks from case parent trio designs for eandidate-gene studies. Hum Hered, 2005;60(2):81-8
[146] 徐叔云，卞如濂，陈修主编．药理实验方法学．第3版．北京：人民卫生出版社，1982．1757
[147] 叶应妩，王毓三．全国临床检验操作规程．东南大学出版社，1991．64
[148] Wick W, Wagner S, Kerkau S, Dichgans J, Tonn JC, Weller M. BCL-2 promotes migration and invasiveness of human glioma cells. FEBS Lett, 1998, 440(3):419-424
[149] Malinda KM, Nomizu M, Chung M, Delgado M, Kuratomi Y, Yamada Y, Kleinman IIK, Ponce ML. Identification of laminin alphal and betal chain peptides active for endothelial cell adhesion, tube formation, and aortic sprouting. FASEB J, 1999,13(1):53-62
[150] Fishman DA, Kearns A, Chilukuri K, Bafetti LM, O'Toole EA, Georgacopoulos J, Ravosa MJ, Stack MS. Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type Ⅰ collagen. Invasion Metastasis, 1998,18(1):15-26
[151] Lalu, M.M., C. Csonka, Z. Giricz, T. Csont, R. Schulz & P. Ferdinandy: Preconditioning decreases ischemia/reperfusion-induced release and activation of matrix metalloproteinase-2. Biochem. Biophys. Res. Commun,2002,296:937-941
[152] Fishman DA, Liu YY, Ellerbroek SM, Sharon Stack M. Lysophosphatidic Acid Promotes Matrix Metalloproteinase (MMP) Activation and MMP-dependent Invasion in Ovarian Cancer Cells. Cancer Research,2001,61:3194-3199
[153] Ribble D, Goldstein NB, Norris DA, Shellman YG. A simple technique for quantifying apoptosis in 96-well plates. BMC Biotechnol, 2005, 5:12.
[154] Telford WG, King LE, Fraker PJ.Comparative evaluation of several DNA binding dyes in the detection of apoptosis-associated chromatin degradation by flow cytometry. Cytometry, 1992,13(2):137-143
[155] 姚林，王广谱．细胞凋亡与癌的发生[J]．卫生毒理学杂志，1996，10(3)：161-162
[156] Steven WH. To die or not to die: an overview of apoptosis and its role in disease[J].JAMA-Journal of the American Medical Association, 1998,279:300-307
[157] 陈意生．肿瘤分子细胞生物学．北京：人民军医出版社，2002．50-71
[158] Nelson AR,Rothenberg ML,Rothenberg ML.Matrix metalloproteinase biologic activity and clinical implications. Journal of Clinical Oncology, 2000,18(05): 1135-1149
[159] Curran S.Matrix metalloproteinases in tumor invasion and metastasis. Journal of Pathology, 1999,189(03)300-308
[160] Ara T,Inoue M, Inoue MD.etermination of imbalance between MMP-2 and TIMP-2 in human neuroblastoma by reverse-tranciption polymerase chain reaction and its correlation with tumor progression. Journal of Pediatric Surgery, 2000,35(03): 432-437
[161] Baker AH. Geoge SJ. Geoge SJ. Divergent effects of tissue inhibitor of metalloproteinase-1,-2 or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro TIMP-3 promotes apoptosis. Journal of Clinical Investigation, 1998, 101 (06): 1478-1487
[162] Ozdemir E, Okuno H, Okuno H. Role of matrix metalloproteinase-9 in the basement memebrane destruction of superficial urothelial carcinomas. Journal Of Urology, 1999,161 (04): 1359
[163] Sier CF, Verheijen JH. Verheijen JHEnhanced urinary gelainase activities (matrix metailoproteinase-2 and 9) are associated with early-stage bladder carcinoma: a cmparison with clinically used tumor markers. Clinical Cancer Research, 2000,6(06): 2333-2340
[164] Hoyhtya M, Hujanen E, Turpeenniemi-Hujanen T, Thorgeirsson U, Liotta LA, Tryggvason K. Modulation of type-Ⅳ collagenase activity and invasive behavior of metastatic human melanoma (A2058) cells in vitro by monoclonal antibodies to type-Ⅳ collagenase. Int J Cancer, 1990, 46(2):282-286
[165] DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE, Taylor SM. Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res,1992,52(3):701-708
[166] 张覃沐主编．抗肿瘤药物的药理与临床应用．第1版．郑州：河南医科大学出版社，1999．69
[167] 张志义，孙燕主编．恶性肿瘤化学治疗学．第1版．上海：上海科学技术出版社，1981．25-33
[168] 徐叔云，卞如镰，陈修主编．药理实验方法学．第1版．北京：人民卫生出版社，1982．1123
[169] 孟胜．克服化疗骨髓毒性的新尝试-反转录病毒介导的耐药基因转染．国外医学肿瘤学分册，1998，25(1)：16
[170] Qgawa M. Differation and proliferation of hematopois setm celltic. Blood, 1993,81(11):288498
[171] Droshkind K. Regulation of hemopoiesis by bone marrow stromal cells and their Produces. Annul REV Immmunol, 1990,8(2): 111-116
[172] 王炯，杨贵．“秘灵王”对骨随受抑模型鼠的免疫调整作用．中国免疫学杂志，1997，13(6)：36095
[173] 潘敏求，黎月恒，孙兆泉，等．癌复康片减低肿瘤化疗反应的临床和实验研究．中国中西医结合外科杂志，1999，5(4)：226-230
[174] Strom TB. The Parallel, time-dependent, bimodal change in LymPhocyte cholinergicbinding activity and cholinergic influence upon lymphocyte mediated cytotoxicity after lymphocyte activation. J Immunol, 1991,127:705-709
[175] Jackson JC. Influence of serotonin on the immune resoonse. Immunology,1985,54:505-507
[176] 杰拉尔德：P墨菲主编．黎介寿主译．肿瘤学手册．第1版．上海：上海科学技术出版社，1998．123
[177] 张均田主编．现代药理实验方法．第1版．北京：北京医科大学中国协和医科大学联合出版社，1998．701
[178] 柏洁，蔡定芳．中医药对放化疗免疫抑制的影响．中国中西医结合杂志，1999，19(2)：124
[179] 吴敏毓，刘恭植主编．医学免疫学．第3版．合肥：中国科学技术大学出版社，1999．137-150
[180] 燕敏，林言蔑，尹浩然等．围手术期静脉营养对胃癌患者免疫功能的影响．中华外科杂志，1990，28(12)：739
[181] 方建明，毕爱华．IL-2与肿瘤．国际免疫学杂志，1988，(01)：137-140
[182] 郑斯祥，王学民．肿瘤IL-2／LAK疗法研究进展．河北医药，1993，(05)：53-56
[183] Gao Y, Yang W, Pan M, et al. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med, 2003, 198(3): 433-442
[184] Kato Y, Tanaka Y, Miyagawa F, et al. Targeting of tumor cells for human gamma delta T cells by nonpeptide antigens. J Immunol, 2001, 167(9): 5092-5098
[185] Wilhelm M, Kunzmann V, Eckstein S, et al. Gamma delta T cells for immune therapy of patients with lymphoid malignancies. Blood, 2003, 102(1): 200-206
[186] Casetti R, Perretta G, Taglioni A, et al. Drug-induced expansion and differentiation of V gamma 9V delta 2 T cells in vivo: the role of exogenous IL-2. J Immunol, 2005, 175(3): 1593-1598
[187] Conti L, Casetti R, Candone M, et al. Reciprocal activating interaction between dendritic cells and parnidronate-stimulated gamma delta T cells: role of CD86 and inflammatory cytokines. J Immunol, 2005, 174(1): 252-260
[188] Kabelitz D, Wesch D, Pitters E, et al. Characterization of tumor reactivity of human V gamma 9V delta 2 gamma delta T cells in vitro and in SCID mice in vivo. J Immunol, 2004, 173(11): 6767-6776
[189] 孙达春，李小亮，张爱华，等．血小板活化对恶性肿瘤转移和预后影响的临床研究．中华血液学杂志，2002，23(9)：484-485
[190] Kim YJ, Borsing L, Varki NM, et al. P-selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci, 1998, 95:9325-9330
[191] 余耀，周信达，刘银坤．血小板粘附分子与肿瘤转移的研究进展．国外医学输血及血液分册，2000，23：5-7
[192] Kato Y, Fujita N, Yano H, et al. Suppression of experimental lun colonization of mouse colon adenocarcinoma 26 in vivo by an anti-idiotype monoclonal antibody recognizing a platelet surface molecule.Cancer Res, 1997,57(14):3040-3043
[193] Thurin M, Kieber-Emrnons T.SA-Lea and tumor metastasis: the old prediction and recent findings. Hybrid Hybridomics, 2002,21(2): 111-116
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