通关藤注射液联合铂类药物治疗原发性肝癌的实验研究
|
摘要
原发性肝癌是我国最常见的恶性肿瘤之一,严重威胁人类的健康和生命。由于该病起病隐袭、进展迅速、早期诊断率低,大多数病人在确诊时已达中晚期,往往失去了手术治疗的机会,只能进行姑息性的系统治疗和支持对症治疗。以往认为肝癌化疗效果差,易产生多药耐药,有效率低,加上化疗药物毒副作用较大,有关研究进展缓慢,急需突破。研究新的高效低毒的治疗药物和合理的中西医结合治疗方案以提高肝癌的治疗效果是肿瘤工作者探索并亟待攻克的难题。
消癌平注射液系由植物通关藤的根、茎或叶经现代工艺所制成的中药制剂,为国家正式上市产品。临床被应用于治疗各种癌症和咳嗽、哮喘等疾病。但目前基础研究十分薄弱,临床研究相当粗浅,有必要对消癌平注射液抗肝癌及其作用机制进行深入而系统的研究。
通过文献考证通关藤制剂的抗肿瘤作用及其机制,明确了通关藤制剂的植物来源和抗肿瘤有效成分,为该类中药有效成分抗肿瘤研究提供了理论依据,从而更好地对其开发利用。实验研究表明:消癌平注射液对体内外肝癌细胞均有一定的抑制作用,其抑制作用随着时间的延长和浓度的增加而逐渐增强。消癌平的抗癌作用可能具有多样化和多靶点的特点,能使癌细胞G_0/G_1期细胞增多,G_2/M期细胞减少,并在形态学上出现诱导凋亡的一些表现;可以抑制Ki-67蛋白表达,使得凋亡抑制蛋白Bcl-2表达减弱,促凋亡蛋白Bax表达增强。
顺铂是原发性肝癌的基本化疗药物之一,但是毒性显著,应用明显受限;如今多种新型铂类药物已经陆续问世,高效低毒,明显提高了其他消化道癌的化疗效果且耐受性良好。在体外实验研究中,比较了不同的铂类药物对于肝癌细胞株HEPG2、SMMC-7721和Bel-7402的抑制作用,为临床上选择恰当的铂类药物治疗肝癌提供参考依据。采用MTT法检测加入不同铂类药物后对于肝癌细胞的抑制作用,观察给药前、后肝癌细胞的形态学变化,计算半数抑制浓度,绘制肝癌细胞生长曲线。流式细胞分析给药后细胞周期的变化。结果显示给予铂类药物后肝癌细胞生长减慢,胞浆内颗粒增多;随着给药时间延长,对肝癌细胞的抑制作用逐渐增强。对于肝癌细胞的抑制作用,顺铂和奥沙利铂强于洛铂、奈达铂和卡铂。流式细胞分析不同铂类药物对细胞周期的变化趋于一致。因此,在体外研究中明确了铂类药物对于肝癌细胞具有抑制作用,顺铂仍为基本用药,而奥沙利铂具有一定的优势,可推荐在临床上用于治疗原发性肝癌。
联合作用的实验研究表明,消癌平与铂类药物对肝癌细胞的抑制作用具有协同作用,这种协同作用需在消癌平达到一定的剂量水平时表现明显;可以增强铂类药物对肝癌的抑制作用。对其协同作用的机制尚待深入研究。
Primary liver cancer is one of the most common malignant tumor in China, a serious threat to human health and life. Because of hidden hit of the disease onset, progress rapidly, the low rate of early diagnosis, most patients had reached advanced stage of disease at the time of diagnosis. Surgical treatment is often lost opportunity with these patients and those can only palliative treatment of the symptomatic treatment and support. Consider the effect of chemotherapy was bad. easy to produce multi-drug resistance, have low efficiency, coupled with drug side effects of chemotherapy drugs, the slow progress of the study, much-needed breakthrough. Research on new drugs and efficient treatment of low toxicity and reasonable treatment in traditional Chinese and western medicine in order to improve the treatment of liver tumor are need to explore and overcome problems.
Xiaoaiping Injection came from the rattan plant root, stem or leaf and was made by the modern process of Marsdenia tenacissima. It being used in clinical treatment of various types of cancer and cough, asthma and other diseases. But it was very weak in basic research and clinical research rather shallow, there have a requirement with depth and systematic study for Xiaoaiping injection and its mechanism of anti-liver cancer.
The article reviewed the progress in the research of antitumor activities and mechanisms of Marsdenia tenacissima. Its origin producing area and antitumor constituents were analyzed. It provides theoretical evidences for study on constituents in this traditional Chinese medicine. Futher studies on the species in Marsdenia tenacissima are needed for better medicinal utilization. Experimental results showed that: Xiaoaiping injection inhibited liver cancer cells in vitro and in vivo, its inhibition increased with the time and concentration gradually. Xiaoaiping had anticancer effects of diversification and target many of the characteristics of cancer cells. It could increase cells in G_0/G_1 phase, decrease cells in G_2/M phase and morphological appeared on some of the performance of induction of apoptosis; It could inhibit the expression of Ki-67 protein, the inhibitor of apoptosis protein Bcl-2 expression decreased, Bax protein expression enhanced.
Cisplatin was one of the essential drag in chemotherapy of hepatocellular carcinoma. It was restricted in clinical application because of its toxicity. To explore the different effect of different platinum complexes in human hepatocellular carcinoma cell line (HEPG2, SMMC-7721 and Bel-7402) by experiment in vitro, this experiment intent to dedicate evidence for choosing platinum complexes in clinical chemotherapy of hepatocellular carcinoma. To observe the cellular morphology after being given different platinum complexes. To calculate inhibitory concentration (IC50) and get cell growth curve by MTT. The cell cycle was analyzed by flow cytometry. We observed the decrease of cell growth, increase of particle of endochylema; increase of the depressant effect to human hepatocellular carcinoma cell line with the increase of time being given platinum complexes. Cisplatin and Oxaliplatin were better than lobaplatin, nedaplatin and carboplatin in the depressant effect to human hepatocellular carcinoma cell line. FCM analysis showed that there appeared similar change in cell cycle after being given platinum complexes. Those showed platinum complexes had depressant effect to human hepatocellular carcinoma cell line in vitro. Cisplatin was the essential drug and Oxaliplatin was another better choice for clinical chemotherapy of hepatocellular carcinoma. The two drags were prefered in chemotherapy of hepatocellular carcinoma.
The role of the United experimental studies had shown that Xiaoaiping with platinum-based drags on liver cancer cells in vitro displayed synergy. Xiaoaiping needed to reach a certain dose level with the synergy of performance significantly. It could enhance platinum-based drags on inhibition of liver cancer. The mechanism of their synergy had yet to be studied in future.
消癌平注射液系由植物通关藤的根、茎或叶经现代工艺所制成的中药制剂,为国家正式上市产品。临床被应用于治疗各种癌症和咳嗽、哮喘等疾病。但目前基础研究十分薄弱,临床研究相当粗浅,有必要对消癌平注射液抗肝癌及其作用机制进行深入而系统的研究。
通过文献考证通关藤制剂的抗肿瘤作用及其机制,明确了通关藤制剂的植物来源和抗肿瘤有效成分,为该类中药有效成分抗肿瘤研究提供了理论依据,从而更好地对其开发利用。实验研究表明:消癌平注射液对体内外肝癌细胞均有一定的抑制作用,其抑制作用随着时间的延长和浓度的增加而逐渐增强。消癌平的抗癌作用可能具有多样化和多靶点的特点,能使癌细胞G_0/G_1期细胞增多,G_2/M期细胞减少,并在形态学上出现诱导凋亡的一些表现;可以抑制Ki-67蛋白表达,使得凋亡抑制蛋白Bcl-2表达减弱,促凋亡蛋白Bax表达增强。
顺铂是原发性肝癌的基本化疗药物之一,但是毒性显著,应用明显受限;如今多种新型铂类药物已经陆续问世,高效低毒,明显提高了其他消化道癌的化疗效果且耐受性良好。在体外实验研究中,比较了不同的铂类药物对于肝癌细胞株HEPG2、SMMC-7721和Bel-7402的抑制作用,为临床上选择恰当的铂类药物治疗肝癌提供参考依据。采用MTT法检测加入不同铂类药物后对于肝癌细胞的抑制作用,观察给药前、后肝癌细胞的形态学变化,计算半数抑制浓度,绘制肝癌细胞生长曲线。流式细胞分析给药后细胞周期的变化。结果显示给予铂类药物后肝癌细胞生长减慢,胞浆内颗粒增多;随着给药时间延长,对肝癌细胞的抑制作用逐渐增强。对于肝癌细胞的抑制作用,顺铂和奥沙利铂强于洛铂、奈达铂和卡铂。流式细胞分析不同铂类药物对细胞周期的变化趋于一致。因此,在体外研究中明确了铂类药物对于肝癌细胞具有抑制作用,顺铂仍为基本用药,而奥沙利铂具有一定的优势,可推荐在临床上用于治疗原发性肝癌。
联合作用的实验研究表明,消癌平与铂类药物对肝癌细胞的抑制作用具有协同作用,这种协同作用需在消癌平达到一定的剂量水平时表现明显;可以增强铂类药物对肝癌的抑制作用。对其协同作用的机制尚待深入研究。
Primary liver cancer is one of the most common malignant tumor in China, a serious threat to human health and life. Because of hidden hit of the disease onset, progress rapidly, the low rate of early diagnosis, most patients had reached advanced stage of disease at the time of diagnosis. Surgical treatment is often lost opportunity with these patients and those can only palliative treatment of the symptomatic treatment and support. Consider the effect of chemotherapy was bad. easy to produce multi-drug resistance, have low efficiency, coupled with drug side effects of chemotherapy drugs, the slow progress of the study, much-needed breakthrough. Research on new drugs and efficient treatment of low toxicity and reasonable treatment in traditional Chinese and western medicine in order to improve the treatment of liver tumor are need to explore and overcome problems.
Xiaoaiping Injection came from the rattan plant root, stem or leaf and was made by the modern process of Marsdenia tenacissima. It being used in clinical treatment of various types of cancer and cough, asthma and other diseases. But it was very weak in basic research and clinical research rather shallow, there have a requirement with depth and systematic study for Xiaoaiping injection and its mechanism of anti-liver cancer.
The article reviewed the progress in the research of antitumor activities and mechanisms of Marsdenia tenacissima. Its origin producing area and antitumor constituents were analyzed. It provides theoretical evidences for study on constituents in this traditional Chinese medicine. Futher studies on the species in Marsdenia tenacissima are needed for better medicinal utilization. Experimental results showed that: Xiaoaiping injection inhibited liver cancer cells in vitro and in vivo, its inhibition increased with the time and concentration gradually. Xiaoaiping had anticancer effects of diversification and target many of the characteristics of cancer cells. It could increase cells in G_0/G_1 phase, decrease cells in G_2/M phase and morphological appeared on some of the performance of induction of apoptosis; It could inhibit the expression of Ki-67 protein, the inhibitor of apoptosis protein Bcl-2 expression decreased, Bax protein expression enhanced.
Cisplatin was one of the essential drag in chemotherapy of hepatocellular carcinoma. It was restricted in clinical application because of its toxicity. To explore the different effect of different platinum complexes in human hepatocellular carcinoma cell line (HEPG2, SMMC-7721 and Bel-7402) by experiment in vitro, this experiment intent to dedicate evidence for choosing platinum complexes in clinical chemotherapy of hepatocellular carcinoma. To observe the cellular morphology after being given different platinum complexes. To calculate inhibitory concentration (IC50) and get cell growth curve by MTT. The cell cycle was analyzed by flow cytometry. We observed the decrease of cell growth, increase of particle of endochylema; increase of the depressant effect to human hepatocellular carcinoma cell line with the increase of time being given platinum complexes. Cisplatin and Oxaliplatin were better than lobaplatin, nedaplatin and carboplatin in the depressant effect to human hepatocellular carcinoma cell line. FCM analysis showed that there appeared similar change in cell cycle after being given platinum complexes. Those showed platinum complexes had depressant effect to human hepatocellular carcinoma cell line in vitro. Cisplatin was the essential drug and Oxaliplatin was another better choice for clinical chemotherapy of hepatocellular carcinoma. The two drags were prefered in chemotherapy of hepatocellular carcinoma.
The role of the United experimental studies had shown that Xiaoaiping with platinum-based drags on liver cancer cells in vitro displayed synergy. Xiaoaiping needed to reach a certain dose level with the synergy of performance significantly. It could enhance platinum-based drags on inhibition of liver cancer. The mechanism of their synergy had yet to be studied in future.
引文
1.邢旺兴,陈斌,宓鹤鸣,等.乌骨藤辨考[J].中药材,2003,26(7):524-526.
2.邢旺兴,程荣珍,陈斌,等.乌骨藤常见混用品种辨析[J].现代中药研究与实践,2004,18(1):33-36.
3.国家中医药管理局、《中华本草》编委会.中华本草(第3册)[M].上海:上海科学技术出版社,1999:7.
4.张雪莹,张慧,翟延君.通关藤两个化合物的研究[J].辽宁中医药大学学报,2007,9(3):130.
5.Cao SS,Zhen YS.Potentiation of antimetabolite antitumor activity in vivo by dipyridamole and arnphotericin B[J].Cancer Chemother Pharmacol,1989,24(3):181-186.
6.李茂全,沈建华,胥彬,等.消癌平对SGC-7901胃癌细胞的作用及其机制的实验研究[J].介入放射学杂志,2001,10(4):228-231.
7.《药理学实验》编写组.药理学实验[M].北京:人民卫生出版社,1985:163
8.朱建平.通关散方源考[J].中国医药学报,2002,17(2):114-115.
9.徐国钧,何宏贤,徐珞珊,等.中国药材学[M].上海:上海科学技术出版社,1990:254.
10.谭朝阳,雷玉萍.HPLC法测定乌骨藤及其制剂消癌平片中绿原酸的含量研究[J].中医药学刊,2004,22(7):1354.
11.彭晓俊,李忠贵.HPLC法测定通光藤中绿原酸的含量[J].江西中医学院学报,2005,17(2):39.
12.潘成学,刘伟,申小静.高效液相色谱法测定消癌平片中绿原酸的含量[J].中国药业,2005,14(8):26-27.
13.刘爱学,陈翠花,郭耀武.消癌平片中绿原酸中HPLC法测定[J].西北药学杂志,2005,20(2):56-58.
14.江行本,高超旭.HPLC法测定消癌平糖浆中绿原酸的含量[J].中国中医药信息杂志,2005,12(4):43.
15.苏天安,岳正刚,郭耀武.高效液相色谱法测定消癌平片中绿原酸的含量[J].陕西中医学 院学报,2005,28(6):46、52.
16.刘峰群,曹红,靳守东,等.比色法测定消癌平注射液中总酚酸的含量[J].华西药学杂志,2003,18(3):220-222.
17.吴卫华,康桢,欧阳冬生,等.绿原酸的药理学研究进展[J].天然产物研究与开发,2006,18(4):691-694.
18.赖玉菡,王曙.HPLC测定通关藤中绿原酸的含量[J].华西药学杂志,2006,21(1)79-81.
19.才凤,张慧,初正云.通关藤及其伪品的FTIR鉴别[J].辽宁中医药大学学报,2007,9(4):58-59.
20.刘峰群,崔燕,凌海慧,等.不同对照品对通关藤注射液总酚酸含量测定的影响[J].药学服务与研究,2006,6(5):383-385.
21.叶栋枢,韦启善,刘宝玉.乌骨藤治疗恶性肿瘤初探[J].中华肿瘤杂志,1987,9(2):126.
22.孙珏,沈建华,朱美华,等.消癌平对人肝癌细胞治疗作用的实验研究[J].上海中医药杂志,2000,34(7):12-14.
23.孙珏,沈建华,朱美华,等.消癌平对人胃癌细胞治疗作用的实验研究[J].上海中医药大学学报,2000,14(2):41-43.
24.陈同生,王龙祥,王会营,等.荧光共振能量转移技术对肺腺癌活细胞消癌平诱导半胱氨酸天冬氨酸酶3活化过程的实时监测[J].中国组织工程研究与临床康复,2007,11(35):7102-7105.
25.周丹,韩大庆,刘伟,等.消癌平片抗肿瘤作用研究[J].吉林中医药,2002,22(1):57、封三.
26.张开通,戚晓东,黄灵,等.重组P53腺病毒联合中药治疗小鼠腹水瘤的疗效[J].中国肿瘤生物治疗杂志,2006,13(6):466-468.
27.罗崇彬.消癌平片抗突变和抗肿瘤作用研究[J].现代医院,2007,7(9):31-32.
28.温建珍,郝青,杨玲.消癌平注射液治疗老年晚期消化道肿瘤57例[J].中国民间疗法,2003,11(6):48.
29.王志良,樊青霞,范魁生.消癌平临床疗效观察[J].河南医科大学学报,1994,29(1):79-80.
30.王志良,王贵吉,岳邦仪.中药通光藤治疗食管癌胃癌的临床观察(附112例报告)[J].河南肿瘤学杂志,1995,8(3):202-204.
31.李凯,邹华伟.消癌平联合化疗治疗晚期食管癌的临床观察[J].中华肿瘤防治杂志,2007,14(16):1272-1273.
32.赵素斌,王如美,李守霞.消癌平治疗原发性肝癌的临床疗效[J].邯郸医学高等专科学校学报,2005,18(5):415-416.
33.卢秋红,邓力.消癌平肝动脉灌注配合肝动脉栓塞化疗治疗肝癌的临床观察[J].现代中西医结合杂志,2004,13(20):2690-2691.
34.山广志,刘文奇.消癌平注射液经肝动脉介入治疗原发性肝癌20例[J].临床肿瘤学杂志,2006,11(9):713-715.
35.王文荣,崔生达,曾黎明.中药消癌平配合超声引导经皮射频治疗中晚期肝癌的临床观察[J].中国中西医结合杂志,2003,23(1):19-21.
36.孙珏,沈建华,朱美华,等.中药消癌平针剂经肝动脉介入治疗转移性肝癌的临床研究[J].上海中医药杂志,2000,1:14-17.
37.黄振倩,谭获,王春燕,等.消癌平注射液联合化疗治疗中晚期肺癌的临床研究[J].临床肿瘤学杂志,2007,12(2):97-99、102.
38.唐域,高雅苓.高龄非小细胞肺癌的化疗49例临床分析[J].实用肿瘤学杂志,2000,14(1):36-37.
39.杨岷,吴静,李永强,等.消癌平注射液联合放疗治疗晚期非小细胞肺癌30例[J].中医研究,2000,13(1):39-41.
40.李东,欧阳建,李翠萍,等.消癌平注射液对白血病细胞NB4作用的初步研究[J].中国生化药物杂志,2007,28(4):247-250.
41.赵晓民,侯伟,闫金玉,等.消癌平注射液治疗急性白血病6例[J].中国中医急症,2007,16(1):105.
42.Schwartz JD,Schwartz M,Mandeli J,et al.Neoadjuvant and adjuvant therapy for respectable hepatocellular carcinoma:review of the randomized clinical trials[J].Lancet Oncol,2002,3(10):593-603.
43.Sun W,Sonnad S,Furth E,et al.Adjuvant chemotherapy in patients with hepatocellular carcinoma after orthotopic liver transplantation[C].Proc Am Soc Clin Oncol,2005,Abstract 4126.
44.Lai CL,Wu PC,Chan GC,et al.Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma.A prospective randomized trial[J].Cancer,1988,62(3):479-483.
45.Ishikawa T,Ichida T,Sugitani S,et al.Improved survival with oral administration of enteric-coated tegafur/uracil for advanced stage IVA hepatocellular carinoma[J]. J Gastroenterol Hepatol,2001,16(4):452-459.
46.Vogel CL, Bayley AC, Brooker RJ, et al. A phase II study of adriamycin (NSC 123127) in patients with hepatocellular carcinoma from Zambia and the United States[J]. Cancer, 1977,39(5): 1923-1929.
47.Hong RL, Tseng YL.A phase II and pharmacokinetic study of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma[J]. Cancer Chemother Pharmacol, 2003, 51 (5): 433-438.
48.Valle JW, Dangoor A, Beech J, et al. Treatment of inoperable hepatocellular carcinoma with pegylated liposomal doxorubicin(PLD): results of a phase II study[J]. Br J Cancer, 2005. 92(4): 628-630.
49.Jurgen P, Ivan Z, Wolfgang S, et al. Systemic chemotherapy with epirubicin for treatment of advanced or multifocal hepatocellular carcinoma[J]. Chemotherapy, 2001.47(5):359-365.
50.Tumolo S. Toffoli G, Bearz A, et al. Oral idarubicin (IDA) for the treatment of hepatocellular carcinoma[c]. Proc Am Soc Clin Oncol, 2002, Abstract 635.
51.Yoshida T. Okazaki N, Ohkura H, et al. Phase II trial of mitroxantrone in patients with hepatocellular carcinoma[J]. Eur J Cancer Clin Oncol. 1988,24(12):1897-1898.
52.Tetef M, Doroshow J, Akman S. et al. 5-Fluorouracil and high-dose calcium leucovorin for hepatocellular carcinoma: a phase II trial[J]. Cancer Invest, 1995,13(5):460-463.
53.Porta C, Moroni M, Nastasi G, et al. 5-Fluorouracil and d,1-leucovorin calcium are active to treat unresectable hepatocellular carcinoma patients: preliminary results of a phase II study[J]. Oncology, 1995, 52(6):487-491.
54.Shiraishi K, Kubo Y, Majima Y, et al. Clinical evaluation of 1-hexylcarbamoyl-5-fiuorouracil (HCFU) in hepatocellular carcinoma[J]. Gan To Kagaku Ryoho, 1984, 11(11):2348-2355.
55.Lencioni M, Falcone A, Allegrini G, et al. Oral doxifluridine in advanced hepatocellular carcinoma: A phase II study[J]. Oncology, 2000, 59(3):204-209.
56.Yehuda Z, Manal M, Alvaro A, et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma[J]. Cancer, 2004, 101(3):578-586.
57.Von Delius S, Lersch C, Mayr M, et al. Capecitabine for treatment of advanced hepatocellular carcinoma[J]. Hepatogastroenterology, 2007,54(80):2310-2314.
58.Morise Z,Sugioka A,Fujita J,et al.S-1 plus cisplatin combination therapy for the patients with primary liver carcinomas[J].Hepatogastroenterology,2007,54(80):2315-2318.
59.Okada S,Okazaki N,Nose H,et al.A phase 2 study of cisplatin in patients with hepatocellular carcinoma[J]k.Oncology,1993,50(1):22-26.
60.Yen Y,Doroshow J,Leong L.et al.Phase Ⅱ study of oxaliplatin in patients with unresectable,metastatic or recurrent hepatocellular cancer[C].Proc Am Soc Clin Oncol,2004,Abstract 4169.
61.O'Reilly EM,Stuart KE,Sanz-Altamira PM,et al.A phase Ⅱ study of irinotecan in patients with advanced hepatocellular carcinoma[J].Cancer,2001,91(1):101-105.
62.Yehuda ZP,Rowinsky E,O'Reilly EM,et al.Phase Ⅱ trial of DX-8951f(exatecan mesylate) in hepatocellular carcinoma(HCC):a final analysis[C].Proc Am Soc Clin Oncol,2002,Abstract 555.
63.王华庆,杨华,宋拯.9-硝基喜树碱治疗肝癌术后双肺转移完全缓解1例[J].癌症进展,2008,6(4):419-421,431.
64.Yang TS,Lin YC,Chert JS,et al.Phase Ⅱ study of gemcitabine in patients with advanced hepatocellular carcinoma[J].Cancer,2000,89(5):750-756.
65.Strumberg D,Erhard J,Harstrick A,et al.Phase Ⅰ study of a weekly 1 h infusion of paclitaxel in patients with unresectable hepatocellular carcinoma[J].Eur J Cancer,1998,34(8):1290-1292.
66.Chao Y,Chan WK,Birkhofer MJ,et aI.Phase Ⅱ and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients[J].Br J Cancer,1998,78(1):34-39.
67.Posey J,Johnson R Mok T,et al.Results of a phase 2/3 open-label,randomized trial of T138067 verses doxorubicin(DOX) in chemotherapy-naive,unresectable hepatocellular carcinoma(HCC)[C].Proc Am Soc Clin Oncol,2005,Abstract 4035.
68.Stuart K,Tessitore J,Rudy J,et al.A phase Ⅱ of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma[J].Cancer,1999,86(3):410-414.
69.Gallo J.Nolatrexed dihydrochloride vs.doxorubicin,a clinical update of a multi-center randomized phase Ⅱ study in ethnic Chinese subjects with unresectable or metastatic HCC[C].Proc Am Soc Clin Oncol,2004,Abstract 4262.
70.Cheng AN,Chen YC,Yeh KH,et al.Chronic oral etoposide and tamoxifen in the treatment of far-advanced hepatocellular carcinoma[J].Cancer,1996,77(5):872-877.
71.Nowak AK,Stockler MR,Chow PK,et al.Use of tamoxifen in advanced-stage hepatocellular carcinoma.A systematic review[J].Cancer,2005,103(7)1408-1414.
72.钱军,秦叔逵,何泽明,等.三氧化二砷注射液治疗中晚期原发性肝胆癌的临床观察[J].中华肿瘤杂志,2001,23(6):487-489.
73.Lee J,Park JO,Kim WS,et al.Phase Ⅱ study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma.Cancer Chemother Pharmacol,2004,54(5):385-390.
74.Tanioka H,Tsuji A,Morita S,et al.Combination chemotherapy with continuous 5-fluorouracil and low-dose cisplatin infusion for advanced hepatocellular carcinoma[J].Anticancer Res,2003,23(2C):1891-1897.
75.Boucher E,Coubinais S,Brissot P.et al.Treatment of hepatocellular carcinoma with systemic chemotherapy combining epirubicin,cisplatinum and infusional 5-fiuorouracil(ECF regimen)[J].Cancer Chemother Pharmacol,2002,50(4):305-308.
76.Ikeda M,Okusaka T,Ueno H,et al.A phase Ⅱ trial of continuous infusion of 5-fluorouracil.mitoxantrone,and cisplatin for metastatic hepatocellular carcinoma[J].Cancer,2005,103(4):756-762.
77.Yuan JN,Chao Y,Lee WP,et al.Chemotherapy with etoposide,doxorubicin,cisplatin,5-fluorouracil,and leucovorin for patients with advanced hepatocellular carcinoma[J].Med Oncol,2008,25(2):201-206.
78.Lee JL,Ryu MH,Chang HM,et al.Efficacy and safety of epirubicin and etoposide combination chemotherapy in advanced hepatocellular carcinoma:A retrospective analysis[J].J Gastroenterol Hepatol,2007,23(5):811-816.
79.Lai CL,Lan JY,Wu PC,et al.Recombinant interferon-alpha inoperable hepatocellular carcinoma:a randomized controlled trial[J].Hepatology,1993,17(3):389-394.
80.Llovet JM,Sala M,Castells L,et al.Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma[J].Hepatology,2000,31(1):54-58.
81.Leung TW,Tang AM,Zee B,et al.Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin,interferon-alpha,doxorubicin and 5-fluorouracil chemotherapy[J].Cancer,2002,94(2):421-7.
82.Shin D,Lee SI,Park J,et al.Systemic chemotherapy with capecitabine,doxorubicin and cisplatin for metastatic hepatocellular carcinoma[C].Proc Am Soc Clin Oncol,2005,Abstract 4177.
83.Park SH,Lee Y,Han SH,et al.Systemic chemotherapy with doxorubicin,cisplatin and capecitabine for metastatic hepatocellular carcinoma[J].Biomedcentral Cancer,2006,6:3-9.
84.Yang TS,Wang CH,Hsieh RK,et al.Gemcitabine and doxorubicin for the treatment of patients with advanced hepatocellular carcinoma:a phase Ⅰ-Ⅱ trial[J].Ann Oncol,2002,13(11):1771-1778.
85.Yang TS,Chang WC,Lin YC,et al.A phase Ⅱ study of gemcitabine and cisplatin for patients with advanced hepatocellular carcinoma[C].Proc Am Soc Clin Oncol,2003,Abstract 1351.
86.盛立军,宋恕平,牛作兴.等.吉西他滨联合顺铂治疗16例晚期肝癌[J].中国癌症杂志,2003,13(1):67-68.
87.陈障树,陈曦,欧阳学农,等.吉西他滨治疗8例晚期肝癌[J].中国癌症杂志,2001,11(6):532-533.
88.练祖平,侯恩存,陆运鑫,等.吉西他滨联合顺铂治疗晚期原发性肝癌的临床观察[J].实用肿瘤学杂志,2007,21(3):224-225,229.
89.秦叔逵,曹梦苒,钱军,等.奥沙利铂为主的FOLFOX方案治疗晚期原发性肝癌[J].临床肿瘤学杂志,2005,10(1):58-60.
90.Qin SK,Wang YJ,Wu Q,et al.Phase Ⅱ study of oxaliplatin+5-fluorouracil/leucovorin in patients with unresectable hepatocellular carcinoma[C].Gastrointestinal Cancer Symposium,2007,Abs151.
91.Frustaci S,Bearz A,Basso B,et al.Efficacy of oxaliplatin and 5-fluorouracil in hepatocarcimoma[C].Proc Am Soc Clin Oncol,2003,Abstract 1346.
92.Boige V,Raoul JL,Pignon JP,et al.Preliminary results of capecitabine-oxaliplatin(XELOX) in hepatocellular carcinoma(HCC)[c].Proc Am Soc Clin Oncol,2005,Abstract 4128.
93.Boige V,Raoul JL,Pignon JP,et al.Multicentre phase Ⅱ trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma:FFCD 03-03 trial[J].Br J Cancer,2007,97(7):862-867.
94.王芳,柳江,阿依夏木.奥沙利铂联合卡培他滨治疗晚期原发性肝癌[J].中国癌症杂志,2006,16(10):880.
95.Taieb J,Mansourbakht T,Ducreux M,et al.Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma(AHCC):Results of a phase Ⅱ study[C].Proc Am Soc Clin Oncol,2004,Abstract 4086.
96.Louafi S,Boige V,Ducreux M,et al.Gemcitabine plus oxaliplatin(GEMOX) in patients with advanced hepatocellular carcinoma(HCC):results of a phase Ⅱ study[J].Cancer,2007,109(7):1384-1390.
97.Asnacios A,Fartoux L,Romano O,et al.Gemcitabine plus oxaliplatin(GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma:results of a multicenter phase 2 study[J].Cancer,2008,112(12):2733-2739.
98.刘芳,张阳,周金平,等.伊立替康联合化疗方案治疗原发性肝癌的临床研究[J].大连医科大学学报,2008,30(1):44-47.
99.白冰,蔡辉.三氧化二砷联合羟基喜树碱治疗晚期原发性肝癌的临床观察[J].医学综述,2007,13(24):2043-2044.
100.Francavilla A,Polimeno L,Dileo A,et al.The effect of estrogen and tamoxifen on hepatocyte proliferation in vivo and in vitro[J].Hepatology,1989.9:614-620.
101.Nowak AK,Stockler MR,Chow PK,et al.Use of tamoxifen in advanced-stage hepatocellular carcinoma.A systematic review[J].Cancer,2005,103(7) 1408-1414.
102.Barbare JC,Bouche O,Bonnetain F,et al.Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma[J].J Clin Oncol,2005,23(19):4338-4346.
103.Villa E,Ferretti I,Grottole A,et al.Hormonal therapy with megestrol in inoperable hepatocellar carcinoma characterized by variant oestrogen receptors[J].Br J Carcer,2001,84(7):881-885.
104.Chao Y,Chan WK,Huang YS,et al.Phase Ⅱ study of flutamide in the treatment of hepatocellular carcinoma[J].Cancer,1996,77(4):635-639.
105.Grimalcli C,Bleiberg H,Gay F,et al.Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma:results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial[J].J Clin Oncol,1998,16(2):411-417.
106.Kouroumalis EA.Octreotide for cancer of the liver and biliary tree[J].Chemotherapy,2001,47(suppl 2):150-161.
107.Yuen MF,Poon RT,Lai CL,et al.A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma[J].Hepatology,2002,36(3):687-691.
108.Slijkhuis WA,Stadheim L,Hassoun R,et al.Octreotide Therapy for Advanced Hepatocellular Carcinoma[J].J of Clin Gastroenterology,2005,39(4):333-338.
109.Lai CL,Lan JY,Wu PC,et al.Recombinant interferon-alpha inoperable hepatocellular carcinoma:a randomized controlled trial[J].Hepatology,1993,17(3):389-394.
110.Llovet JM,Sala M,Castells L,et al.Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma[J].Hepatology,2000,31(1):54-58.
111.Masato S,Hiroaki N,Keizo D,et al.Subcutaneous interferon-α therapy for advanced hepatocellular carcinoma with tumor thrombi in the major portal branches[J].Cancer,2002,94(2):435-442.
112.Patt YZ,Hassan MM,Lozano RD,et al.Thalidomide in the treatment of patients with hepatocellular carcinoma[J].Cancer,2005,103(4):749-755.
113.Jeong W,Chun HG,Cer D,et al.A combination of capecitabine and thalidomide in patients with hepatocellular carcinoma[c].Proc Am Soc Clin Oncol,2006,Abstract 4142.
114.Zhu AX,Fuchs CS,Clark JW,et al.A phase Ⅱ study of epirubicin and thalidomide in unresectable or metastatic hepatocellular carcinoma[J].The Oncologist,2005,10:392-398.
115.汤钊猷主编。现代肿瘤学[M]。第2版,上海:上海医科大学出版社,2000:758.
116.KH Han,JY Park.Chemotherapy for advanced hepatocellular carcinoma[J].J Gastroenterol Hepatol,2008,23:811-816.
117.刘洪尊,李电东,甄永苏,等.力达霉素增强顺铂诱导人肝癌BEL-7402细胞凋亡作用及机制研究[J].药学学报,2003,38(4):250-254.
118.娄小娥,陈智.中药现代化[J].中华医学杂志,2006,86(1):68-70.
119.Hook SS,Lin JJ,Dutta A.Mechanisms to control rereplication and implications for cancer[J].Curr Opin Cell Biol,2007,19(6):663-671.
120.彭海燕,章永红.中医药治疗原发性肝癌的现状与展望[J].中西医结合肝病杂志,2006,16(3):184-187.
121.王廷祥,王苗娟.论中晚期肝癌的综合治疗[J].浙江中医药大学学报,2006,30(3):270-271.
2.邢旺兴,程荣珍,陈斌,等.乌骨藤常见混用品种辨析[J].现代中药研究与实践,2004,18(1):33-36.
3.国家中医药管理局、《中华本草》编委会.中华本草(第3册)[M].上海:上海科学技术出版社,1999:7.
4.张雪莹,张慧,翟延君.通关藤两个化合物的研究[J].辽宁中医药大学学报,2007,9(3):130.
5.Cao SS,Zhen YS.Potentiation of antimetabolite antitumor activity in vivo by dipyridamole and arnphotericin B[J].Cancer Chemother Pharmacol,1989,24(3):181-186.
6.李茂全,沈建华,胥彬,等.消癌平对SGC-7901胃癌细胞的作用及其机制的实验研究[J].介入放射学杂志,2001,10(4):228-231.
7.《药理学实验》编写组.药理学实验[M].北京:人民卫生出版社,1985:163
8.朱建平.通关散方源考[J].中国医药学报,2002,17(2):114-115.
9.徐国钧,何宏贤,徐珞珊,等.中国药材学[M].上海:上海科学技术出版社,1990:254.
10.谭朝阳,雷玉萍.HPLC法测定乌骨藤及其制剂消癌平片中绿原酸的含量研究[J].中医药学刊,2004,22(7):1354.
11.彭晓俊,李忠贵.HPLC法测定通光藤中绿原酸的含量[J].江西中医学院学报,2005,17(2):39.
12.潘成学,刘伟,申小静.高效液相色谱法测定消癌平片中绿原酸的含量[J].中国药业,2005,14(8):26-27.
13.刘爱学,陈翠花,郭耀武.消癌平片中绿原酸中HPLC法测定[J].西北药学杂志,2005,20(2):56-58.
14.江行本,高超旭.HPLC法测定消癌平糖浆中绿原酸的含量[J].中国中医药信息杂志,2005,12(4):43.
15.苏天安,岳正刚,郭耀武.高效液相色谱法测定消癌平片中绿原酸的含量[J].陕西中医学 院学报,2005,28(6):46、52.
16.刘峰群,曹红,靳守东,等.比色法测定消癌平注射液中总酚酸的含量[J].华西药学杂志,2003,18(3):220-222.
17.吴卫华,康桢,欧阳冬生,等.绿原酸的药理学研究进展[J].天然产物研究与开发,2006,18(4):691-694.
18.赖玉菡,王曙.HPLC测定通关藤中绿原酸的含量[J].华西药学杂志,2006,21(1)79-81.
19.才凤,张慧,初正云.通关藤及其伪品的FTIR鉴别[J].辽宁中医药大学学报,2007,9(4):58-59.
20.刘峰群,崔燕,凌海慧,等.不同对照品对通关藤注射液总酚酸含量测定的影响[J].药学服务与研究,2006,6(5):383-385.
21.叶栋枢,韦启善,刘宝玉.乌骨藤治疗恶性肿瘤初探[J].中华肿瘤杂志,1987,9(2):126.
22.孙珏,沈建华,朱美华,等.消癌平对人肝癌细胞治疗作用的实验研究[J].上海中医药杂志,2000,34(7):12-14.
23.孙珏,沈建华,朱美华,等.消癌平对人胃癌细胞治疗作用的实验研究[J].上海中医药大学学报,2000,14(2):41-43.
24.陈同生,王龙祥,王会营,等.荧光共振能量转移技术对肺腺癌活细胞消癌平诱导半胱氨酸天冬氨酸酶3活化过程的实时监测[J].中国组织工程研究与临床康复,2007,11(35):7102-7105.
25.周丹,韩大庆,刘伟,等.消癌平片抗肿瘤作用研究[J].吉林中医药,2002,22(1):57、封三.
26.张开通,戚晓东,黄灵,等.重组P53腺病毒联合中药治疗小鼠腹水瘤的疗效[J].中国肿瘤生物治疗杂志,2006,13(6):466-468.
27.罗崇彬.消癌平片抗突变和抗肿瘤作用研究[J].现代医院,2007,7(9):31-32.
28.温建珍,郝青,杨玲.消癌平注射液治疗老年晚期消化道肿瘤57例[J].中国民间疗法,2003,11(6):48.
29.王志良,樊青霞,范魁生.消癌平临床疗效观察[J].河南医科大学学报,1994,29(1):79-80.
30.王志良,王贵吉,岳邦仪.中药通光藤治疗食管癌胃癌的临床观察(附112例报告)[J].河南肿瘤学杂志,1995,8(3):202-204.
31.李凯,邹华伟.消癌平联合化疗治疗晚期食管癌的临床观察[J].中华肿瘤防治杂志,2007,14(16):1272-1273.
32.赵素斌,王如美,李守霞.消癌平治疗原发性肝癌的临床疗效[J].邯郸医学高等专科学校学报,2005,18(5):415-416.
33.卢秋红,邓力.消癌平肝动脉灌注配合肝动脉栓塞化疗治疗肝癌的临床观察[J].现代中西医结合杂志,2004,13(20):2690-2691.
34.山广志,刘文奇.消癌平注射液经肝动脉介入治疗原发性肝癌20例[J].临床肿瘤学杂志,2006,11(9):713-715.
35.王文荣,崔生达,曾黎明.中药消癌平配合超声引导经皮射频治疗中晚期肝癌的临床观察[J].中国中西医结合杂志,2003,23(1):19-21.
36.孙珏,沈建华,朱美华,等.中药消癌平针剂经肝动脉介入治疗转移性肝癌的临床研究[J].上海中医药杂志,2000,1:14-17.
37.黄振倩,谭获,王春燕,等.消癌平注射液联合化疗治疗中晚期肺癌的临床研究[J].临床肿瘤学杂志,2007,12(2):97-99、102.
38.唐域,高雅苓.高龄非小细胞肺癌的化疗49例临床分析[J].实用肿瘤学杂志,2000,14(1):36-37.
39.杨岷,吴静,李永强,等.消癌平注射液联合放疗治疗晚期非小细胞肺癌30例[J].中医研究,2000,13(1):39-41.
40.李东,欧阳建,李翠萍,等.消癌平注射液对白血病细胞NB4作用的初步研究[J].中国生化药物杂志,2007,28(4):247-250.
41.赵晓民,侯伟,闫金玉,等.消癌平注射液治疗急性白血病6例[J].中国中医急症,2007,16(1):105.
42.Schwartz JD,Schwartz M,Mandeli J,et al.Neoadjuvant and adjuvant therapy for respectable hepatocellular carcinoma:review of the randomized clinical trials[J].Lancet Oncol,2002,3(10):593-603.
43.Sun W,Sonnad S,Furth E,et al.Adjuvant chemotherapy in patients with hepatocellular carcinoma after orthotopic liver transplantation[C].Proc Am Soc Clin Oncol,2005,Abstract 4126.
44.Lai CL,Wu PC,Chan GC,et al.Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma.A prospective randomized trial[J].Cancer,1988,62(3):479-483.
45.Ishikawa T,Ichida T,Sugitani S,et al.Improved survival with oral administration of enteric-coated tegafur/uracil for advanced stage IVA hepatocellular carinoma[J]. J Gastroenterol Hepatol,2001,16(4):452-459.
46.Vogel CL, Bayley AC, Brooker RJ, et al. A phase II study of adriamycin (NSC 123127) in patients with hepatocellular carcinoma from Zambia and the United States[J]. Cancer, 1977,39(5): 1923-1929.
47.Hong RL, Tseng YL.A phase II and pharmacokinetic study of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma[J]. Cancer Chemother Pharmacol, 2003, 51 (5): 433-438.
48.Valle JW, Dangoor A, Beech J, et al. Treatment of inoperable hepatocellular carcinoma with pegylated liposomal doxorubicin(PLD): results of a phase II study[J]. Br J Cancer, 2005. 92(4): 628-630.
49.Jurgen P, Ivan Z, Wolfgang S, et al. Systemic chemotherapy with epirubicin for treatment of advanced or multifocal hepatocellular carcinoma[J]. Chemotherapy, 2001.47(5):359-365.
50.Tumolo S. Toffoli G, Bearz A, et al. Oral idarubicin (IDA) for the treatment of hepatocellular carcinoma[c]. Proc Am Soc Clin Oncol, 2002, Abstract 635.
51.Yoshida T. Okazaki N, Ohkura H, et al. Phase II trial of mitroxantrone in patients with hepatocellular carcinoma[J]. Eur J Cancer Clin Oncol. 1988,24(12):1897-1898.
52.Tetef M, Doroshow J, Akman S. et al. 5-Fluorouracil and high-dose calcium leucovorin for hepatocellular carcinoma: a phase II trial[J]. Cancer Invest, 1995,13(5):460-463.
53.Porta C, Moroni M, Nastasi G, et al. 5-Fluorouracil and d,1-leucovorin calcium are active to treat unresectable hepatocellular carcinoma patients: preliminary results of a phase II study[J]. Oncology, 1995, 52(6):487-491.
54.Shiraishi K, Kubo Y, Majima Y, et al. Clinical evaluation of 1-hexylcarbamoyl-5-fiuorouracil (HCFU) in hepatocellular carcinoma[J]. Gan To Kagaku Ryoho, 1984, 11(11):2348-2355.
55.Lencioni M, Falcone A, Allegrini G, et al. Oral doxifluridine in advanced hepatocellular carcinoma: A phase II study[J]. Oncology, 2000, 59(3):204-209.
56.Yehuda Z, Manal M, Alvaro A, et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma[J]. Cancer, 2004, 101(3):578-586.
57.Von Delius S, Lersch C, Mayr M, et al. Capecitabine for treatment of advanced hepatocellular carcinoma[J]. Hepatogastroenterology, 2007,54(80):2310-2314.
58.Morise Z,Sugioka A,Fujita J,et al.S-1 plus cisplatin combination therapy for the patients with primary liver carcinomas[J].Hepatogastroenterology,2007,54(80):2315-2318.
59.Okada S,Okazaki N,Nose H,et al.A phase 2 study of cisplatin in patients with hepatocellular carcinoma[J]k.Oncology,1993,50(1):22-26.
60.Yen Y,Doroshow J,Leong L.et al.Phase Ⅱ study of oxaliplatin in patients with unresectable,metastatic or recurrent hepatocellular cancer[C].Proc Am Soc Clin Oncol,2004,Abstract 4169.
61.O'Reilly EM,Stuart KE,Sanz-Altamira PM,et al.A phase Ⅱ study of irinotecan in patients with advanced hepatocellular carcinoma[J].Cancer,2001,91(1):101-105.
62.Yehuda ZP,Rowinsky E,O'Reilly EM,et al.Phase Ⅱ trial of DX-8951f(exatecan mesylate) in hepatocellular carcinoma(HCC):a final analysis[C].Proc Am Soc Clin Oncol,2002,Abstract 555.
63.王华庆,杨华,宋拯.9-硝基喜树碱治疗肝癌术后双肺转移完全缓解1例[J].癌症进展,2008,6(4):419-421,431.
64.Yang TS,Lin YC,Chert JS,et al.Phase Ⅱ study of gemcitabine in patients with advanced hepatocellular carcinoma[J].Cancer,2000,89(5):750-756.
65.Strumberg D,Erhard J,Harstrick A,et al.Phase Ⅰ study of a weekly 1 h infusion of paclitaxel in patients with unresectable hepatocellular carcinoma[J].Eur J Cancer,1998,34(8):1290-1292.
66.Chao Y,Chan WK,Birkhofer MJ,et aI.Phase Ⅱ and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients[J].Br J Cancer,1998,78(1):34-39.
67.Posey J,Johnson R Mok T,et al.Results of a phase 2/3 open-label,randomized trial of T138067 verses doxorubicin(DOX) in chemotherapy-naive,unresectable hepatocellular carcinoma(HCC)[C].Proc Am Soc Clin Oncol,2005,Abstract 4035.
68.Stuart K,Tessitore J,Rudy J,et al.A phase Ⅱ of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma[J].Cancer,1999,86(3):410-414.
69.Gallo J.Nolatrexed dihydrochloride vs.doxorubicin,a clinical update of a multi-center randomized phase Ⅱ study in ethnic Chinese subjects with unresectable or metastatic HCC[C].Proc Am Soc Clin Oncol,2004,Abstract 4262.
70.Cheng AN,Chen YC,Yeh KH,et al.Chronic oral etoposide and tamoxifen in the treatment of far-advanced hepatocellular carcinoma[J].Cancer,1996,77(5):872-877.
71.Nowak AK,Stockler MR,Chow PK,et al.Use of tamoxifen in advanced-stage hepatocellular carcinoma.A systematic review[J].Cancer,2005,103(7)1408-1414.
72.钱军,秦叔逵,何泽明,等.三氧化二砷注射液治疗中晚期原发性肝胆癌的临床观察[J].中华肿瘤杂志,2001,23(6):487-489.
73.Lee J,Park JO,Kim WS,et al.Phase Ⅱ study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma.Cancer Chemother Pharmacol,2004,54(5):385-390.
74.Tanioka H,Tsuji A,Morita S,et al.Combination chemotherapy with continuous 5-fluorouracil and low-dose cisplatin infusion for advanced hepatocellular carcinoma[J].Anticancer Res,2003,23(2C):1891-1897.
75.Boucher E,Coubinais S,Brissot P.et al.Treatment of hepatocellular carcinoma with systemic chemotherapy combining epirubicin,cisplatinum and infusional 5-fiuorouracil(ECF regimen)[J].Cancer Chemother Pharmacol,2002,50(4):305-308.
76.Ikeda M,Okusaka T,Ueno H,et al.A phase Ⅱ trial of continuous infusion of 5-fluorouracil.mitoxantrone,and cisplatin for metastatic hepatocellular carcinoma[J].Cancer,2005,103(4):756-762.
77.Yuan JN,Chao Y,Lee WP,et al.Chemotherapy with etoposide,doxorubicin,cisplatin,5-fluorouracil,and leucovorin for patients with advanced hepatocellular carcinoma[J].Med Oncol,2008,25(2):201-206.
78.Lee JL,Ryu MH,Chang HM,et al.Efficacy and safety of epirubicin and etoposide combination chemotherapy in advanced hepatocellular carcinoma:A retrospective analysis[J].J Gastroenterol Hepatol,2007,23(5):811-816.
79.Lai CL,Lan JY,Wu PC,et al.Recombinant interferon-alpha inoperable hepatocellular carcinoma:a randomized controlled trial[J].Hepatology,1993,17(3):389-394.
80.Llovet JM,Sala M,Castells L,et al.Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma[J].Hepatology,2000,31(1):54-58.
81.Leung TW,Tang AM,Zee B,et al.Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin,interferon-alpha,doxorubicin and 5-fluorouracil chemotherapy[J].Cancer,2002,94(2):421-7.
82.Shin D,Lee SI,Park J,et al.Systemic chemotherapy with capecitabine,doxorubicin and cisplatin for metastatic hepatocellular carcinoma[C].Proc Am Soc Clin Oncol,2005,Abstract 4177.
83.Park SH,Lee Y,Han SH,et al.Systemic chemotherapy with doxorubicin,cisplatin and capecitabine for metastatic hepatocellular carcinoma[J].Biomedcentral Cancer,2006,6:3-9.
84.Yang TS,Wang CH,Hsieh RK,et al.Gemcitabine and doxorubicin for the treatment of patients with advanced hepatocellular carcinoma:a phase Ⅰ-Ⅱ trial[J].Ann Oncol,2002,13(11):1771-1778.
85.Yang TS,Chang WC,Lin YC,et al.A phase Ⅱ study of gemcitabine and cisplatin for patients with advanced hepatocellular carcinoma[C].Proc Am Soc Clin Oncol,2003,Abstract 1351.
86.盛立军,宋恕平,牛作兴.等.吉西他滨联合顺铂治疗16例晚期肝癌[J].中国癌症杂志,2003,13(1):67-68.
87.陈障树,陈曦,欧阳学农,等.吉西他滨治疗8例晚期肝癌[J].中国癌症杂志,2001,11(6):532-533.
88.练祖平,侯恩存,陆运鑫,等.吉西他滨联合顺铂治疗晚期原发性肝癌的临床观察[J].实用肿瘤学杂志,2007,21(3):224-225,229.
89.秦叔逵,曹梦苒,钱军,等.奥沙利铂为主的FOLFOX方案治疗晚期原发性肝癌[J].临床肿瘤学杂志,2005,10(1):58-60.
90.Qin SK,Wang YJ,Wu Q,et al.Phase Ⅱ study of oxaliplatin+5-fluorouracil/leucovorin in patients with unresectable hepatocellular carcinoma[C].Gastrointestinal Cancer Symposium,2007,Abs151.
91.Frustaci S,Bearz A,Basso B,et al.Efficacy of oxaliplatin and 5-fluorouracil in hepatocarcimoma[C].Proc Am Soc Clin Oncol,2003,Abstract 1346.
92.Boige V,Raoul JL,Pignon JP,et al.Preliminary results of capecitabine-oxaliplatin(XELOX) in hepatocellular carcinoma(HCC)[c].Proc Am Soc Clin Oncol,2005,Abstract 4128.
93.Boige V,Raoul JL,Pignon JP,et al.Multicentre phase Ⅱ trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma:FFCD 03-03 trial[J].Br J Cancer,2007,97(7):862-867.
94.王芳,柳江,阿依夏木.奥沙利铂联合卡培他滨治疗晚期原发性肝癌[J].中国癌症杂志,2006,16(10):880.
95.Taieb J,Mansourbakht T,Ducreux M,et al.Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma(AHCC):Results of a phase Ⅱ study[C].Proc Am Soc Clin Oncol,2004,Abstract 4086.
96.Louafi S,Boige V,Ducreux M,et al.Gemcitabine plus oxaliplatin(GEMOX) in patients with advanced hepatocellular carcinoma(HCC):results of a phase Ⅱ study[J].Cancer,2007,109(7):1384-1390.
97.Asnacios A,Fartoux L,Romano O,et al.Gemcitabine plus oxaliplatin(GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma:results of a multicenter phase 2 study[J].Cancer,2008,112(12):2733-2739.
98.刘芳,张阳,周金平,等.伊立替康联合化疗方案治疗原发性肝癌的临床研究[J].大连医科大学学报,2008,30(1):44-47.
99.白冰,蔡辉.三氧化二砷联合羟基喜树碱治疗晚期原发性肝癌的临床观察[J].医学综述,2007,13(24):2043-2044.
100.Francavilla A,Polimeno L,Dileo A,et al.The effect of estrogen and tamoxifen on hepatocyte proliferation in vivo and in vitro[J].Hepatology,1989.9:614-620.
101.Nowak AK,Stockler MR,Chow PK,et al.Use of tamoxifen in advanced-stage hepatocellular carcinoma.A systematic review[J].Cancer,2005,103(7) 1408-1414.
102.Barbare JC,Bouche O,Bonnetain F,et al.Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma[J].J Clin Oncol,2005,23(19):4338-4346.
103.Villa E,Ferretti I,Grottole A,et al.Hormonal therapy with megestrol in inoperable hepatocellar carcinoma characterized by variant oestrogen receptors[J].Br J Carcer,2001,84(7):881-885.
104.Chao Y,Chan WK,Huang YS,et al.Phase Ⅱ study of flutamide in the treatment of hepatocellular carcinoma[J].Cancer,1996,77(4):635-639.
105.Grimalcli C,Bleiberg H,Gay F,et al.Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma:results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial[J].J Clin Oncol,1998,16(2):411-417.
106.Kouroumalis EA.Octreotide for cancer of the liver and biliary tree[J].Chemotherapy,2001,47(suppl 2):150-161.
107.Yuen MF,Poon RT,Lai CL,et al.A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma[J].Hepatology,2002,36(3):687-691.
108.Slijkhuis WA,Stadheim L,Hassoun R,et al.Octreotide Therapy for Advanced Hepatocellular Carcinoma[J].J of Clin Gastroenterology,2005,39(4):333-338.
109.Lai CL,Lan JY,Wu PC,et al.Recombinant interferon-alpha inoperable hepatocellular carcinoma:a randomized controlled trial[J].Hepatology,1993,17(3):389-394.
110.Llovet JM,Sala M,Castells L,et al.Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma[J].Hepatology,2000,31(1):54-58.
111.Masato S,Hiroaki N,Keizo D,et al.Subcutaneous interferon-α therapy for advanced hepatocellular carcinoma with tumor thrombi in the major portal branches[J].Cancer,2002,94(2):435-442.
112.Patt YZ,Hassan MM,Lozano RD,et al.Thalidomide in the treatment of patients with hepatocellular carcinoma[J].Cancer,2005,103(4):749-755.
113.Jeong W,Chun HG,Cer D,et al.A combination of capecitabine and thalidomide in patients with hepatocellular carcinoma[c].Proc Am Soc Clin Oncol,2006,Abstract 4142.
114.Zhu AX,Fuchs CS,Clark JW,et al.A phase Ⅱ study of epirubicin and thalidomide in unresectable or metastatic hepatocellular carcinoma[J].The Oncologist,2005,10:392-398.
115.汤钊猷主编。现代肿瘤学[M]。第2版,上海:上海医科大学出版社,2000:758.
116.KH Han,JY Park.Chemotherapy for advanced hepatocellular carcinoma[J].J Gastroenterol Hepatol,2008,23:811-816.
117.刘洪尊,李电东,甄永苏,等.力达霉素增强顺铂诱导人肝癌BEL-7402细胞凋亡作用及机制研究[J].药学学报,2003,38(4):250-254.
118.娄小娥,陈智.中药现代化[J].中华医学杂志,2006,86(1):68-70.
119.Hook SS,Lin JJ,Dutta A.Mechanisms to control rereplication and implications for cancer[J].Curr Opin Cell Biol,2007,19(6):663-671.
120.彭海燕,章永红.中医药治疗原发性肝癌的现状与展望[J].中西医结合肝病杂志,2006,16(3):184-187.
121.王廷祥,王苗娟.论中晚期肝癌的综合治疗[J].浙江中医药大学学报,2006,30(3):270-271.