靶向性重組腺病毒對裸鼠肝癌種植瘤的治療作用_《中國普外基礎與臨床雜志》

作者：

王煒 , 沈浩元 , 劉猛

廣州醫學院第一附屬醫院肝膽外科（廣東廣州 510120）;

關鍵詞：

肝細胞性肝癌 Caspase-3 凋亡種植瘤裸鼠

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目的觀察靶向性重組腺病毒Ad-EAFP-PALB/r-Caspase-3對原發性肝癌HepG2細胞及裸鼠皮下種植瘤的治療作用。方法采用先前構建的靶向性重組腺病毒Ad-EAFP-PALB/r-Caspase-3感染肝癌HepG 2細胞、乳腺癌MDA-MB-231細胞以及正常肝L-02細胞，觀察細胞形態學改變，并通過流式細胞術檢測細胞凋亡指數; 采用裸鼠皮下種植瘤模型、重組腺病毒瘤內給藥治療，觀察腫瘤生長情況及病理學改變。結果流式細胞學可見HepG 2細胞凋亡和明顯的凋亡峰，MDA-MB-231和L-02細胞凋亡指數分別為0和7.3%，明顯低于HepG2細胞（48.2%），P lt;0.01。種植腫瘤細胞2周后HepG 2細胞組、MDA-MB-231細胞組和對照組腫瘤體積大小分別為(0.26±0.31) cm 3、(0.25±0.15) cm 3和(0.26±0.28) cm 3，各組間差異無統計學意義（P gt;0.05）; 種植腫瘤細胞4周后HepG 2細胞組、MDA-MB-231細胞組和對照組腫瘤體積大小分別為(0.53±0.12) cm 3、(0.49±0.22) cm 3和(0.54±0.13) cm 3，各組間差異無統計學意義（P gt;0.05）; HepG 2細胞組腫瘤經重組腺病毒Ad-EAFP-PALB/r-Caspase-3治療后8周時腫瘤體積為(0.65±0.13) cm 3，明顯小于MDA-MB-231細胞組〔(1.27±0.32) cm 3〕和對照組〔(1.43±1.09) cm 3〕，P lt;0.01，而后兩組之間比較差異無統計學意義（P gt;0.05）。治療后HepG 2細胞組腫瘤細胞出現壞死區，伴淋巴浸潤細胞和凋亡細胞; 對照組腫瘤細胞區域內未見明顯壞死區; 而MDA-MB-231細胞組腫瘤細胞呈實性排列，呈小腺腔樣結構，異型性明顯，瘤巨細胞及多核瘤細胞可見，治療前、后未見明顯變化。結論靶向性重組腺病毒Ad-EAFP-PALB/r-Caspase-3具有有效靶向性凋亡誘導作用，體內、外治療原發性肝癌有效，可能為原發性肝癌的靶向性基因治療提供新途徑。

引用本文： 王煒,沈浩元,劉猛. 靶向性重組腺病毒對裸鼠肝癌種植瘤的治療作用. 中國普外基礎與臨床雜志, 2011, 18(7): 722-727. doi: 復制

1.	王煒, 程衛, 丘昶儒. 肝細胞肝癌靶向性rCaspase3重組腺病毒的構建與表達 [J]. 中國普外基礎與臨床雜志, 2008, 15(8): 589594.
2.	王煒, 沈浩元, 丘昶儒, 等. 靶向性反向半胱氨酸天冬氨酸蛋白酶3重組腺病毒誘導肝癌細胞凋亡的實驗研究 [J]. 中華生物醫學工程雜志, 2010, 16(4): 298303.
3.	陳汝福, 孫宏武, 鄒倩. 反義硫代寡脫氧核苷酸抑制裸鼠人膽管癌生長的研究 [J]. 中華實驗外科雜志, 2000, 17(1): 2223.
4.	畢允力, 高解春, 許德華. 5氟胞嘧啶對表達胞嘧啶脫氨酶的人腎母細胞瘤裸鼠異種移植瘤的療效 [J]. 中華腫瘤雜志, 2000, 22(2): 113115.
5.	陳孝平, 張萬廣. 原發性肝癌面臨的難點與對策 [J]. 中國普外基礎與臨床雜志, 2008, 25(4): 231233.
6.	Araida T, Higuchi R, Hamano M, et al. Hepatic resection in 485 R0 pT2 and pT3 cases of advanced carcinoma of the gallbladder: results of a Japanese Society of Biliary Surgery survey—a multicenter study [J]. Hepatobiliary Pancreat Surg, 2009, 16(2): 204215.
7.	Cescon M, Cucchetti A, Grazi GL, et al. Indication of the extent of hepatectomy for hepatocellular carcinoma on cirrhosis by a simple algorithm based on preoperative variables [J]. Arch Surg, 2009, 144(1): 5763.
8.	Ishizawa T, Hasegawa K, Kokudo N, et al. Risk factors and management of ascites after liver resection to treat hepatocellular carcinoma [J]. Arch Surg, 2009, 144(1): 4651.
9.	Cho JY, Han HS, Yoon YS, et al. Outcomes of laparoscopic liver resection for lesions located in the right side of the liver [J]. Arch Surg, 2009, 144(1): 2529.
10.	Miyazawa M, Aikawa M, Okada K, et al. Extended left hepatic lobectomy for hepatic hilar bile duct cancer: a novel surgical procedure in which the right hepatic duct is transected before the hepatoduodenal ligament is skeletonized [J]. Dig Surg, 2009, 26(1): 1519.
11.	Smerdou C, Menne S, HernandezAlcoceba R, et al. Gene therapy for HCV/HBVinduced hepatocellular carcinoma [J]. Curr Opin Investig Drugs, 2010, 11(12): 13681377.
12.	Sharapova OA, Pozdnykova NV, Laurinavichyute DK, et al. Highefficient expression, refolding and purification of functional recombinant Cterminal fragment of human alphafetoprotein [J]. Protein Expr Purif, 2010, 73(1): 3135.
13.	Lam PY, Sia KC, Khong JH, et al. An efficient and safe herpes simplex virus type 1 amplicon vector for transcriptionally targeted therapy of human hepatocellular carcinomas [J]. Mol Ther, 2007, 15(6): 11291136.
14.	Nussbaum T, Samarin J, Ehemann V, et al. Autocrine insulinlike growth factorII stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis [J]. Hepatology, 2008, 48(1): 146156.
15.	Sadeghi H, Hitt MM. Transcriptionally targeted adenovirus vectors [J]. Curr Gene Ther, 2005, 5(4): 411427.
16.	Kanai F. Transcriptional targeted gene therapy for hepatocellular carcinoma by adenovirus vector [J]. Mol Biotechnol, 2001, 18(3): 243250.
17.	Srinivasula SM, Ahmad M, MacFarlane M, et al. Generation of constitutively active recombinant caspases3 and 6 by rearrangement of their subunits [J]. J Biol Chem, 1998, 273(17): 1010710111.
18.	王煒, 秦兆寅, 王劍利, 等. 重組的rCaspase3促凋亡基因體內外治療胰腺癌的試驗研究 [J]. 中華肝膽外科雜志, 2003, 9(5): 303305.
19.	王煒, 秦兆寅, 劉志國. 重組型Caspase3基因的構建及其在胰腺癌細胞中凋亡活性的觀察 [J]. 中國普外基礎與臨床雜志, 2002, 9(4): 249251.
20.	Park HJ, Kim MJ, Ha E, et al. Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNUC4 [J]. Phytomedicine, 2008, 15(12): 147151.
21.	Mouratidis PX, Colston KW, Dalgleish AG. Doxycycline induces caspasedependent apoptosis in human pancreatic cancer cells [J]. Int J Cancer, 2007, 120(4): 743752.
22.	Végran F, Boidot R, Oudin C, et al. Overexpression of caspase3s splice variant in locally advanced breast carcinoma is associated with poor response to neoadjuvant chemotherapy [J]. Clin Cancer Res, 2006, 12(19): 57945800.
23.	Aquino Esperanza JA, Aguirre MV, Aispuru GR, et al. In vivo 5fluorouracil[corrected] induced apoptosis on murine thymocytes: involvement of FAS, Bax and Caspase3 [J]. Cell Biol Toxicol, 2008, 24(5): 411422.
24.	易石堅, 李蘭蘭, 鐘德許, 等. 裸鼠皮下人肝癌種植瘤模型的建立 [J]. 中國醫藥導報, 2008, 21(5): 2728.
25.	李立, 吳沛宏, 黃嘉凌, 等. 重組人內皮抑素腺病毒抑制肝癌裸鼠移植瘤生長 [J]. 中華肝臟病雜志, 2008, 16(9): 542545.
26.	Kurio N, Shimo T, Fukazawa T, et al. Antitumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGFIR in vitro and in vivo [J]. Exp Cell Res, 2011, 317(8): 11341146.

1. 王煒, 程衛, 丘昶儒. 肝細胞肝癌靶向性rCaspase3重組腺病毒的構建與表達 [J]. 中國普外基礎與臨床雜志, 2008, 15(8): 589594.
2. 王煒, 沈浩元, 丘昶儒, 等. 靶向性反向半胱氨酸天冬氨酸蛋白酶3重組腺病毒誘導肝癌細胞凋亡的實驗研究 [J]. 中華生物醫學工程雜志, 2010, 16(4): 298303.
3. 陳汝福, 孫宏武, 鄒倩. 反義硫代寡脫氧核苷酸抑制裸鼠人膽管癌生長的研究 [J]. 中華實驗外科雜志, 2000, 17(1): 2223.
4. 畢允力, 高解春, 許德華. 5氟胞嘧啶對表達胞嘧啶脫氨酶的人腎母細胞瘤裸鼠異種移植瘤的療效 [J]. 中華腫瘤雜志, 2000, 22(2): 113115.
5. 陳孝平, 張萬廣. 原發性肝癌面臨的難點與對策 [J]. 中國普外基礎與臨床雜志, 2008, 25(4): 231233.
6. Araida T, Higuchi R, Hamano M, et al. Hepatic resection in 485 R0 pT2 and pT3 cases of advanced carcinoma of the gallbladder: results of a Japanese Society of Biliary Surgery survey—a multicenter study [J]. Hepatobiliary Pancreat Surg, 2009, 16(2): 204215.
7. Cescon M, Cucchetti A, Grazi GL, et al. Indication of the extent of hepatectomy for hepatocellular carcinoma on cirrhosis by a simple algorithm based on preoperative variables [J]. Arch Surg, 2009, 144(1): 5763.
8. Ishizawa T, Hasegawa K, Kokudo N, et al. Risk factors and management of ascites after liver resection to treat hepatocellular carcinoma [J]. Arch Surg, 2009, 144(1): 4651.
9. Cho JY, Han HS, Yoon YS, et al. Outcomes of laparoscopic liver resection for lesions located in the right side of the liver [J]. Arch Surg, 2009, 144(1): 2529.
10. Miyazawa M, Aikawa M, Okada K, et al. Extended left hepatic lobectomy for hepatic hilar bile duct cancer: a novel surgical procedure in which the right hepatic duct is transected before the hepatoduodenal ligament is skeletonized [J]. Dig Surg, 2009, 26(1): 1519.
11. Smerdou C, Menne S, HernandezAlcoceba R, et al. Gene therapy for HCV/HBVinduced hepatocellular carcinoma [J]. Curr Opin Investig Drugs, 2010, 11(12): 13681377.
12. Sharapova OA, Pozdnykova NV, Laurinavichyute DK, et al. Highefficient expression, refolding and purification of functional recombinant Cterminal fragment of human alphafetoprotein [J]. Protein Expr Purif, 2010, 73(1): 3135.
13. Lam PY, Sia KC, Khong JH, et al. An efficient and safe herpes simplex virus type 1 amplicon vector for transcriptionally targeted therapy of human hepatocellular carcinomas [J]. Mol Ther, 2007, 15(6): 11291136.
14. Nussbaum T, Samarin J, Ehemann V, et al. Autocrine insulinlike growth factorII stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis [J]. Hepatology, 2008, 48(1): 146156.
15. Sadeghi H, Hitt MM. Transcriptionally targeted adenovirus vectors [J]. Curr Gene Ther, 2005, 5(4): 411427.
16. Kanai F. Transcriptional targeted gene therapy for hepatocellular carcinoma by adenovirus vector [J]. Mol Biotechnol, 2001, 18(3): 243250.
17. Srinivasula SM, Ahmad M, MacFarlane M, et al. Generation of constitutively active recombinant caspases3 and 6 by rearrangement of their subunits [J]. J Biol Chem, 1998, 273(17): 1010710111.
18. 王煒, 秦兆寅, 王劍利, 等. 重組的rCaspase3促凋亡基因體內外治療胰腺癌的試驗研究 [J]. 中華肝膽外科雜志, 2003, 9(5): 303305.
19. 王煒, 秦兆寅, 劉志國. 重組型Caspase3基因的構建及其在胰腺癌細胞中凋亡活性的觀察 [J]. 中國普外基礎與臨床雜志, 2002, 9(4): 249251.
20. Park HJ, Kim MJ, Ha E, et al. Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNUC4 [J]. Phytomedicine, 2008, 15(12): 147151.
21. Mouratidis PX, Colston KW, Dalgleish AG. Doxycycline induces caspasedependent apoptosis in human pancreatic cancer cells [J]. Int J Cancer, 2007, 120(4): 743752.
22. Végran F, Boidot R, Oudin C, et al. Overexpression of caspase3s splice variant in locally advanced breast carcinoma is associated with poor response to neoadjuvant chemotherapy [J]. Clin Cancer Res, 2006, 12(19): 57945800.
23. Aquino Esperanza JA, Aguirre MV, Aispuru GR, et al. In vivo 5fluorouracil[corrected] induced apoptosis on murine thymocytes: involvement of FAS, Bax and Caspase3 [J]. Cell Biol Toxicol, 2008, 24(5): 411422.
24. 易石堅, 李蘭蘭, 鐘德許, 等. 裸鼠皮下人肝癌種植瘤模型的建立 [J]. 中國醫藥導報, 2008, 21(5): 2728.
25. 李立, 吳沛宏, 黃嘉凌, 等. 重組人內皮抑素腺病毒抑制肝癌裸鼠移植瘤生長 [J]. 中華肝臟病雜志, 2008, 16(9): 542545.
26. Kurio N, Shimo T, Fukazawa T, et al. Antitumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGFIR in vitro and in vivo [J]. Exp Cell Res, 2011, 317(8): 11341146.

《中國普外基礎與臨床雜志》

靶向性重組腺病毒對裸鼠肝癌種植瘤的治療作用

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

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《中國普外基礎與臨床雜志》

靶向性重組腺病毒對裸鼠肝癌種植瘤的治療作用

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

摘要全文圖表視頻參考文獻施引文獻補充材料