• 1.昆明醫(yī)學院第二附屬醫(yī)院肝膽二科(昆明 650101);;
  • 2.昆明醫(yī)學院(昆明 650031);

目的  探討血管生長抑素基因聯(lián)合生長抑素在體外對人胰腺癌細胞BXPC-3和血管內皮細胞ECV-304增殖的抑制作用。方法  重組pcDNA3/angio質粒轉染人胰腺癌細胞BXPC-3，利用RT-PCR和Western blot檢測其表達及分泌血管生長抑素的情況； MTT法和流式細胞儀檢測生長抑素和血管生長抑素對BXPC-3和ECV-304細胞增殖的影響。結果  轉染后的BXPC-3細胞表達并分泌血管生長抑素。一定濃度（≥10 μg/ml）的生長抑素對BXPC-3細胞的增殖有明顯抑制作用（P＜0.01），并在一定濃度范圍內呈劑量依賴性，同時能誘導BXPC-3細胞凋亡（P＜0.01）； 但其對ECV-304細胞的增殖無明顯影響（P gt;0.05）。血管生長抑素對ECV-304細胞的增殖有明顯抑制作用（P＜0.01），并能誘導其凋亡（P＜0.01）； 但對BXPC-3細胞的增殖無明顯影響（P gt;0.05）。血管生長抑素聯(lián)合生長抑素對BXPC-3及ECV-304細胞的增殖均有明顯抑制作用（P＜0.01），也可誘導其凋亡（P＜0.01），但無協(xié)同增強效應。結論  ①生長抑素主要通過直接抑制胰腺癌細胞增殖、促進其凋亡而發(fā)揮抗胰腺癌作用； 在體外其對血管內皮細胞無抑制作用。②血管生長抑素主要通過特異性地抑制胰腺癌血管內皮細胞的增殖并誘導其凋亡，從而抑制新生毛細血管的生成，致胰腺癌細胞壞死和腫瘤消退。

引用本文： 朱紅,郭永章,楊鴻煒,鄒浩,王琨,黃松泉. 血管生長抑素基因聯(lián)合生長抑素治療人胰腺癌的體外研究. 中國普外基礎與臨床雜志, 2009, 16(6): 460-465. doi: 復制

1. Chi SL, Pizzo SV. Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase[Ｊ]. Cancer Res, 2006; 66(2): 875-882.
2. 張延齡. 胰腺癌的基因治療研究 [Ｊ]. 臨床外科雜志, 2004; 12(4): 242-243.
3. Tirone TA, Wang XP, Templeton NS, et al. Cell-specific cytotoxicity of human pancreatic adenocarcinoma cells using rat insulin promoter thymidine kinase-directed gene therapy [Ｊ]. World J Surg, 2004; 28(8): 826-833.
4. Mkinen K, Loimas S, Wahlfors J, et al. Evaluation of herpes simplex thymidine kinase mediated gene therapy in experimental pancreatic cancer [Ｊ]. J Gene Med, 2000; 2(5): 361-367.
5. Carrió M, Visa J, Cascante A, et al. Intratumoral activation of cyclophosphamide by retroviral transfer of the cytochrome P450 2B1 in a pancreatic tumor model. Combination with the HSVtk/GCV system [Ｊ]. J Gene Med, 2002; 4(2):141-149.
6. Shen GH, Ghazizadeh M, Kawanami O, et al. Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma[Ｊ]. Br J Cancer, 2000; 83(2):196-203.
7. Ikeda N, Nakajima Y, Sho M, et al. The association of K-ras gene mutation and vascular endothelial growth factor gene expression in pancreatic carcinoma[Ｊ]. Cancer, 2001; 92(3): 488-499.
8. 李繼坤， 鄭淼， 李遠芳， 等. p53及VEGF表達與結、直腸癌血道轉移發(fā)生的關系 [Ｊ]. 中國普外基礎與臨床雜志， 2002； 9（2）： 112-114.
9. Benjamin LE, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal [Ｊ]. Proc Natl Acad Sci USA, 1997; 94(16): 8761-8766.
10. Gourley M, Williamson JS. Angiogenesis: new targets for the development of anticancer chemotherapies [Ｊ]. Curr Pharm Des, 2000; 6(4): 417-439.
11. Niedergethmann M, Hildenbrand R, Wostbrock B, et al. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas [Ｊ]. Pancreas, 2002; 25(2): 122-129.
12. 劉江偉， 李開宗， 竇科峰. 環(huán)氧化酶-2和血管內皮生長因子在胰腺癌組織中的表達及其相關性研究 [Ｊ]. 中國普外基礎與臨床雜志, 2003; 10（6）: 539-541.
13. Galaup A, Opolon P, Bouquet C, et al. Combined effects of docetaxel and angiostatin gene therapy in prostate tumor model [Ｊ]. Mol Ther, 2003; 7(6): 731-740.
14. 何長生， 全竹富. 生長抑素抗腫瘤機制及其對胰腺癌的治療展望 [Ｊ]. 腸外與腸內營養(yǎng)， 2006; 13(6): 373-376.
15. Kouroumalis E, Skordilis P, Thermos K, et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study[Ｊ]. Gut, 1998; 42(3): 442-447.
16. Casini Raggi C, Calabrò A, Renzi D, et al. Quantitative evaluation of somatostatin receptor subtype 2 expression in sporadic colorectal tumor and in the corresponding normal mucosa [Ｊ]. Clin Cancer Res, 2002; 8(2): 419-427.
17. 華赟鵬， 賴佳明， 梁力建， 等. 奧曲肽下調cMet的表達抑制肝細胞癌的生長 [Ｊ]. 中國普外基礎與臨床雜志, 2006; 13（2）: 158-162.
18. 張燕玲， 張正. 生長抑素類似物對肝癌細胞凋亡及c-myc蛋白表達的影響 [Ｊ]. 中國普外基礎與臨床雜志, 2003; 10（1）： 25-27.
19. Radulovic S, Comaru-Schally AM, Milovanovic S, et al. Somatostatin analogue RC-160 and LH-RH antagonist SB-75 inhibit growth of MIA PaCa-2 human pancreatic cancer xenografts in nude mice [Ｊ]. Pancreas， 1993; 8(1): 88-97.
20. 劉正人， 吳高松， 杜志勇， 等. 奧曲肽對胰腺癌細胞轉染SSTR2后的作用 [Ｊ]. 中國普通外科雜志， 2004； 13(6)： 424-427.
21. Patel YC, Panetta R, Escher E, et al. Expression of multiple somatostatin receptor genes in AtT-20 cells. Evidence for a novel somatostatin-28 selective receptor subtype [Ｊ]. J Biol Chem， 1994; 269(2): 1506-1509.
22. 張浩, 李昱驥, 周建平, 等. 表皮生長因子促進胰腺癌細胞侵襲和轉移的實驗研究 [Ｊ]. 中國普外基礎與臨床雜志, 2008; 15(3): 180-184.
23. 張群華， 倪泉興， 沈兆中， 等. 生長抑素對胰腺癌生長抑制和凋亡作用的實驗研究 [Ｊ]. 外科理論與實踐， 2002； 7（5）：352-355.
24. Zalatnai A, Szegedi Z, Bocsi J. Flow cytometric evidence of apoptosis in human pancreatic cancer xenografts treated with Sandostatin (octreotide) [Ｊ]. Anticancer Res， 2000; 20(3A): 1663-1666.
25. Qin RY, Fang RL, Gupta MK, et al. Alteration of somatostatin receptor subtype 2 gene expression in pancreatic tumor angiogenesis [Ｊ]. World J Gastroenterol， 2004; 10(1): 132-135.
26. Kumar M, Liu ZR, Thapa L, et al. Antiangiogenic effect of somatostatin receptor subtype 2 on pancreatic cancer cell line: Inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 expression in vitro [Ｊ]. World J Gastroenterol， 2004; 10(3): 393-399.
27. Ren SG, Ezzat S, Melmed S, et al. Somatostatin analog induces insulin-like growth factor binding protein-1 (IGFBP-1) expression in human hepatoma cells [Ｊ]. Endocrinology, 1992; 131(5): 2479-2481.
  1. 1. Chi SL, Pizzo SV. Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase[Ｊ]. Cancer Res, 2006; 66(2): 875-882.
  2. 2. 張延齡. 胰腺癌的基因治療研究 [Ｊ]. 臨床外科雜志, 2004; 12(4): 242-243.
  3. 3. Tirone TA, Wang XP, Templeton NS, et al. Cell-specific cytotoxicity of human pancreatic adenocarcinoma cells using rat insulin promoter thymidine kinase-directed gene therapy [Ｊ]. World J Surg, 2004; 28(8): 826-833.
  4. 4. Mkinen K, Loimas S, Wahlfors J, et al. Evaluation of herpes simplex thymidine kinase mediated gene therapy in experimental pancreatic cancer [Ｊ]. J Gene Med, 2000; 2(5): 361-367.
  5. 5. Carrió M, Visa J, Cascante A, et al. Intratumoral activation of cyclophosphamide by retroviral transfer of the cytochrome P450 2B1 in a pancreatic tumor model. Combination with the HSVtk/GCV system [Ｊ]. J Gene Med, 2002; 4(2):141-149.
  6. 6. Shen GH, Ghazizadeh M, Kawanami O, et al. Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma[Ｊ]. Br J Cancer, 2000; 83(2):196-203.
  7. 7. Ikeda N, Nakajima Y, Sho M, et al. The association of K-ras gene mutation and vascular endothelial growth factor gene expression in pancreatic carcinoma[Ｊ]. Cancer, 2001; 92(3): 488-499.
  8. 8. 李繼坤， 鄭淼， 李遠芳， 等. p53及VEGF表達與結、直腸癌血道轉移發(fā)生的關系 [Ｊ]. 中國普外基礎與臨床雜志， 2002； 9（2）： 112-114.
  9. 9. Benjamin LE, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal [Ｊ]. Proc Natl Acad Sci USA, 1997; 94(16): 8761-8766.
  10. 10. Gourley M, Williamson JS. Angiogenesis: new targets for the development of anticancer chemotherapies [Ｊ]. Curr Pharm Des, 2000; 6(4): 417-439.
  11. 11. Niedergethmann M, Hildenbrand R, Wostbrock B, et al. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas [Ｊ]. Pancreas, 2002; 25(2): 122-129.
  12. 12. 劉江偉， 李開宗， 竇科峰. 環(huán)氧化酶-2和血管內皮生長因子在胰腺癌組織中的表達及其相關性研究 [Ｊ]. 中國普外基礎與臨床雜志, 2003; 10（6）: 539-541.
  13. 13. Galaup A, Opolon P, Bouquet C, et al. Combined effects of docetaxel and angiostatin gene therapy in prostate tumor model [Ｊ]. Mol Ther, 2003; 7(6): 731-740.
  14. 14. 何長生， 全竹富. 生長抑素抗腫瘤機制及其對胰腺癌的治療展望 [Ｊ]. 腸外與腸內營養(yǎng)， 2006; 13(6): 373-376.
  15. 15. Kouroumalis E, Skordilis P, Thermos K, et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study[Ｊ]. Gut, 1998; 42(3): 442-447.
  16. 16. Casini Raggi C, Calabrò A, Renzi D, et al. Quantitative evaluation of somatostatin receptor subtype 2 expression in sporadic colorectal tumor and in the corresponding normal mucosa [Ｊ]. Clin Cancer Res, 2002; 8(2): 419-427.
  17. 17. 華赟鵬， 賴佳明， 梁力建， 等. 奧曲肽下調cMet的表達抑制肝細胞癌的生長 [Ｊ]. 中國普外基礎與臨床雜志, 2006; 13（2）: 158-162.
  18. 18. 張燕玲， 張正. 生長抑素類似物對肝癌細胞凋亡及c-myc蛋白表達的影響 [Ｊ]. 中國普外基礎與臨床雜志, 2003; 10（1）： 25-27.
  19. 19. Radulovic S, Comaru-Schally AM, Milovanovic S, et al. Somatostatin analogue RC-160 and LH-RH antagonist SB-75 inhibit growth of MIA PaCa-2 human pancreatic cancer xenografts in nude mice [Ｊ]. Pancreas， 1993; 8(1): 88-97.
  20. 20. 劉正人， 吳高松， 杜志勇， 等. 奧曲肽對胰腺癌細胞轉染SSTR2后的作用 [Ｊ]. 中國普通外科雜志， 2004； 13(6)： 424-427.
  21. 21. Patel YC, Panetta R, Escher E, et al. Expression of multiple somatostatin receptor genes in AtT-20 cells. Evidence for a novel somatostatin-28 selective receptor subtype [Ｊ]. J Biol Chem， 1994; 269(2): 1506-1509.
  22. 22. 張浩, 李昱驥, 周建平, 等. 表皮生長因子促進胰腺癌細胞侵襲和轉移的實驗研究 [Ｊ]. 中國普外基礎與臨床雜志, 2008; 15(3): 180-184.
  23. 23. 張群華， 倪泉興， 沈兆中， 等. 生長抑素對胰腺癌生長抑制和凋亡作用的實驗研究 [Ｊ]. 外科理論與實踐， 2002； 7（5）：352-355.
  24. 24. Zalatnai A, Szegedi Z, Bocsi J. Flow cytometric evidence of apoptosis in human pancreatic cancer xenografts treated with Sandostatin (octreotide) [Ｊ]. Anticancer Res， 2000; 20(3A): 1663-1666.
  25. 25. Qin RY, Fang RL, Gupta MK, et al. Alteration of somatostatin receptor subtype 2 gene expression in pancreatic tumor angiogenesis [Ｊ]. World J Gastroenterol， 2004; 10(1): 132-135.
  26. 26. Kumar M, Liu ZR, Thapa L, et al. Antiangiogenic effect of somatostatin receptor subtype 2 on pancreatic cancer cell line: Inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 expression in vitro [Ｊ]. World J Gastroenterol， 2004; 10(3): 393-399.
  27. 27. Ren SG, Ezzat S, Melmed S, et al. Somatostatin analog induces insulin-like growth factor binding protein-1 (IGFBP-1) expression in human hepatoma cells [Ｊ]. Endocrinology, 1992; 131(5): 2479-2481.