The Synergistic Anti-tumor Effect of Endostatin on a Tumor-progression Murine Lung Cancer Model_West China Medical Journal

Authors：

ZHANG Wei , WU Lu , WANG Zi , LIU Yanyang ,  LUO Feng.

Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LUO Feng., Email: zhangweizzyy@126.com

Keywords：

内皮抑素; 肿瘤进展; 化学疗法; 协同作用

DOI：

10.7507/1002-0179.20130308

Video：

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目的　建立重组人内皮抑素（恩度）联合顺铂一线治疗肿瘤进展的小鼠模型，继续应用内皮抑素联合紫杉醇二线治疗，研究内皮抑素协同紫杉醇抗肿瘤的作用及其机制。方法　建立小鼠Lewis 肺癌移植瘤动物模型，内皮抑素联合顺铂治疗后观察肿瘤生长情况，遴选出肿瘤进展小鼠16只，随机留取1只，余15只小鼠随机分成紫杉醇组和联合用药组治疗，观察疗效。另取上述肿瘤进展小鼠1只，剥离肿瘤组织，重新接种，将成瘤小鼠随机分成生理盐水组，紫杉醇组及联合用药组治疗，观察疗效。治疗结束后24 h处死所有小鼠，采用免疫组织化学CD31单克隆抗体标记检测微血管密度（MVD），采用原位末端转移酶（TUNEL）检测细胞凋亡。结果　只肿瘤进展小鼠中，联合用药组相比紫杉醇组生存时间无明显延长，但肿瘤体积增长较慢；而在重新接种成瘤的小鼠中，联合用药组较其余各组微血管密度明显减低（P＜0.05），凋亡指数明显增加（P＜0.05），肿瘤体积抑制明显。结论　在内皮抑素联合顺铂治疗肿瘤进展的小鼠模型中，继续应用内皮抑素治疗与紫杉醇有较明显的协同抗肿瘤作用。

Citation： ZHANG Wei,WU Lu,WANG Zi,LIU Yanyang,LUO Feng.. The Synergistic Anti-tumor Effect of Endostatin on a Tumor-progression Murine Lung Cancer Model. West China Medical Journal, 2013, 28(7): 989-993. doi: 10.7507/1002-0179.20130308 Copy

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4.	Ma J, Waxman DJ. Combination of anti-angiogenesis with chemotherapy for more effective cancer treatment[J]. Molecular Cancer Therapeutics, 2008, 7(12): 3670-3684.
5.	O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth[J]. Cell, 1997, 88(2): 277-285.
6.	Cao Y. Endogenous angiogenesis inbibitors and their therapeutic implications[J]. Int J Biochem Cell Biol, 2001, 33 (4): 357-369.
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8.	黎培员, 冯作化, 张桂梅, 等.化疗联合重组Endostatin对小鼠种植瘤的治疗作用[J].中国肿瘤生物治疗杂志, 2002, 9(1): 43-47.
9.	Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial[J]. Lancet Oncol, 2013, 14(1): 29-37.
10.	Huang G, Chen L. Recombinant human endostatin improves anti-tumor efficacy of paclitaxel by normalizing tumor vasculature in Lewis lung carcinoma[J]. J Cancer Res Clin Oncol, 2010, 136(8): 1201-1211.
11.	Weidner N, Semple JP, Folkman J, et al.Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma[J]. N Engl J Med, 1991, 324(1): 1-8.
12.	Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease[J]. Nat Med, 1995, 1(1): 27-31.
13.	Dhanabal M, Ramchandran R, Waterman MJ, et al. Endostatin induces endothelial cell apoptosis[J]. J Biol Chem, 1999, 274(17): 11721-11726.
14.	Skovseth DK, Veuger MJ, Haraldsen G, et al. Endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis, and perivascular cell recruitment in vivo[J]. Blood, 2005,105(3): 1044-1051.
15.	Wang HL, Ning T, Luo F, et al. Effect of endostatin on preventing postoperative progression of distant metastasis in a murine lung cancer model[J]. Tumori, 2011, 97(6): 787-793.
16.	Saarela J, Ylikärppä R, Rehn M, et al. Complete primary structure of two variant forms of human type XVIII collagen and tissue-specific diffences in the expression of the corresponding transcript[J]. Matrix Biol, 1998, 16(6): 319-328.

1. 　Junttila MR, Karnezis AN, Garcia D, et al. Selective activation of p53-mediated tumor suppression in high-grade tumors[J]. Nature, 2010, 468(7323): 567-571.
2. 　Folkman J. Role of angiogenesis in tumor growth and metastasis[J]. Semin Oncol, 2002, 29(6 Suppl 16): 15-18.
3. 　Ning T, Yan X, Lu ZJ, et al. Gene therapy with the angiogenesis inhibitor endostatin in an orthotopic lung cancer murine model[J]. Hum Gene Ther, 2009, 20(2): 103-111.
4. 　Ma J, Waxman DJ. Combination of anti-angiogenesis with chemotherapy for more effective cancer treatment[J]. Molecular Cancer Therapeutics, 2008, 7(12): 3670-3684.
5. 　O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth[J]. Cell, 1997, 88(2): 277-285.
6. 　Cao Y. Endogenous angiogenesis inbibitors and their therapeutic implications[J]. Int J Biochem Cell Biol, 2001, 33 (4): 357-369.
7. 　Boehm T, Folkman J, Browder T, et al. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance[J]. Nature, 1997, 390(6658): 404-407.
8. 　黎培员, 冯作化, 张桂梅, 等.化疗联合重组Endostatin对小鼠种植瘤的治疗作用[J].中国肿瘤生物治疗杂志, 2002, 9(1): 43-47.
9. 　Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial[J]. Lancet Oncol, 2013, 14(1): 29-37.
10. 　Huang G, Chen L. Recombinant human endostatin improves anti-tumor efficacy of paclitaxel by normalizing tumor vasculature in Lewis lung carcinoma[J]. J Cancer Res Clin Oncol, 2010, 136(8): 1201-1211.
11. 　Weidner N, Semple JP, Folkman J, et al.Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma[J]. N Engl J Med, 1991, 324(1): 1-8.
12. 　Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease[J]. Nat Med, 1995, 1(1): 27-31.
13. 　Dhanabal M, Ramchandran R, Waterman MJ, et al. Endostatin induces endothelial cell apoptosis[J]. J Biol Chem, 1999, 274(17): 11721-11726.
14. 　Skovseth DK, Veuger MJ, Haraldsen G, et al. Endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis, and perivascular cell recruitment in vivo[J]. Blood, 2005,105(3): 1044-1051.
15. 　Wang HL, Ning T, Luo F, et al. Effect of endostatin on preventing postoperative progression of distant metastasis in a murine lung cancer model[J]. Tumori, 2011, 97(6): 787-793.
16. 　Saarela J, Ylikärppä R, Rehn M, et al. Complete primary structure of two variant forms of human type XVIII collagen and tissue-specific diffences in the expression of the corresponding transcript[J]. Matrix Biol, 1998, 16(6): 319-328.

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The Synergistic Anti-tumor Effect of Endostatin on a Tumor-progression Murine Lung Cancer Model

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