N-去硫酸肝素对胃癌血管生成及抑制作用的研究

Effect of N-desulfated Heparin on Angiogenesis and Growth of Subcutaneous Implantation of Human Gastric Carcinoma

目的：研究N-去硫酸肝素对人胃癌裸鼠模型肿瘤生长抑制、血管生成和细胞凋亡的影响。方法：建立人胃癌皮下移植裸鼠模 型，随机分成4组。移植1周后，分别从腹腔注射生理盐水(对照组)，卡铂(5 mg·kg^(-1) ·d^(-1) )，N-去硫酸肝素(10 mg·kg^(-1) ·d^(-1) )， 及卡铂(5 mg·kg^(-1) ·d^(-1) )与 N-去硫酸肝素(10 mg·kg^(-1) ·d^(-1) )，每周3次，共3周。第7周处死动物，测量肿瘤大小与重量、抑瘤 率、微血管密度(MVD)、胃癌细胞凋亡指数(AI)。结果：对照组、卡铂组、N-去硫酸肝素组、卡铂与 N-去硫酸肝素联合组的肿瘤重量 (mg)分别为1750． 4±144． 2、 1655． 0±157． 4、 1118． 0±116． 2与725． 6±130． 0，抑瘤率分别为5． 6%、36． 1%和58． 5%。MVD 分别为 14． 8±4． 5、 13． 2±4． 1、 3． 8±1． 7与3． 4±1． 8。凋亡指数分别为1． 37±0． 19、 3． 85±0． 22、 11． 81±2． 9与18． 85±3． 24。与对照组、卡铂 组相比，N-去硫酸肝素组、卡铂与 N-去硫酸肝素联合组的胃癌生长、微血管密度明显抑制，细胞凋亡明显增高。结论：N-去硫酸肝 素通过抑制肿瘤血管生成，诱导肿瘤细胞凋亡，从而抑制肿瘤的生长。N-去硫酸肝素无明显出血等不良反应。

Objective： To investigate the effect of N-desulfated heparin on tumor angiogenesis, cell apoptosis and growth of subcutaneous implantation of human gastric carcinoma. Methods： Human gastric cancer SGC - 7901 tissues were implanted into the dorsal subcutis of the nude mice. Mice were randomly divided into 4 groups which included control group（normal saline）, carboplatin group（carboplatin 5mg/kg i. p. ）, NNH group （N-desulfated heparin 10mg/kg i. p. ）, and carboplatin in combination with NNH group. Mice were sacrificed seven weeks after implantation. The tumor weight, tumor growth inhibition（TGI）, intratumoral microvessel density （MVD） and apoptosis index （M） were evaluated respectively. Results~ The tumor weight in control group, carboplatin group, NNH group and combination group was 1750. 4 ± 144. 2mg, 1655.0 ± 157.0mg, 1118.0 ± 116. 2 mg and 725.6 ± 130. 0mg, respectively. And TGI was 5.6 M, 36. 1 % and 38.5 respectively. MVD was 14. 8 ± 4. 5, 13.2 ± 4. 1, 3. 8 ± 1.7 and 3.4 ± 1.8 in the groups respectively. AI was 1.3 ± 0. 19, 3.85 ± 0. 22, 11. 81 ± 2. 90 and 18.85 ± 3.24 respectively. The MVD decreased significantly compared with the control group and carboplatin group. The AI was increased significantly in the carboplatin, NNH or the combination group. The growth of human gastric cancer implanted in nude mice was more significantly inhibited in the NNH group and combination group than in control group and carboplatin group（P〈0. 05）. Conclusion： N-desulfated heparin can inhibit the growth of gastric cancer through inhibiting tumor angiogenesis and inducing cancer cell apoptosis with no obvious anticoagulant activity.