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针对病种:膀胱癌

发表时间:1998年11月15日

发表国家:美国

登载刊物:癌症研究

研究单位:美国哈佛大学医学院BIDMC生命科学中心

研究人员:布兰克林等

主要结论:金雀异黄素通过直接作用于肿瘤细胞、间接作用于膀胱血管,来抑制膀胱肿瘤的生长.

Cancer Res. 1998 Nov 15;58(22):5231-8.
Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis
Zhou JR, Mukherjee P, Gugger ET, Tanaka T, Blackburn GL, Clinton SK.
(Beth Israel-Deaconess Medical Center, Harvard Medical School)

Soy isoflavones exhibit a number of biological effects, suggesting that they may have a role in cancer prevention. Our objectives are to determine whether components of soy products or purified soy isoflavones can inhibit the progression of bladder cancer. We compared the in vitro effects of pure soy isoflavones and soy phytochemical concentrate on growth curves, cell cycle progression, and apoptosis in murine and human bladder cancer cell lines.Pure soy isoflavones (genistein, genistin, daidzein, and biochanin A) and soy phytochemical concentrate exhibit dose-dependent growth inhibition of murine (MB49 and MBT-2) and human (HT-1376, UM-UC-3, RT-4, J82, and TCCSUP) bladder cancer cell lines, although the degree of inhibition varies among lines. Soy isoflavones induce a G2-M cell cycle arrest in all human and murine lines evaluated by flow cytometry.In addition, some bladder cancer lines show DNA fragmentation consistent with apoptosis. We next evaluated the ability of genistein, soy phytochemical concentrate, and soy protein isolate, respectively, to inhibit the growth of transplantable murine bladder cancer in vivo. C57BL/6 mice were randomly assigned to treatment groups (n = 12/group):(a) AIN-76A diet; (b) AIN-76A diet plus genistein, i.p., 50 mg/kg body weight/day; (c) AIN-76A diet with soy phytochemical concentrate at 0.2% of the diet; (d) AIN-76A diet with soy phytochemical concentrate at 1.0% of the diet; and (e) AIN-76A diet with soy protein isolate, 20% by weight. Mice were inoculated s.c. with 5 x 10(4) syngeneic MB49 bladder carcinoma cells, and tumor growth was quantitated. Neither genistein nor soy products reduced body weight gain. Tumor volumes from mice treated with genistein, dietary soy phytochemical concentrate at 1%, or dietary soy protein isolate were reduced by 40% (P < 0.007), 48% (P < 0.001), or 37% (P < 0.01), respectively, compared with controls. We characterized the effects of treatment on several biomarkers in tumor tissue: proliferation index by proliferating cell nuclear antigen staining, apoptotic index by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining, and angiogenesis by microvessel quantitation. Soy products reduced angiogenesis, increased apoptosis, and slightly reduced proliferation while showing nohistopathological effects on the normal bladder mucosa. Our data suggest that soy isoflavones can inhibit bladder tumor growth through a combination of direct effects on tumor cells and indirect effects on the tumor neovasculature. Soy products warrant further investigation in bladder cancer prevention and treatment programs or as antiangiogenic agents.

《癌症研究》1998年1月15日
大豆异黄酮(金雀异黄素)通过改变细胞周期,凋亡,血管生成抑制小鼠膀胱肿瘤
布兰克林等
(美国哈佛大学医学院附属BIDMC生命科学中心)

大豆异黄酮(金雀异黄素)表现出大量的生物效应,证明他们在预防癌症方面具有重要作用。我们的目标是要确定那种大豆成分或纯化的大豆异黄酮抑制膀胱癌的进展。 
我们比较纯大豆异黄酮、大豆植物浓缩物对鼠和人类膀胱肿瘤的生长曲线、细胞周期和细胞凋亡的体外作用。纯大豆异黄酮(金雀异黄素、染料木苷、黄豆苷元,和鸡豆黄素a) 和 大豆植物浓缩物对小鼠(MB49 和 MBT-2)和人 (HT-1376, UM-UC-3, RT-4, J82, 和TCCSUP) 膀胱癌细胞系显示剂量依赖性生长抑制,虽然抑制的程度不同。我们利用流式细胞仪证明大豆异黄酮可阻滞所有人和小鼠细胞周期停滞在G2-M期。此外,某些膀胱癌症显示 DNA 碎片与凋亡一致。 
我们下一步分别评估金雀异黄素浓缩物和大豆分离蛋白对移植性小鼠膀胱肿瘤体内的生长抑制能力。C57BL/6 小鼠被随机分配给治疗组 (n = 12/组):(a) AIN-76A饮食 ;(b) AIN-76A饮食加金雀异黄素,腹腔注射,50 毫克/公斤/天;(c) AIN-76A饮食加0.2%的大豆植物浓缩物; (d) AIN-76A饮食 加1%的大豆植物浓缩物;(e) AIN-76A加分离大豆蛋白,以重量的 20%计。 
小鼠用5 x 10(4)同基因MB49膀胱肿瘤细胞皮下接种,定量肿瘤生长。无论是金雀异黄素还是豆制品都可减少体重的增加。与对照组相比,分别用染料木素,1%膳食大豆植物浓缩物,或大豆分离蛋白处理,小鼠肿瘤体积以40%(P< 0.007),48%(P<0.001),或37%(P<0.01)减少。我们用肿瘤组织中几种生物标志物衡量处理效果:以增殖细胞核抗原测组织增殖、以末端凋亡指数的末端脱氧核苷酸转移酶介导的TUNEL染色法测细胞凋亡指数,以微血管定量法测新血管生成。可减少血管生成,增加细胞凋亡,和稍降低细胞增殖,不显示对正常膀胱黏膜上的组织病理学影响。

我们的数据表明大豆异黄酮(金雀异黄素)通过直接作用于肿瘤细胞和间接作用于膀胱肿瘤心血管系统来抑制膀胱肿瘤生长。
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