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赵娅菽, 邓丽聪, 曹玥, 等. 人参皂苷Rg3与5-氟尿嘧啶联用对结肠癌小鼠肿瘤的血管生成与肿瘤生长抑制效果的实验研究[J]. 四川大学学报(医学版), 2024, 55(1): 111-117. DOI: 10.12182/20240160506
引用本文: 赵娅菽, 邓丽聪, 曹玥, 等. 人参皂苷Rg3与5-氟尿嘧啶联用对结肠癌小鼠肿瘤的血管生成与肿瘤生长抑制效果的实验研究[J]. 四川大学学报(医学版), 2024, 55(1): 111-117. DOI: 10.12182/20240160506
ZHAO Yashu, DENG Licong, CAO Yue, et al. Inhibitory Effect of Ginsenoside Rg3 Combined With 5-Fluorouracil on Tumor Angiogenesis and Tumor Growth of Colon Cancer in Mice: An Experimental Study[J]. Journal of Sichuan University (Medical Sciences), 2024, 55(1): 111-117. DOI: 10.12182/20240160506
Citation: ZHAO Yashu, DENG Licong, CAO Yue, et al. Inhibitory Effect of Ginsenoside Rg3 Combined With 5-Fluorouracil on Tumor Angiogenesis and Tumor Growth of Colon Cancer in Mice: An Experimental Study[J]. Journal of Sichuan University (Medical Sciences), 2024, 55(1): 111-117. DOI: 10.12182/20240160506

人参皂苷Rg3与5-氟尿嘧啶联用对结肠癌小鼠肿瘤的血管生成与肿瘤生长抑制效果的实验研究

Inhibitory Effect of Ginsenoside Rg3 Combined With 5-Fluorouracil on Tumor Angiogenesis and Tumor Growth of Colon Cancer in Mice: An Experimental Study

  • 摘要:
    目的 评价人参皂苷Rg3和5-氟尿嘧啶(5-fluorouracil, 5-FU)联用对结肠癌小鼠肿瘤的血管生成与肿瘤生长的抑制作用。
    方法 建立CT26结肠癌荷瘤小鼠模型,建模成功后将40只荷瘤小鼠随机分为对照组、人参皂苷Rg3组、5-FU组及Rg3与5-FU联用组。5-FU组按20 mg/kg剂量腹腔注射,0.2 mL/只,每天1次,连续注射10 d;Rg3组,按20 mg/kg剂量灌胃,0.2 mL/只,每天1次,连续灌胃21 d;Rg3+5-FU联合组用药剂量和方式同5-FU组和Rg3组;对照组腹腔注射生理盐水0.2 mL/d,连续注射10 d。通过免疫组化检测血管内皮细胞生长因子(VEGF)和CD31的表达,检测肿瘤组织微血管密度(MVD),彩色多普勒血流成像(CDFI)检测血流信号及肿瘤坏死情况;观测小鼠的生活质量、存活率、肿瘤体积、肿瘤质量及抑瘤率。
    结果 治疗21 d后,与对照组相比,各治疗组肿瘤体积、肿瘤质量均明显减少,联合组减少最为明显。Rg3组、5-FU组及联合组抑瘤率分别为29.96%、68.78%及73.42%,单用Rg3对肿瘤生长具有一定的抑制作用,但5-FU单用或与Rg3联用对肿瘤的抑制作用更强,联合组抑瘤率虽然高于5-FU组水平,但差异无统计学意义(P>0.05)。彩色多普勒检测显示,Rg3组和联合组小鼠肿瘤内部可见明显的多局部、较大的肿瘤坏死区域,而5-FU组和对照组仅有较小的肿瘤坏死区域,联合组的肿瘤坏死率为(55.63±3.12)%,高于其他各组水平(P<0.05)。CDFI检测小鼠肿瘤内血流情况显示,联合组肿瘤内血流信号多为0-Ⅰ级,对照组血流信号最丰富,多为Ⅱ-Ⅲ级,Rg3组和5-FU组肿瘤内血流信号丰富程度介于对照组和联合组之间。与对照组相比,Rg3组、5-FU组和联合组肿瘤组织MVD和VEGF表达水平均降低,其中联合组降低最为显著(P<0.05)。HE染色结果提示,对照组小鼠肿瘤的坏死情况明显,血管较多;Rg3组、5-FU组血管较少,肿瘤内出现空隙状坏死;联合组的肿瘤组织血管最少,可见条索状坏死。自治疗开始后18 d小鼠开始出现死亡,对照组小鼠在42 d全部死亡,此时Rg3组、5-FU组和联合组分别还有3只、5只、7只小鼠存活,存活率分别为30%、50%、70%。治疗开始后60 d时,各组小鼠全部死亡。
    结论 人参皂苷Rg3与5-FU联用不仅能够显著抑制结肠癌小鼠肿瘤的血管生成,并且显著抑制了肿瘤生长,提高了荷瘤小鼠的生活质量、延长了生存期。

     

    Abstract:
    Objective To evaluate the inhibitory effect of ginsenoside Rg3 combined with 5-fluorouracil (5-FU) on tumor angiogenesis and tumor growth in colon cancer in mice.
    Methods CT26 mouse model of colon cancer was established and the mice were randomly assigned to the control group, the ginsenoside Rg3 group, the 5-FU group, and the Rg3 combined with 5-FU group. The 5-FU group was injected intraperitoneally at the dose of 20 mg/kg, 0.2 mL/animal, and once a day for 10 days. Treatment for the Rg3 group was given at the dose of 20 mg/kg, 0.2 mL/animal, and once a day for 21 days via gastric gavage. The dose and the mode of treatment for the Rg3+5-FU combination group were the same as those for the 5-FU and the Rg3 group. The control group was intraperitoneally injected with 0.2 mL/d of normal saline for 10 days. The expression of vascular endothelial growth factor (VEGF) and CD31 and the microvascular density (MVD) of the tumor tissues were examined by immunohistochemistry. The blood flow signals and tumor necrosis were examined by color Doppler flow imaging (CDFI). The quality of life, survival rate, tumor volume, tumor mass, and tumor inhibition rate of the mice were monitored.
    Results After 21 days of treatment, the tumor volume and the tumor mass of all treatment groups were significantly decreased compared with those the control group, with the combination treatment group exhibiting the most significant decrease. The tumor inhibition rates of the Rg3 group, the 5-FU group, and the combination group were 29.96%, 68.78%, and 73.42%, respectively. Rg3 treatment alone had inhibitory effect on tumor growth to a certain degree, while 5-FU treatment alone or 5-FU combined with Rg3 had a stronger inhibitory effect on tumor growth. The tumor inhibition rate of the combination group was higher than that of the 5-FU group, but the difference was not statistically significant (P>0.05). Color Doppler ultrasound showed that there were multiple localized and large tumor necrotic areas that were obvious and observable in the Rg3 group and the combination group, and that there were only small tumor necrotic areas in the 5-FU group and the control group. The tumor necrosis rate of the combination group was (55.63±3.12)%, which was significantly higher than those of the other groups (P<0.05). CDFI examination of the blood flow inside of the tumor of the mice showed that the blood flow signals in the combination group were mostly grade 0-Ⅰ, and that the blood flow signals in the control group were the most abundant, being mostly grade Ⅱ-Ⅲ. The abundance of the blood flow signals in the Rg3 and 5-FU groups were between those of the control group and the combination group. Compared with those of the control group, the expression levels of MVD and VEGF in the tumor tissues of the Rg3 group, the 5-FU group, and the combination group were significantly decreased, with the combination group showing the most significant decrease (P<0.05). HE staining results indicated that there was significant tumor necrosis in mice in the control group and that there were more blood vessels. In contrast, in the tumor of the Rg3 group and the 5-FU group, there were fewer blood vessels and necrotic gaps appeared within the tumors. In the combination group, the tumor tissues had the fewest blood vessels and rope-like necrosis was observed. The mice started dying on the 18th day after treatment started, and all the mice in the control group died on the 42nd day. By this time, there were 3, 5, and 7 mice still alive in the Rg3 group, the 5-FU group, and the combination group, respectively, presenting a survival rate of 30%, 50%, and 70%, respectively. All mice in all the groups died on day 60 after treatment started.
    Conclusion Ginsenoside Rg3 combined with 5-FU can significantly inhibit tumor angiogenesis and tumor growth of colon cancer in mice and improve the survival and quality of life of tumor-bearing mice.

     

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