坎地沙坦诱导肿瘤血管正常化增强阿霉素抗肿瘤作用研究

Study on Tumor Blood Vessel Normalization to Enhance the Antitumor Effect of Adriamycin Induced by Candesartan

关键词:  坎地沙坦  阿霉素  肿瘤血管正常化  抗肿瘤作用

Key words:  candesartan  adriamycin  tumor blood vessel normalization  antitumor effect

摘要:

目的 探讨坎地沙坦诱导肿瘤血管正常化对阿霉素抗肿瘤作用的影响。方法 培养4T1乳腺癌细胞和成纤维细胞3T3细胞，按1：3的比例混合后于裸鼠皮下接种，构建荷瘤裸鼠模型。比较研究坎地沙坦、阿霉素、坎地沙坦联合阿霉素对肿瘤体积增长的抑制作用，计算肿瘤抑制率，通过酶联免疫吸附法检测各组裸鼠血清中I型胶原、透明质酸和TGF-β1的含量，采用免疫组化法检测各组瘤块中的CD31、TSP-1及HIF-1α表达情况，考察肿瘤血管正常化相关指标。结果 坎地沙坦、阿霉素、坎地沙坦联合阿霉素均能抑制肿瘤体积的增长，其中坎地沙坦联合阿霉素组对肿瘤体积的抑制作用明显优于其他2组，坎地沙坦、阿霉素、坎地沙坦联合阿霉素的肿瘤抑制率分别为33.33%，40.00%，53.33%。较其他试验组相比，坎地沙坦联合阿霉素组的荷瘤裸鼠血清I型胶原、透明质酸和TGF-β1含量下降更显著，同时坎地沙坦联合阿霉素组的CD31与HIF-1α表达明显下降，而TSP-1表达上升。结论 坎地沙坦可以通过减少肿瘤组织纤维化，降低血管密度，改善肿瘤血管功能来诱导肿瘤血管正常化，从而提高阿霉素抗肿瘤作用。

Abstract:

OBJECTIVE To explore the enhanced anti-tumor effect of adriamycin based on normalization of tumor blood vessels induced by candesartan. METHODS 4T1 breast cancer cells and fibroblasts 3T3 cells were cultured and mixed at a ratio of 1:3 and inoculated subcutaneously in nude mice to construct a nude mouse model bearing tumors. The inhibitory effects of candesartan, adriamycin, and adriamycin combined with candesartan on tumor growth were compared. Tumor suppression rate was calculated. The contents of type I collagen, hyaluronic acid and TGF-β1 in rats serum were detected by enzyme linked immunosorbent assay, and the expression of CD31, TSP-1 and HIF-1α were detected by immunohistochemistry, the related indexes of tumor vascular normalization were observed. RESULTS Candesartan, adriamycin, adriamycin combined with candesartan could inhibit the growth of tumor. Among them, adriamycin combined with candesartan group significantly inhibited tumor growth better than the other two groups. The percentage of tumor inhibition rate of candesartan group, adriamycin group, adriamycin combined with candesartan group was 33.33%, 40.00%, 53.33%, respectively. Compared with other experimental groups, the content of type I collagen, hyaluronic acid and TGF-β1 in adriamycin combined with candesartan group decreased significantly, while the expression of CD31 and HIF-1α in adriamycin combined with candesartan group decreased significantly, and the expression of TSP-1 increased. CONCLUSION Candesartan may improve the antitumor effect of adriamycin by reducing the fibrosis of tumor tissue, reducing vascular density and inducing the normalization of tumor blood vessels.