Mast Cell Biology Group, Centre on Theoretical Problems in Physical and Chemical Pharmacology, Russian Academy of Sciences.
Timpharm LTD, Moscow, Russia.
Anticancer Drugs. 2018 Nov;29(10):956-964. doi: 10.1097/CAD.0000000000000670.
Cetirizine (CET) and thalidomide (THA) have been previously found to influence angiogenesis. The present study aimed to assess the ability of these drugs to influence mammary carcinogenesis in rats.
Sixty Sprague-Dawley female rats, aged 8 weeks, received 15 mg of 7,12-dimethylbenz(a)anthracene (DMBA) intragastrically. CET and THA (1.0 and 3.0 mg/kg, respectively) were administered orally for 118 days after DMBA administration. At the end of the treatment period, mammary tumors were counted and weighed, and their morphology was analyzed using light microscopy. In tumor tissue, proliferation and apoptotic indices and microvessel density were determined using immunohistochemical techniques; the levels of angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, were measured by western blotting.
CET and THA, administered separately, failed to influence tumor formation and angiogenesis. In contrast, the drug combination decreased latency to first tumor (significant difference from vehicle-treated control and groups that received either drug alone, P<0.01) and significantly lowered tumor number per rat, number of malignant tumors per rat, tumor burden, and tumor number per tumor-bearing animal (P<0.05 or <0.01). In tissue of malignant tumors, the drug combination decreased the number of proliferating cells, microvessel density, and levels of vascular endothelial growth factor and basic fibroblast growth factor and stimulated apoptosis (difference from all other groups, P<0.01).
It was shown for the first time that H1-antagonist and THA synergistically inhibit DMBA-induced mammary carcinogenesis; this effect was associated with a decrease in tumor angiogenesis. Further study of the anticancer and antiangiogenic activity of the combination may provide a new approach to breast cancer treatment.
西替利嗪（CET）和沙利度胺（THA）先前被发现影响血管生成。本研究旨在评估这些药物影响大鼠乳腺致癌作用的能力。
60 只 8 周龄 Sprague-Dawley 雌性大鼠经胃内给予 15mg 7,12-二甲基苯并蒽（DMBA）。DMBA 给药后，分别给予 CET 和 THA（1.0 和 3.0mg/kg）口服 118 天。在治疗期末，计数乳腺肿瘤并称重，用光镜分析其形态。在肿瘤组织中，通过免疫组织化学技术测定增殖和凋亡指数以及微血管密度；通过 Western 印迹法测定血管生成因子血管内皮生长因子和碱性成纤维细胞生长因子的水平。
单独给予 CET 和 THA 均不能影响肿瘤形成和血管生成。相反，药物联合降低了首次肿瘤的潜伏期（与对照组和单独用药组相比差异有统计学意义，P<0.01），显著降低了每只大鼠的肿瘤数、每只大鼠的恶性肿瘤数、肿瘤负担和每只荷瘤动物的肿瘤数（P<0.05 或<0.01）。在恶性肿瘤组织中，药物联合降低了增殖细胞数、微血管密度以及血管内皮生长因子和碱性成纤维细胞生长因子的水平，并刺激了细胞凋亡（与所有其他组相比差异均有统计学意义，P<0.01）。
首次表明 H1 拮抗剂和 THA 协同抑制 DMBA 诱导的乳腺致癌作用；这种作用与肿瘤血管生成减少有关。进一步研究该联合的抗癌和抗血管生成活性可能为乳腺癌治疗提供一种新方法。
