Tinley Tina L, Leal Rachel M, Randall-Hlubek Deborah A, Cessac James W, Wilkens Lynne R, Rao Pemmaraju N, Mooberry Susan L
Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, San Antonio, Texas 78227, USA.
Cancer Res. 2003 Apr 1;63(7):1538-49.
2-Methoxyestradiol (2-ME2) is a natural estrogen metabolite that, while devoid of estrogenic effects, has both antiangiogenic and antitumor effects. 2-ME2 is currently being evaluated in Phase I and Phase II clinical trials for the treatment of multiple types of cancer. Novel analogues of 2-ME2 were tested for activities that predict antiangiogenic and antitumor effects. Selected analogues were tested for inhibitory activity against endothelial cell proliferation and invasion. The results show that these analogues are effective inhibitors of endothelial cell activities that may predict antiangiogenic activity, and one analogue, 2-methoxy-14-dehydroestradiol (14-dehydro-2-ME2), was 6-15-fold more potent than the parental compound in these assays. The analogues were also evaluated for inhibition of proliferation and cytotoxicity against multiple tumor cell lines and found to be potent and effective. 14-Dehydro-2-ME2 was approximately 15-fold more potent than 2-ME2 against various tumor cell lines, and 2-methoxy-15-dehydroestradiol was particularly effective against DU 145 and PC3 prostate cancer cell lines. In vivo antitumor activity was observed for the three analogues tested in the murine xenograft MDA-MB-435 model; however, 2-ME2 provided no antitumor activity in this trial. The two most effective analogues, 14-dehydro-2-ME2 and 2-methoxyestradiol-15 alpha,16 alpha-acetonide, provided 29.4% and 26.7% inhibition of tumor burden, respectively. Mechanism of action studies indicate that the analogues cause mitotic spindle disruption, mitotic arrest, microtubule depolymerization, and inhibition of the assembly of purified tubulin similar to the effects of 2-ME2. Consistent with antimitotics that inhibit the dynamic instability of tubulin and initiate apoptosis, these novel 2-ME2 analogues cause Bcl-2 phosphorylation and activation of mitogen-activated protein kinase signaling pathways.
2-甲氧基雌二醇（2-ME2）是一种天然雌激素代谢产物，虽不具有雌激素效应，但具有抗血管生成和抗肿瘤作用。目前2-ME2正处于治疗多种癌症的I期和II期临床试验阶段。对2-ME2的新型类似物进行了测试，以评估其预测抗血管生成和抗肿瘤作用的活性。对选定的类似物进行了抑制内皮细胞增殖和侵袭的活性测试。结果表明，这些类似物是内皮细胞活性的有效抑制剂，可能预示着抗血管生成活性，其中一种类似物2-甲氧基-14-脱氢雌二醇（14-脱氢-2-ME2）在这些试验中的效力比母体化合物高6至15倍。还评估了这些类似物对多种肿瘤细胞系的增殖抑制和细胞毒性，发现它们具有强效且有效。14-脱氢-2-ME2对各种肿瘤细胞系的效力比2-ME2高约15倍，2-甲氧基-15-脱氢雌二醇对DU 145和PC3前列腺癌细胞系特别有效。在小鼠异种移植MDA-MB-435模型中测试的三种类似物均观察到体内抗肿瘤活性；然而，2-ME2在该试验中未显示出抗肿瘤活性。两种最有效的类似物，14-脱氢-2-ME2和2-甲氧基雌二醇-15α,16α-缩酮，分别对肿瘤负荷有29.4%和26.7%的抑制作用。作用机制研究表明，这些类似物会导致有丝分裂纺锤体破坏、有丝分裂停滞、微管解聚，并抑制纯化微管蛋白的组装，其作用与2-ME2相似。与抑制微管蛋白动态不稳定性并引发细胞凋亡的抗有丝分裂药物一致，这些新型2-ME2类似物会导致Bcl-2磷酸化并激活丝裂原活化蛋白激酶信号通路。
