A second-generation 2-Methoxyestradiol prodrug is effective against Barrett's adenocarcinoma in a mouse xenograft model.
A second-generation 2-Methoxyestradiol prodrug is effective against Barrett's adenocarcinoma in a mouse xenograft model.
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DOI：
10.1158/1535-7163.mct-12-0777
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发表时间：
2013-03
影响因子：
5.7
通讯作者：
Banerjee SK
中科院分区：
文献类型：
--
作者：
Kambhampati S;Rajewski RA;Tanol M;Haque I;Das A;Banerjee S;Jha S;Burns D;Borrego-Diaz E;Van Veldhuizen PJ;Banerjee SK
2-甲氧基雌二醇（2-ME 2）是雌二醇的内源性代谢产物。在临床前模型中，2-ME 2对不同类型的肿瘤有效。不幸的是，口服给药后仅能达到较低的2-ME 2全身浓度，甚至在向患者给予非常高的剂量后也是如此。为了解决这个问题，我们现在合成并测试了一种新的2-ME 2前药，由于在3-位添加了生物可逆的亲水基团，该前药是水溶性的，并且由于添加了酯部分以掩盖17位醇，因此可以更有效地抵抗代谢失活。我们在此首次报道，2-ME 2的这种双重前药作为抗增殖和抗癌剂对于针对巴雷特食管腺癌（BEAC）的体外和体内研究都是有效的，并且在抑制BEAC异种移植物的生长方面提供比2-ME 2更大的效力。最后，研究表明，与2-ME 2一样，2-ME 2-PD 1通过可能破坏微管网络而表现出抗癌作用。
2-Methoxyestradiol (2-ME2) is an endogenous metabolite of estradiol. In preclinical models, 2-ME2 is effective against different types of tumors. Unfortunately, only low systemic concentrations of 2-ME2 can be achieved following oral administration, even after very high doses are administered to patients. In an effort to solve this problem we have now synthesized and tested a new prodrug of 2-ME2 that is water soluble due to a bio-reversible hydrophilic group added at the 3-position and more effectively resists metabolic inactivation due to an ester moiety added to mask the 17-position alcohol. We are reporting here for the first time that this double prodrug of 2-ME2 is effective as an antiproliferative and anti-cancer agent for both in vitro and in vivo studies against Barrett's esophageal adenocarcinoma (BEAC), and provided greater potency than 2-ME2 in inhibiting the growth of BEAC xenografts. Finally, studies indicate that, like 2-ME2, the 2-ME2-PD1 exhibits anticancer effect through possible disruption of microtubule-network.