The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer.
The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer.
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DOI：
10.1186/1471-2407-11-471
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发表时间：
2011-11-02
期刊：
影响因子：
3.8
通讯作者：
Akporiaye ET
中科院分区：
文献类型：
--
作者：
Hahn T;Bradley-Dunlop DJ;Hurley LH;Von-Hoff D;Gately S;Mary DL;Lu H;Penichet ML;Besselsen DG;Cole BB;Meeuwsen T;Walker E;Akporiaye ET
HER 2/neu是一种致癌基因，由于其以配体非依赖性方式抑制生长信号的能力而促进肿瘤转化，在20-30%的与侵袭性疾病相关的人乳腺癌中过表达，并且已被曲妥珠单抗（Herceptin®）成功靶向。由于曲妥珠单抗单独使用仅达到15-30%的反应率，因此现在通常与常规化疗药物联合使用。虽然曲妥珠单抗联合化疗大大提高了缓解率和生存率，但这些常规化疗药物通常与胃肠道和心脏毒性、骨髓和免疫抑制相关。这些缺点需要开发新的，毒性较小的药物，可以与曲妥珠单抗联合使用。最近，我们报道了口服α-生育酚氧乙酸（α-TEA），一种新型的α-生育酚的醚衍生物，显着抑制原发性肿瘤的生长，并减少肺转移的发生率在移植和自发性小鼠乳腺癌模型中，没有明显的毒性。在本研究中，我们检查了α-TEA + HER 2/neu特异性抗体治疗对体外表达HER 2/neu的乳腺癌细胞和体内HER 2/neu阳性人异种移植肿瘤模型的影响。我们在体外证明，α-TEA+抗HER 2/neu抗体对小鼠乳腺肿瘤细胞和人乳腺癌细胞的细胞毒性作用增加，并且α-TEA的抗肿瘤作用与HER 2/neu状态无关。更重要的是，在人乳腺癌异种移植模型中，α-TEA+曲妥珠单抗联合治疗比曲妥珠单抗单药治疗肿瘤消退更快，无肿瘤动物更多。由于α-TEA的癌细胞选择性，并且因为α-TEA杀死HER 2/neu阳性和HER 2/neu阴性乳腺癌细胞，所以当与HER 2/neu抗体组合使用时，其具有比现有化疗药物有效且毒性更低的潜力。
HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®). Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity. In this study we examined the effect of α-TEA plus HER2/neu-specific antibody treatment on HER2/neu-expressing breast cancer cells in vitro and in a HER2/neu positive human xenograft tumor model in vivo. We show in vitro that α-TEA plus anti-HER2/neu antibody has an increased cytotoxic effect against murine mammary tumor cells and human breast cancer cells and that the anti-tumor effect of α-TEA is independent of HER2/neu status. More importantly, in a human breast cancer xenograft model, the combination of α-TEA plus trastuzumab resulted in faster tumor regression and more tumor-free animals than trastuzumab alone. Due to the cancer cell selectivity of α-TEA, and because α-TEA kills both HER2/neu positive and HER2/neu negative breast cancer cells, it has the potential to be effective and less toxic than existing chemotherapeutic drugs when used in combination with HER2/neu antibody.
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