Dartmouth Hitchcock Medical Center, Dept. of Surgery, Manchester, NH 03104, USA.
Eur J Cancer. 2010 Jun;46(9):1537-53. doi: 10.1016/j.ejca.2010.02.018. Epub 2010 Mar 18.
Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target specific agents that result in a substantial decrease in tumour growth when given alone. Tamoxifen activates SERM stimulated breast and endometrial tumour growth. Tamoxifen and brivanib alaninate have side-effects that can affect therapeutic outcomes. The primary goal of the current study was to evaluate the therapeutic effects of lower doses of both agents when given in combination to mice with SERM sensitive, oestrogen stimulated tumour xenografts (MCF-7 E2 tumours). Experiments were conducted to evaluate the response of SERM stimulated breast (MCF-7 Tam, MCF-7 Ral) and endometrial tumours (EnCa 101) to demonstrate the activity of brivanib alaninate in SERM resistant models.
In the current study, tumour xenografts were minced and bi-transplanted into the mammary fat pads of athymic, ovariectomised mice. Preliminary experiments were conducted to determine an effective oral dose of tamoxifen and brivanib alaninate that had minimal effect on tumour growth. Doses of 125 microg of tamoxifen and 0.05 mg/g of brivanib alaninate were evaluated. An experiment was designed to evaluate the effect of the two agents together when started at the time of tumour implantation. An additional experiment was done in which tumours were already established and then treated, to obtain enough tumour tissue for molecular analysis.
Brivanib alaninate was effective at inhibiting tumour growth in SERM sensitive (MCF-7 E2) and SERM stimulated (EnCa 101, MCF-7 Ral, MCF-7 Tam) models. The effect of the low dose drug combination as an anti-tumour strategy for SERM sensitive (MCF-7 E2) in early treatment was as effective as higher doses of either drug used alone. In established tumours, the combination is successful at decreasing tumour growth, while neither agent alone is effective. Molecular analysis revealed a decreased phosphorylation of VEGFR-2 in tumours that were treated with brivanib alaninate and an increase in VEGFA transcription to compensate for the blockade of VEGFR-2 by increasing the transcription of VEGFA. Tamoxifen increases the phosphorylation of VEGFR-2 and this effect is abrogated by brivanib alaninate. There was also increased necrosis in tumours treated with brivanib alaninate.
Historically, tamoxifen has a role in blocking angiogenesis as well as the blockade of the ER. Tamoxifen and a low dose of an angiogenesis inhibitor, brivanib alaninate, can potentially be combined not only to maximise therapeutic efficacy but also to retard SERM resistant tumour growth.
他莫昔芬是一种选择性雌激素受体调节剂（SERM），而布立尼布丙氨酸是一种血管内皮生长因子受体 2（VEGFR-2）抑制剂，当单独使用时，这两种靶向药物都会导致肿瘤生长显著减少。他莫昔芬激活了雌激素刺激的乳腺和子宫内膜肿瘤的 SERM 刺激生长。他莫昔芬和布立尼布丙氨酸都有影响治疗效果的副作用。目前研究的主要目的是评估这两种药物的较低剂量联合使用时对具有 SERM 敏感性、雌激素刺激肿瘤异种移植（MCF-7 E2 肿瘤）的小鼠的治疗效果。进行了实验以评估 SERM 刺激的乳腺（MCF-7 Tam、MCF-7 Ral）和子宫内膜肿瘤（EnCa 101）对布立尼布丙氨酸活性的反应，以证明其在 SERM 耐药模型中的活性。
在目前的研究中，肿瘤异种移植物被切碎并双移植到无胸腺、卵巢切除的小鼠的乳腺脂肪垫中。进行了初步实验以确定对肿瘤生长影响最小的有效口服他莫昔芬和布立尼布丙氨酸剂量。评估了 125μg 他莫昔芬和 0.05mg/g 布立尼布丙氨酸的剂量。设计了一个实验来评估两种药物一起开始时对肿瘤植入的影响。还进行了另外一个实验，其中已经建立了肿瘤，然后进行治疗，以获得足够的肿瘤组织进行分子分析。
布立尼布丙氨酸在 SERM 敏感（MCF-7 E2）和 SERM 刺激（EnCa 101、MCF-7 Ral、MCF-7 Tam）模型中有效抑制肿瘤生长。作为早期治疗 SERM 敏感（MCF-7 E2）的低剂量药物联合作为抗肿瘤策略的效果与单独使用较高剂量的任何一种药物一样有效。在已建立的肿瘤中，联合治疗成功地降低了肿瘤生长，而单独使用任何一种药物均无效。分子分析显示，用布立尼布丙氨酸治疗的肿瘤中 VEGFR-2 的磷酸化减少，并且通过增加 VEGFA 的转录来补偿 VEGFR-2 的阻断，从而增加 VEGFA 的转录。他莫昔芬增加了 VEGFR-2 的磷酸化，而布立尼布丙氨酸则消除了这种作用。用布立尼布丙氨酸治疗的肿瘤中也有更多的坏死。
从历史上看，他莫昔芬在阻断血管生成以及阻断 ER 方面都有作用。他莫昔芬和低剂量的血管生成抑制剂布立尼布丙氨酸不仅可以联合使用以最大程度地提高治疗效果，还可以延缓 SERM 耐药性肿瘤的生长。
