Treatment of hormone sensitive breast cancer tumors with endocrine therapy such as antiestrogens or aromatase inhibitors has improved the outcome significantly. Studies including our own have shown that downregulation of ERα with pure antiestrogen fulvestrant in combination with aromatase inhibitors may prolong responsiveness of the tumors to endocrine therapy. Fulvestrant has been studied as second line or first line treatment for post-menopausal hormone receptor positive breast cancers as a single agent or in combination with AIs. Studies have also suggested that further escalation of dose may improve benefit. However, dose escalation of fulvestrant, which is administered via intramuscular injection, is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active antiestrogen, AZD9496 was developed. In addition to being orally active, AZD9496 is designed as a selective ERα downregulator (SERD). In the current study, we compared the effect of AZD9496 and fulvestrant on the growth of MCF-7Ca (human estrogen receptor positive MCF-7 cells stably transfected with human placental aromatase gene) xenografts grown in ovariectomized athymic nude mice. AZD9496 was also compared to fulvestrant in vitro as a single agent or in combination with anastrozole. Our current study shows that AZD9496 is equally effective as fulvestrant at controlling the growth of hormone sensitive human breast cancer tumors. Similar to fulvestrant, AZD9496 inhibits cellular aromatase activity through ERα mediated signaling. However, unlike fulvestrant, combination of AZD9496 with anastrozole did not produce increased tumor inhibition. Our results show that AZD9496 was significantly better at inhibiting cellular aromatase which contributed to its anticancer activity. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was significantly lower than that for mice treated with androstenedione. This reduction in uterine weight was due to AZD9496 mediated inhibition of aromatase activity and not a direct effect on uterine ERα expression. We also observed that anti-cancer efficacy of AZD9496 depended on its ability to inhibit cellular aromatase. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its selectivity for mammary ER and ability to inhibit aromatase in addition of downregulating ERα that can be obtained upon oral administration. As such, AZD9496 may prove to be a better option than fulvestrant for the treatment of hormone sensitive human breast cancer.

用内分泌疗法（例如抗雌激素或芳香化酶抑制剂）治疗激素敏感性乳腺癌肿瘤可显着改善预后。包括我们自己在内的研究表明，用纯抗雌激素氟维司群与芳香化酶抑制剂联合下调ERα可能会延长肿瘤对内分泌治疗的反应性。沙丁胺醇已作为一种单一药物或与AI联合用作绝经后激素受体阳性乳腺癌的二线或一线治疗药物。研究还表明，进一步提高剂量可能会改善疗效。但是，氟维司群的剂量递增是通过肌肉注射由于溶解度差而很难。为了克服可注射药物的这一缺点，开发了新型口服活性抗雌激素药AZD9496。除具有口服活性外，AZD9496还设计为选择性ERα下调剂（SERD）。在当前的研究中，我们比较了AZD9496和氟维司群对卵巢切除的无胸腺裸鼠中MCF-7Ca（被人胎盘芳香酶基因稳定转染的人雌激素受体阳性MCF-7细胞）异种移植物生长的影响。AZD9496还与氟维司群进行了体外比较作为单一药物或与阿那曲唑合用。我们目前的研究表明，AZD9496在控制激素敏感性人类乳腺癌肿瘤的生长方面与氟维司群同等有效。与氟维司群相似，AZD9496通过ERα介导的信号传导抑制细胞芳香酶活性。但是，与氟维司群不同，AZD9496与阿那曲唑的组合不会产生增加的肿瘤抑制作用。我们的结果表明，AZD9496在抑制细胞芳香酶方面表现出显着的优势，这有助于其抗癌活性。接下来，我们测量了AZD9496对小鼠子宫的影响。AZD9496处理的小鼠的子宫重量显着低于雄烯二酮处理的小鼠。子宫重量的减少是由于AZD9496介导的芳香化酶活性抑制，而不是对子宫ERα表达的直接影响。我们还观察到AZD9496的抗癌功效取决于其抑制细胞芳香酶的能力。这些结果表明，AZD9496可能是氟维司群的更好替代品，因为它对乳腺ER的选择性以及抑制口服后可获得的ERα的抑制作用以及抑制芳香化酶的能力。因此，在治疗激素敏感性人类乳腺癌方面，AZD9496可能比氟维司汀更好。这些结果表明，AZD9496可能是氟维司群的更好替代品，因为它对乳腺ER的选择性以及抑制口服后可获得的ERα的抑制作用以及抑制芳香化酶的能力。因此，在治疗激素敏感性人类乳腺癌方面，AZD9496可能比氟维司汀更好。这些结果表明，AZD9496可能是氟维司群的更好替代品，因为它对乳腺ER的选择性以及抑制口服后可获得的ERα的抑制作用以及抑制芳香化酶的能力。因此，在治疗激素敏感性人类乳腺癌方面，AZD9496可能比氟维司汀更好。