Department of Surgery, The University of Kansas Medical Center, Kansas City, KS, USA.
Surgery. 2010 Dec;148(6):1228-36; discussion 1236. doi: 10.1016/j.surg.2010.09.026.
Most medullary thyroid carcinomas (MTC) recur or progress despite curative resection. Current targeted therapies show promise but lack durable efficacy and tolerability. The purpose of this study was to build on previous in vitro work and evaluate withaferin A (WA), a novel RET inhibitor, in a metastatic murine model of MTC.
A total of 5 million DRO-81-1 human MTC cells injected in the left posterior neck of nu/nu mice generated metastases uniformly to the liver, spleen, and/or lungs. Treatment with WA (8 mg/kg/day, intraperitoneally, for 21 days) was started for neoplasms > 100 mm(3). Endpoints were survival, neoplasm > 15,00 mm(3), decreased body weight, or body score (all measured three times/wk).
All controls (saline; n = 5) died or deteriorated from metastatic disease by 7 weeks postinjection. All treated animals were alive (WA; n = 5), having tumor regression and growth delay without toxicity or weight loss at 6 weeks posttreatment (P < .01). Tumor cells treated with WA demonstrated inhibition of total and phospho-RET levels by Western blot analysis in a dose-dependent manner (almost complete inhibition with treatment of 5 μM WA) as well as potent inhibition of phospho-ERK and phospho-Akt levels.
WA is a novel natural-product RET-inhibitor with efficacy in a metastatic murine model of MTC. Further long-term efficacy/toxicity studies are warranted to evaluate this compound for clinical translation.
尽管经过根治性切除术，大多数甲状腺髓样癌（MTC）仍会复发或进展。目前的靶向治疗显示出前景，但缺乏持久的疗效和耐受性。本研究的目的是在前瞻性体外研究的基础上，评估新型 RET 抑制剂白藜芦醇 A（WA）在 MTC 转移性小鼠模型中的疗效。
将 500 万个 DRO-81-1 人 MTC 细胞注入 nu/nu 小鼠的左颈后，均匀转移至肝脏、脾脏和/或肺部。当肿瘤>100mm³时，开始用 WA（8mg/kg/天，腹腔内注射，共 21 天）进行治疗。终点为生存、肿瘤>15000mm³、体重下降或体评分（每周测量三次）。
所有对照组（生理盐水；n=5）在注射后 7 周内因转移性疾病死亡或恶化。所有治疗组动物均存活（WA；n=5），肿瘤消退且生长延迟，无毒性或体重减轻，在治疗后 6 周时（P<0.01）。WA 处理的肿瘤细胞通过 Western blot 分析显示总 RET 和磷酸化 RET 水平呈剂量依赖性抑制（用 5μM WA 处理几乎完全抑制），同时还显著抑制磷酸化 ERK 和磷酸化 Akt 水平。
WA 是一种新型天然产物 RET 抑制剂，在 MTC 转移性小鼠模型中具有疗效。需要进一步进行长期疗效/毒性研究，以评估该化合物的临床转化。
