Cambios en la morfología y la microdensidad neovascular corneal inducidos tras la administración tópica de bevacizumab y sunitinib en un modelo animal

ObjectiveTo evaluate the effects of topical bevacizumab and topical sunitinib on vascular microdensity and morphology of corneal neovascularization (NV).MethodsA total of 33 rabbits were distributed into 3 groups: group 1 (control; n=11): saline; group 2 (n=11): bevacizumab 5 mg/ml; and group 3 (n=11): sunitinib 0.5 mg/ml. A corneal NV model was used, based on sutures in the right eye of each rabbit. Each treatment was administered topically 3 times daily for 14 days. Corneas were then processed for the study of vascular microdensity (6 eyes) and vascular morphology analysis (5 eyes) using enzymatic staining histological techniquesResultsThe vascular response in group 3 was limited to small-sized tree formations with various vascular axes compared with the extensive, lush and directional corneal NV of group 1 and 2. In the histological sections near the limb, there were no differences in vascular microdensity studies between the three groups. However, the mean sectional area of vessels (MSAV) in group 3 was 41.88% lower than in group 1 and 19.19% lower than in group 2. In distal sections, there were no differences between groups 1 and 2. However, group 3 was characterized by absence of vessels.ConclusionsBevacizumab produced no changes in the morphology of the vessels or the vascular microdensity. Sunitinib reduced the size of the new vessels and induced changes in the vascular tree.     

Evaluation of anastomotic strength and drug safety after short-term sunitinib administration in rabbits

Background

Sunitinib (Sutent) is a Food and Drug Administration–approved receptor tyrosine kinase inhibitor found to reduce postoperative adhesion formation in animal models. The objective of the present study was to evaluate anastomotic healing and potential drug-related toxicities after short-term sunitinib administration in New Zealand White rabbits.

Materials and methods

Under an approved study protocol, 40 rabbits underwent a laparotomy followed by colonic transection and anastomosis. Animals were randomly assigned to treatment with oral sunitinib (10 mg/kg/d) or placebo, received one preoperative dose followed by 10 postoperative doses, and were divided into two groups following the procedure: group I animals were euthanized on completion of drug treatment and group II animals were euthanized 30 d after completion of treatment. Prior to study completion, animals underwent an echocardiogram and laboratory test results were obtained. At necropsy, intestinal bursting strength (in mmHg) was evaluated.

Results

All animals survived until designated euthanasia. There was no evidence of intra-abdominal sepsis or intestinal obstruction. Sunitinib-treated animals were found to have lower intestinal anastomotic strength compared with placebo-treated animals, as measured by bursting pressure at euthanasia, and a greater percentage of bursting at the anastomosis. On echocardiography, all ejection and shortening fractions were within established normal reference values. There were no significant differences in liver enzymes between animals. There were no wound infections, dehiscence, or delayed wound healing in any animal.

Conclusions

These results caution against the administration of sunitinib in cases involving intestinal anastomoses because of the elevated risk of anastomotic leak. No evidence of cardiotoxicity, hepatotoxicity, or detrimental effect on wound healing was found in any animal.     

舒尼替尼通过抑制 Akt／mTOR 信号通路诱导肾癌细胞自噬

目的：研究舒尼替尼引起的肾癌细胞出现细胞自噬的机制。方法：以肾癌细胞系ACHN细胞为细胞模型,利用3-(4,5-二甲基)-5-(3-羧甲基苯环)-2-(4-硫基苯)-2H 四唑盐复合物［3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,innersalt,MTS］检测法观察舒尼替尼对ACHN 细胞活性的影响;应用RNA干扰技术敲降自噬相关蛋白Beclin1和微管相关蛋白1轻链3融合蛋白（microtubule associated protein 1 light chain 3 fusion protein, LC3）检测自噬与舒尼替尼引起的细胞凋亡。使用电子显微镜和荧光显微镜观察在舒尼替尼作用下自噬体的形成;蛋白质免疫印迹检测舒尼替尼对LC3-Ⅱ的积累,自噬相关信号通路蛋白激酶B(protein kinase B, PKB/Akt)、哺乳动物雷帕霉素受体( mammalian target of rapamycin, mTOR) 及聚腺苷二磷酸核糖聚合酶( poly ADP-ribose polymerase,PARP) 切割的变化和过量表达,以及敲降Akt检测诱导自噬的变化。结果: 舒尼替尼能显著抑制ACHN的细胞活性,这种作用具有时间和浓度依赖性;敲降自噬相关蛋白Beclin1和LC3减少自噬可改变舒尼替尼引起PARP的切割;透射和荧光显微镜观察结果表明,舒尼替尼引起细胞自噬体明显增加;蛋白质免疫印迹结果显示舒尼替尼增加自噬同时减少了Akt/mTOR的磷酸化。过量表达持续活化的Akt抑制了该化合物引起的自噬,而敲降Akt可促进自噬发生。mTOR抑制剂雷帕霉素能上调舒尼替尼引起的自噬并促进细胞活性的丢失。结论：舒尼替尼通过抑制Akt/mTOR信号通路促进肾癌细胞ACHN的自噬,其诱导的自噬与凋亡有关。     

Is sunitinib-induced hypothyroidism a predictive clinical marker for better response in metastatic renal cell carcinoma patients?

Background: The main goal of this study was to examine whether the occurrence of hypothyroidism during sunitinib therapy in patients with metastatic renal cell carcinoma (mRCC) is associated with a better outcome.

Methods: The study enrolled 81 patients with pathologically proven mRCC who were treated with sunitinib between March 2008 and June 2013.Thyroid function evaluation comprised (free-thyroxine) FT4 and thyroid-stimulating hormone (TSH) before treatment and at day 1 of each 6-week cycle. Survival analysis was performed using the Kaplan–Meier method, and the differences among the groups were determined using the log-rank test.

Results: Hypothyroidism occurred in 30 (37%) of 81 patients within a median 3 months (range 1–18) of treatment initiation. There was a statistically significant correlation between the occurrence of hypothyroidism during treatment and the rate of objective remission (ORR) (hypothyroid patients vs euthyroid patients: 46.7 vs 13.7%, respectively; P?=?0.001). Median progression-free survival (PFS) was 10 (95% CI 6.13–13.8) months in the euthyroid patients, and 17 (95% CI 9.33–24.6) months in the hypothyroid patients (P?=?0.001). The median overall survival (OS) was 39 (95% CI 25.4–52.5) months in the hypothyroid patients and 20 (95% CI 14.7–25.2) months in the euthyroid patients (P?=?0.019).

Conclusions: The occurrence of hypothyroidism during treatment in patients was significantly associated with longer PFS, OS and better ORR in the current study.     

舒尼替尼治疗伊马替尼耐药胃肠间质瘤的疗效及安全性分析

目的探讨舒尼替尼治疗伊马替尼耐药胃肠间质瘤（GIST）的疗效及安全性。方法回顾性分析2008年5月至2012年4月间在福建医科大学附属协和医院接受舒尼替尼治疗的48例伊马替尼耐药GIST患者的临床资料。舒尼替尼用药方案：18例患者采用50mg／d服药4周,停药2周（50mg／d4／2组）;30例患者采用37．5mg／d连续口服（37．5mg／dCDD组）。结果48例患者舒尼替尼中位治疗时间为56周．按Choi标准于治疗后24周进行近期疗效评估．获完全缓解1例,部分缓解12例,疾病稳定21例,疾病进展14例,客观有效率为27．1％（13／48）,疾病控制率为70．8％（34／48）。48例患者中位随访时间为89周,中位无进展生存期（PLUS）为48周,中位总体生存期（OS）为92周。分组分析显示：既往伊马替尼剂量为400mg／d者,其PFS和Os均优于既往伊马替尼剂量大于400mg／d者（中位PFS：53比35周,P=0．018;中位OS：157比71周,P=0．003）;外显子11突变者0s劣于外显子9突变者（中位0s：71比157周,P=O．008）。治疗期间的主要不良反应有手足综合征（25例,52．1％）、恶心（24例,50．0％）、疲乏（23例,47．9％）和中性粒细胞减少（21例,43．7％）。按舒尼替尼给药方案分组分析,50mg／d4／2组腹泻及手足综合征的发生情况较37．5mg／dCDD组更为严重（P=0．027,P=0．048）。结论舒尼替尼治疗伊马替尼耐药的GIST疗效较好。在伊马替尼400mg／d耐药后应直接换用舒尼替尼而不要加大伊马替尼用药剂量。外显子9突变者舒尼替尼的治疗效果优于外显子11突变者。舒尼替尼37．5mg／d连续口服的用药方案安全性较好。     

Randomized phase II study of sunitinib versus standard of care for patients with previously treated advanced triple-negative breast cancer

PurposeThis randomized, open-label phase II study compared the efficacy of sunitinib monotherapy with that of single-agent standard-of-care (SOC) chemotherapy in patients with previously treated advanced triple-negative breast cancer (TNBC).MethodsPatients with advanced TNBC, relapsed after anthracycline- and taxane-based chemotherapy, were randomized to receive either sunitinib (37.5 mg/day) or the investigator's choice of SOC therapy. Progression-free survival was the primary endpoint.ResultsMedian progression-free survival was 2.0 months with sunitinib and 2.7 months with SOC chemotherapy (one-sided P = 0.888). Median overall survival was not prolonged with sunitinib (9.4 months) compared with SOC chemotherapy (10.5 months; one-sided P = 0.839). The objective response rate was 3% with sunitinib and 7% with SOC chemotherapy (one-sided P = 0.962).ConclusionsSunitinib monotherapy did not improve efficacy compared with SOC chemotherapy in patients with previously treated advanced TNBC, for which identification of effective treatments and therapeutic targets remains an urgent need.Trial registrationNCT00246571.     

新型多聚体微泡携带舒尼替尼抑制人肾癌GRC-1细胞生长及促凋亡的实验研究

目的 观察新型多聚体微泡携带舒尼替尼对人肾癌GRC-1细胞生长及凋亡的影响.方法 将体外培养的人肾癌GRC-1细胞随机分为6组:空白对照组、单纯微泡组、单纯脂质体组、舒尼替尼组、新型多聚体微泡载舒尼替尼不联合超声组、新型多聚体微泡载舒尼替尼联合超声组.MTT法观察不同处理组细胞生存率,Sigma-FITC荧光染色及透射电镜检测细胞凋亡.结果 新型多聚体微泡载舒尼替尼联合超声组对人肾癌GRC-1细胞的生长抑制及促进凋亡作用强于其他处理组及对照组.结论 新型多聚体微泡携带舒尼替尼在超声作用下对人肾癌GRC-1细胞生长有明显抑制作用,并诱导细胞凋亡.     

Magnetic resonance imaging identifies early effects of sunitinib treatment in human melanoma xenografts

Background

Antiangiogenic treatment may change the tumor microenvironment and hence influence the effect of conventional therapies. The potential of diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced MRI (DCE-MRI) in assessing microenvironmental effects of sunitinib treatment was investigated in this preclinical study.

Methods

Sunitinib-treated and untreated A-07 tumors were subjected to DW-MRI and DCE-MRI, and parametric images of ADC and K^trans were produced. Microvascular density, hypoxic fraction, and necrotic fraction were assessed from immunohistochemical preparations, and tumor interstitial fluid pressure (IFP) was assessed with probe measurement.

Results

Sunitinib-treated tumors showed reduced microvascular density, increased hypoxic fraction, increased necrotic fraction, increased ADC, and reduced K^trans, but did not differ from untreated tumors in growth rate and IFP.

Conclusions

Sunitinib treatment affected the tumor microenvironment without affecting tumor size. DW-MRI and DCE-MRI were sensitive to the sunitinib-induced changes in the tumor microenvironment.