Sunitinib-induced hyperammonemic encephalopathy in metastatic gastrointestinal stromal tumors:A case report

BACKGROUND Sunitinib,a multi-targeted tyrosine kinase inhibitor(TKI),has been approved for the salvage treatment of gastrointestinal stromal tumors(GIST).Hyperammonemic encephalopathy is a rare but severe complication of sunitinib use.Here,we present the case of a 66-year-old male with metastatic GIST without underlying liver cirrhosis who developed sunitinib-induced hyperammonemic encephalopathy.CASE SUMMARY A 66-year-old male with metastatic GIST was admitted because of reduced consciousness.Imatinib was administered as the first-line systemic therapy.He experienced repeated episodes of peritonitis due to tumor perforation,and surgery was performed.Progressive disease was confirmed based on increased liver metastasis,and sunitinib was initiated as a salvage treatment.However,23 d after the third course of sunitinib,he presented to the emergency room with an episode of altered consciousness and behavioral changes.Based on the patient clinical history and examination findings,sunitinib-induced encephalopathy was suspected.Sunitinib was discontinued,and the patient was treated for hyperammonemia.The patient had a normal level of consciousness four days later,and the serum ammonia level gradually decreased.No further neurological symptoms were reported in subsequent follow-ups.CONCLUSION TKI-induced hyperammonemic encephalopathy is potentially life-threatening.Patients receiving TKIs experiencing adverse reactions should undergo systemic evaluation and prompt treatment.

sunitinib对人气道平滑肌细胞增殖、迁移和ERK磷酸化的影响

目的:探讨sunitinib对血小板源性生长因子(platelet-derived growth factor,PDGF)-BB刺激的人气道平滑肌细胞(hu-man airway smooth muscle cells,HASMCs)增殖和迁移的影响,及其对细胞外信号调节激酶(extracellular signal regulated kinases,ERK)信号通路的干预作用。方法:体外培养HASMCs分为6组:对照组、PDGF-BB组、sunitinib与PDGF-BB联合干预组、suni-tinib组、U0126组、PDGF-BB与U0126联合干预组。流式细胞术检测HASMCs细胞周期,Transwell法观察细胞迁移,Westernblot法检测ERK的磷酸化。结果:与对照组相比,PDGF-BB(20 ng/ml)显著诱导HASMCs增殖和迁移(P<0.01),sunitinib(3nmol/L)显著抑制PDGF-BB诱导的HASMCs的增殖和迁移,其作用与U0126相当(P>0.05)。PDGF-BB组ERK磷酸化水平较对照组明显增高(P<0.01)。sunitinib干预后可使PDGF-BB诱导的ERK磷酸化程度下降,其对PDGF-BB诱导的ERK磷酸化的抑制作用与ERK特异性拮抗剂U0126对PDGF-BB诱导的ERK磷酸化的抑制作用相当。结论:sunitinib抑制PDGF-BB诱导的HASMCs的增殖和迁移,可能是通过调节ERK通路起作用。

Sunitinib在胃肠间质瘤靶向治疗中的应用

胃肠间质瘤是一种在组织学和免疫组织化学方面有别于其他软组织肿瘤的多形胃肠道间质肿瘤。胃肠间质瘤对传统的化学治疗和放射治疗均不敏感,在伊马替尼时代以前,外科手术治疗是仅有的有效治疗方式。近几年的伊马替尼临床治疗和Ⅲ期临床试验发现,大部分转移胃肠间质瘤(gastrointe stinalstromal tumor,GIST)患者最终对伊马替尼治疗无效。Sunitinib成为伊马替尼治疗失败后有效的替代治疗。

sunitinib对气道平滑肌细胞增殖和迁移的影响及机制

目的:探讨sunitinib(sunitinib malate)对血小板源性生长因子BB(PDGF-BB)刺激的人气道平滑肌细胞(human airway smooth muscle cell,HASMCs)增殖和迁移的影响及其机制。方法:体外培养HASMCs分为:对照组、PDGF-BB组、PDGF-BB与sunitinib干预组、sunitinib组,四甲基偶氮唑蓝(MTT)微量比色法测定HASMCs增殖,流式细胞术检测HASMCs细胞周期,改良的Boyden微孔膜双槽法观察细胞迁移,Westernblot检测PDGFR-β和AKT的磷酸化。结果:与对照组相比,PDGF-BB(20ng/ml)显著诱导HASMCs的增殖和迁移(P<0.05),sunitinib(0.3～9.0nmol/L)呈浓度依赖性抑制PDGF-BB诱导的HASMCs增殖和迁移;PDGF-BB(20ng/ml)刺激HASMCs后,细胞周期S期比例显著高于对照组(P<0.05),PDGF-BB与sunitinib干预组细胞周期S期比例低于PDGF-BB组(P<0.05);PDGF-BB组PDGFR-β和AKT的磷酸化水平较对照组为高(P<0.05),PDGF-BB与sunitinib干预组其表达量低于PDGF-BB组。结论:sunitinib抑制PDGF-BB诱导的HASMCs增殖和迁移,可能是通过调节PI3K/AKT通路起作用。

Comparison of efficacy, safety, and quality of life between sorafenib and sunitinib as first.line therapy for Chinese patients with metastatic renal cell carcinoma

Background: Sorafenib and sunitinib are widely used as first-line targeted therapy for metastatic renal cell carcinoma(mRCC) in China.This study aimed to compare the efficacy, safety, and quality of life(QoL) in Chinese mRCC patients treated with sorafenib and sunitinib as first-line therapy.Methods: Clinical data of patients with mRCC who received sorafenib(400 mg twice daily; 4 weeks) or sunitinib(50 mg twice daily; on a schedule of 4 weeks on treatment followed by 2 weeks off) were retrieved. Primary outcomes were overall survival(OS), progression-free survival(PFS), adverse events(AEs), and QoL(SF-36 scores), and secondary outcomes were associations of clinical characteristics with QoL.Results: Medical records of 184 patients(110 in the sorafenib group and 74 in the sunitinib group) were reviewed.PFS and OS were comparable between the sorafenib and sunitinib groups(both P > 0.05).The occurrence rates of leukocytopenia, thrombocytopenia, and hypothyroidism were higher in the sunitinib group(36.5% vs. 10.9%,P< 0.001; 40.5% vs. 10.9%, P < 0.001; 17.6% vs. 3.6%, P = 0.001), and that of diarrhea was higher in the sorafenib group(62.7% vs. 35.2%, P < 0.001). There was no significant difference in SF-36 scores between the two groups. Multivariate analysis indicated that role-physical and bodily pain scores were associated with the occurrence rate of grade 3 or 4 AEs(P = 0.017 and 0.005).Conclusions: Sorafenib has comparable efficacy and lower toxicity profile than sunitinib as first-line therapy for mRCC. Both agents showed no significant impact on QoL of patients.

Clinical Response with Sunitinib Therapy in the Treatment of Anaplastic Thyroid Cancer

Background: Anaplastic thyroid cancer (ATC), while rare, carries a uniformly poor prognosis. Current treatment includes surgery when possible, radiotherapy, and chemotherapy. Multiple chemotherapeutic agents are in the process of clinical testing, and promising agents include those in the tyrosine kinase inhibitor family. Our patient represents a novel case of ATC treated with sunitinib, one such tyrosine kinase inhibitor. Methods/Results: We utilized the experimental sunitinib in conjunction with radiation therapy to treat a patient with aggressive ATC in whom curative resection was unable to be achieved due to carotid sheath and tracheal involvement. The patient had marked clinical response and sustained stable disease for 8 months, which coincides with reported data regarding sunitinib to treat other thyroid malignancies. Conclusion: Our case illustrates the efficacy of sunitinib therapy as a possible adjunct in the treatment of ATC.

Efficacy and Safety of Sunitinib in Japanese Patients with Metastatic Renal Cell Carcinoma

Objective: This study aim to assess the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (mRCC) in general clinical practice. Patients and Methods: Non-selected fifty eight Japanese patients with mRCC were treated with sunitinib. Overall survival (OS) and time to treatment failure (TTF) were estimated. Response rate and safety profiles were also assessed. Results: Partial response, stable disease, and progressive disease were observed in 13 (22.4%), 26 (44.8%), and 19 (32.8%) patients, respectively. The median TTF was 5.4 months, and the median OS was 11.2 months. In the prior nephrectomy group, the median TTF was 9.0 months, and the median OS was 16.4 months. In the non-nephrectomy group, the median TTF was 1.1 months, and the median OS was 2.8 months. The most frequently occurring Grade 3/4 adverse events (AEs) were anorexia (17.2%), fatigue (12.1%), thrombocytopenia (13.8%), and anemia (12.1%). Conclusions: Sunitinib has a favorable risk/benefit profile in Japanese mRCC patients with a history of nephrectomy.

Sustained long-term clinical and radiological response with sunitinib for metastatic renal-cell carcinoma (RCC)

The authors herein report the case of a 67-year-old woman with metastatic renal-cell carcinoma (RCC), who has had a sustained clinical and stable radiological response to long-term therapy with an oral multi-targeted tyrosine kinase inhibitor (TKI), sunitinib with minimal lasting toxicity.

Pazopanib Induced Hand-Foot Syndrome in a Patient Previously Treated with Sunitinib: A Possible Cumulative Skin Toxicity?

Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia, is a skin toxicity that could be observed during target therapies such as with tyrosine-kinase inhibitors (TKI). It usually develops within the first 2 - 4 weeks of drug administration. We present a case of HFS induced by Pazopanib after 2 months of treatment, in patients previously treated with Sunitinib, suggesting a possible cumulative toxicity of two drugs. The clinical and therapeutic management of skin adverse reactions during TKI therapy usually requires 25% dose reduction and adequate local treatment. It is important for the clinicians to recognize clinical signs and symptoms of such skin toxicities. Attention should be paid especially when two or more drugs from the same class are used in combined treatment.

Sunitinib Reduces Acute Myeloid Leukemia Clonogenic Cells in Vitro and Has Potent Inhibitory Effect on Sorted AML ALDH+ Cells

Sunitinib is an orally administered, multi-target tyrosine kinase inhibitor that has been approved by the FDA for the treatment of renal cell carcinoma and imatinib resistant gastro-intestinal tumors. Anti-leukemic activity of sunitinib has been examined in early clinical trials with limited success. However, recent trials on acute myeloid leukemia (AML) patients carrying FLT3 mutations have shown promising results. Effects of sunitinib on leukemic clonogenic cells and potential leukemic stem cells have not been examined so far. We analyzed the anti-proliferative and apoptotic properties of sunitinib on AML-derived cell lines. We also tested the effect of sunitinib on AML patient derived clonogenic cells (AML-CFC), as well as flow-sorted potential leukemic progenitors. Peripheral blood or bone marrow samples were obtained from newly diagnosed AML patients and flow sorted for CD34+ CD133+ or ALDH+ cells. Umbilical cord blood derived CD34+ cells were used as normal controls. Sunitinib induced growth arrest and apoptosis in AML derived cell lines. In addition, 7 μM sunitinib induced 75% reduction of AML-CFC as compared to DMSO treated control (±6.79%;n = 4). In contrast, 7 μM sunitinib treatment of umbilical cord blood derived normal CD34+ cells showed 29% reduction in AML-CFC (±6.77%;n = 5). Treatment of ALDH+ cells sorted from 2 AML cases and CD34+ CD133+ cells from one patient showed reduction of AML-CFC on treatment with sunitinib. Our study highlighted a potent anti-proliferative and proapoptotic effect of sunitinib on AML cell lines, AML patient derived clonogenic cells and potential leukemic stem cells.

Sunitinib inhibits renal cancer cell growth and invasion in vitro through Wnt/β-catenin signaling pathway: an experimental study

Objective:To study the effect of sunitinib on renal cancer cell growth and invasion in vitro as well as Wnt/β-catenin signaling pathway.Methods: Renal cancer cell lines ACHN were cultured and processed with different doses of sunitinib (1 μmol/L, 2 μmol/L, 4 μmol/L and 8 μmol/L), and sunitinib-free processing condition was used as negative control. 24 h after processing, the mRNA expression levels of apoptosis genes, invasion genes and Wnt/β-catenin signaling pathways in cells were detected.Results: 24 h after treatment, NPRL2, Bax, caspase-3 and caspase-9 mRNA expression in 1 μmol/L, 2 μmol/L, 4 μmol/L and 8 μmol/L sunitinib groups were significantly higher than those in negative control group while MMP2, MMP9, Vimentin, N-cadherin, Wnt andβ-catenin mRNA expression were significantly lower than those in negative control group;the higher the dose of sunitinib, the higher the NPRL2, Bax, caspase-3 and caspase-9 mRNA expression while the lower the MMP2, MMP9, Vimentin, N-cadherin, Wnt andβ-catenin mRNA expression in cells.Conclusion: Sunitinib can inhibit the Wnt/β-catenin signaling pathway in renal cancer cells to increase the expression of apoptosis genes, inhibit the expression of invasion genes and thereby inhibit the cell growth and invasion.

Sunitinib对视网膜微血管内皮细胞增殖和迁移的影响

目的探讨苹果酸舒尼替尼(Sunitinib)对体外培养的恒河猴视网膜微血管内皮细胞(RF/6A)增殖和迁移及KDR mRNA表达的影响。方法选取不同浓度的Sunitinib作用于RF/6A,分别于培养24h和48h后采用SRB染色法观察不同浓度的Sunitinib对RF/6A增殖的影响;采用细胞划痕修复实验观察不同浓度的Sunitinib对RF/6A迁移的影响;同时利用RT-PCR法检测不同浓度的Sunitinib处理前后RF/6AKD RmRNA表达水平的变化。结果 Sunitinib对RF/6A的增殖有抑制作用且呈时间-剂量依赖性,0.00125mg·L-1、0.0025mg·L-1、0.005mg·L-1、0.01mg·L-1、0.02mg·L-1和0.04mg·L-1浓度的Sunitinib作用24h,对RF/6A增殖的抑制率分别为(12.009±0.038)%、(21.440±0.007)%、(35.434±0.015)%、(43.125±0.002)%、(53.700±0.001)%、(60.971±0.003)%,各组两两比较差异均有统计学意义(均为P<0.01);而48h后,其抑制率则分别为(36.872±0.006)%、(40.673±0.013)%、(47.313±0.004)%、(55.910±0.003)%、(63.120±0.003)%、(69.975±0.014)%,各组两两比较差异均有统计学意义(均为P<0.01)。培养基中加入0mg·L-1、0.0025mg·L-1、0.005mg·L-1、0.01mg·L-1、0.02mg·L-1浓度的Sunitinib24h后RF/6A的迁移距离分别为(203.3±2.2)μm、(145.4±4.4)μm、(123.9±2.6)μm、(96.1±3.1)μm、(46.6±2.9)μm。而48h后则为(313.1±4.1)μm、(213.9±2.8)μm、(193.9±4.2)μm、(134.5±3.2)μm、(109.9±5.7)μm。在同一时段,各组两两比较差异均有统计学意义(均为P<0.01)。0mg·L-1、0.0025mg·L-1、0.005mg·L-1、0.01mg·L-1、0.02mg·L-1浓度的Sunitinib作用24h后,RF/6AKDR mRNA的相对表达量分别为0.583±0.004、0.570±0.008、0.553±0.007、0.531±0.003、0.513±0.005。而48h后则分别为0.628±0.005、0.610±0.002、0.588±0.002、0.564±0.005、0.525±0.004。在同一时段,各组两两比较差异均有统计学意义(P<0.01)。结论 Sunitinib能够抑制视网膜微血管内皮细胞的增殖和迁移,其机制可能是通过下调VEGFR mRNA的表达来实现的。

Clinical efficacy and tolerance of sunitinib in the treatment of advanced renal cell carcinoma

Objective To evaluate the clinical efficacy and side effects of sunitinib in treatment of advanced renal cell carcinoma. Methods Forty-five patients with advanced renal cell carcinorna and an average age of 48. 6 yrs were treated with sunitinib. of the study group。

Effect of sunitinib on metastatic gastrointestinal stromal tumor in patients with neurofibromatosis type 1: A case report

Gastrointestinal stromal tumor (GIST) represents the most common mesenchymal malignancy of the gastrointestinal (GI) tract. In neurofibromatosis (NF), the increased incidence of tumor needs to be considered even in non-symptomatic individuals. Patients with neurofibromatosis NF type 1 have an increased risk of developing GI tumors including rare types such as GIST. We report a case of GIST in a 53-year-old male patient with neurofibromatosis. The patient was diagnosed with NF four years ago and his medical history revealed that he was hospitalized 5 times with a provisional diagnosis of massive lower gastrointestinal bleeding. GIST was diagnosed at explorative laparotomy and the tumor was 21 cm × 13 cm × 7 cm in size. Immunohistochemical examination showed that vimentin, actin and CD117 were positive. Computerized tomography showed peritoneal implants three months later. Imatinib mesylate (600 mg/d) was initiated. However, control computerized tomography revealed liver and omental metastasis. The dosage was elevated to 800 mg/d. Despite high dosage, the progression of the metastatic lesions continued in the liver and omentum. The patient started oral sunitinib malate (Sutent? Pfizer Inc, New York, NY, USA) 50 mg per day for 4 consecutive weeks, followed by 2 wk off per treatment cycle. The metastatic lesions in the liver and omentum were decreased in size after four courses, suggesting that sunitinib is also an effective treatment modality for metastatic GIST in NF patients.

Perforation of the colon by invading recurrent gastrointestinal stromal tumors during sunitinib treatment

The molecular targets of sunitinib are receptor tyrosine kinases (RTKs),and this drug has also been known to exert blocking effects on the activation of KIT,which is similar to the mechanism of action of imatinib. Moreover,sunitinib has an additional anti-angiogenic effect through its inhibition of the vascular endothelial growth factor receptor activation. We report here a 70-year-old patient diagnosed with a recurrent gastrointestinal stromal tumor (GIST),which invaded the transverse colon and led to a perforation during sunitinib treatment. A computed tomography scan and 3-dimensional reconstruction showed necrosis of the recurrent hepatic mass and perforation of the invaded transverse colon. After percutaneous drainage of the intraperitoneal abscess,antibiotic treatment and restricted diet,the condition of the patient improved. The present case is the first to report that sunitinib,which is administered to treat GIST resistant to imatinib,can cause unexpected colon perforation and subsequent peritonitis.

Distinct antifibrogenic effects of erlotinib,sunitinib and sorafenib on rat pancreatic stellate cells

AIM:To study if three clinically available small molecule kinase inhibitors(SMI),erlotinib,sunitinib and sorafenib,exert antifibrogenic effects on pancreatic stellate cells(PSC)and analyze the basis of their action.METHODS:Cultured rat PSC were exposed to SMI.Cell proliferation and viability were assessed employing 5-bromo-2’-deoxyuridine incorporation assay and flow cytometry,respectively.2-Deoxy-2-[18F]fluoroglucose(18F-FDG)uptake was measured to study metabolic activity.Exhibition of the myofibroblastic PSC phenotype was monitored by immunofluorescence analysis ofα-smooth muscle actin(α-SMA)expression.Levels of mRNA were determined by real-time PCR,while protein expression and phosphorylation were analyzed by immunoblotting.Transforming growth factor-β1 (TGF-β1)levels in culture supernatants were quantified by ELISA.RESULTS:All three SMI inhibited cell proliferation and18F-FDG uptake in a dose-dependent manner and without significant cytotoxic effects.Furthermore,additive effects of the drugs were observed.Immunoblot analysis showed that sorafenib and sunitib,but not erlotinib,efficiently blocked activation of the AKT pathway,while all three drugs displayed little effect on phosphorylation of ERK1/2.Cells treated with sorafenib or sunitinib expressed less interleukin-6 mRNA as well as less collagen type 1 mRNA and protein.Sorafenib was the only drug that also upregulated the expression of matrix metalloproteinase-2 and reduced the secretion of TGF-β1 protein.All three drugs showed insignificant or discordant effects on the mRNA and protein levels ofα-SMA.CONCLUSION:The tested SMI,especially sorafenib,exert inhibitory effects on activated PSC,which should be further evaluated in preclinical studies.

Effects of Sunitinib Malate on Growth of Human Bladder Transitional Cell Line T24 In Vitro

Objective To investigate the growth-inhibitory effect of sunitinib malate on human bladder transitional cell carcinoma(TCC) in vitro. Methods Human bladder TCC cell line T24 was cultured and exposed to graded concentrations of sunitinib malate for 72 hours in vitro to determine the sensitivities to drug. Cell viability was measured by MTT assay. Cell apoptotic morphology was observed by fluorescence microscope following DAPI staining. Band expressions of Fas, Fas ligand, poly(ADP-ribose) polymerase(PARP) and β-actin were analyzed by Western blot. Wound healing process of T24 cells exposed to sunitinib malate was assayed. Results Sunitinib malate exerted a concentration-dependent and time-dependent inhibitory effect on the T24 cell lines. Fluorescence microscopy showed that small vacuoles appeared in the nuclei of T24 cells and the vacuoles were bigger with higher drug concentrations. The expressions of Fas ligand and PARP in T24 cells treated with sunitinib malate exhibited a concentration-dependent increase. Moreover sunitinib malate suppressed the wound healing process in a concentration-dependent manner. Conclusion Sunitinib malate exerted marked inhibitory activity against bladder cancer cell line T24.

Sunitinib对支气管哮喘气道重塑小鼠模型Erk通路和cyclin D1表达的影响

目的探讨sunitinib对支气管哮喘(简称哮喘)气道重塑的干预作用及可能的作用机制。方法 18只BALB/c小鼠随机分为对照组、哮喘组以及sunitinib组,每组6只;以卵清蛋白(OVA)致敏、激发,建立慢性哮喘气道重塑模型。Sunitinib组每次雾化吸入前半小时给予sunitinib(40mg/kg)灌胃给药。OVA末次激发结束后24h处死小鼠,HE染色观察气道炎症及形态学改变,采用ELISA法检测支气管肺泡灌洗液(BALF)中IL-4、IL-13和血清总IgE的表达,免疫组织化学法观察肺组织增殖细胞核抗原(proliferatingcell nuclear antigen,PCNA)、α平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)表达水平。蛋白印记法(Westernblot)测定细胞外信号调节蛋白激酶(extracellular signal-regulated kinase,Erk)蛋白磷酸化水平及细胞周期蛋白D1(cyclin D1)的表达。结果 HE染色示哮喘组小鼠黏膜下层和平滑肌层增厚,管腔狭窄,大量炎性细胞浸润,sunitinib组上述改变较哮喘组为轻;sunitinib干预后哮喘小鼠BALF中Th2细胞因子IL-4、IL-13和血清总IgE以及肺组织羟脯氨酸含量显著降低(P<0.01)。哮喘组小鼠气道PCNA阳性细胞百分比、α-SMA表达及肺组织Erk磷酸化水平、cyclin D1蛋白表达较对照组明显升高(P<0.01),sunitinib干预后其表达均降低(P<0.01)。结论 Sunitinib可能通过抑制Erk途径影响cyclin D1的表达,抑制了慢性哮喘模型中气道平滑肌的增殖,发挥抗气道重塑作用。

Sunitinib对支气管哮喘气道重塑小鼠模型Erk通路和cyclin D1表达的影响

目的探讨sunitinib对支气管哮喘（简称哮喘）气道重塑的干预作用及可能的作用机制。方法18只BALB／c小鼠随机分为对照组、哮喘组以及sunitinib组，每组6只；以卯清蛋白（OVA）致敏、激发，建立慢性哮喘气道重塑模型。Sunitinib组每次雾化吸入前半小时给予sunitinib（40mg／kg）灌胃给药。OVA末次激发结束后24h处死小鼠，HE染色观察气道炎症及形态学改变，采用ELISA法检测支气管肺泡灌洗液（BALF）中IL-4、IL-13和血清总IgE的表达，免疫组织化学法观察肺组织增殖细胞核抗原（proliferating cell nuclear antigen，PCNA）、α平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）表达水平。蛋白印记法（Western blot）测定细胞外信号调节蛋白激酶（extracellular signal-regulated kinase，Erk）蛋白磷酸化水平及细胞周期蛋白D1（cyclin D1）的表达。结果HE染色示哮喘组小鼠黏膜下层和平滑肌层增厚，管腔狭窄，大量炎性细胞浸润，sunitinib组上述改变较哮喘组为轻；sunitinib干预后哮喘小鼠BALF中Th2细胞因子IL-4、IL-13和血清总IgE以及肺组织羟脯氨酸含量显著降低（P〈0．01）。哮喘组小鼠气道PCNA阳性细胞百分比、α-SMA表达及肺组织Erk磷酸化水平、cyclin D1蛋白表达较对照组明显升高（P〈0．01），sunitinib干预后其表达均降低（P〈0．01）。结论Sunitinib可能通过抑制Erk途径影响cyclin D1的表达，抑制了慢性哮喘模型中气道平滑肌的增殖，发挥抗气道重塑作用。

sunitinib对人气道平滑肌细胞分泌纤维连接蛋白的影响及其机制研究

目的探讨sunitinib对血管内皮生长因子165（VEGFm）刺激的人气道平滑肌细胞（human airway smooth muscle cells，HASMCs）合成、分泌纤维连接蛋白（fibronectin，FN）的影响及其相关机制。方法将HAsMCs分成6个组：对照组、VEGF165组、VEGF。与sunitinib联合干预组、sunitinib组、U0126组、U0126与sunitinib联合干预组。Western blot检测P—VEGFR2、P—ERK表达水平。ELISA检测细胞上清液中FN的表达水平。结果与对照组相比，VEGFt6。组p—VEGFR2、p-ERK及FN表达水平增高（P〈0．05）；sunitinib（3nmol／L）干预后p-VEGFR2、p-ERK及FN表达水平下降（P〈0．05），其对ERK磷酸化及FN表达的抑制作用与ERK特异性拮抗剂U0126对ERK磷酸化及FN表达的抑制作用相当（P〉0．05）。结论sunitinib抑制VEGF165；诱导的HASMCs合成、分泌FN，可能是通过抑制VEGFR2磷酸化水平从而进一步调控ERK通路起作用。