Objective To analyze adverse drug reactions(ADR)caused by sunitinib and provide reference for clinical safety.Methods The case reports of ADR related to sunitinib in six Chinese and English databases from 2006 to 2021...Objective To analyze adverse drug reactions(ADR)caused by sunitinib and provide reference for clinical safety.Methods The case reports of ADR related to sunitinib in six Chinese and English databases from 2006 to 2021 were searched to extract relevant data,and then statistical analysis was performed.Results and Conclusion A total of 147 articles were included,involving 156 cases and 283 adverse events.Adverse reactions occurred at the highest rate after 31 to 180 days of drug administration,and ADR involved organs/systems mainly in blood and lymphatic disorders(17.67%),gastrointestinal disorders(15.55%),and skin and subcutaneous tissue disorders(10.60%).The adverse effects caused by sunitinib involve multiple organs/systems throughout the body.Besides,there are many severe fatal cases.During clinical medication,patients should be monitored regularly,and drugs should be reduced or stopped timely when adverse reactions occur to reduce the risk of clinical medication.展开更多
Background:Sunitinib resistance is a major challenge in advanced renal cell carcinoma(RCC).Clinically,elucidating the underlying mechanisms and developing practical countermeasures for sunitinib resistance in RCC is d...Background:Sunitinib resistance is a major challenge in advanced renal cell carcinoma(RCC).Clinically,elucidating the underlying mechanisms and developing practical countermeasures for sunitinib resistance in RCC is desirable.In previous studies,we found that circAGAP1 expression was significantly upregulated in clear cell RCC(ccRCC)and was strongly associated with poor prognosis.However,the role of circAGAP1 in sunitinib resistance in ccRCC remains unclear.Methods:We used public databases for bioinformatics analysis to identify the binding targets of circAGAP1.Additionally,the effects of circAGAP1 on the proliferation,clonogenesis,apoptosis,and migration of ccRCC cells were analyzed using quantitative real-time PCR,cell counting kit-8 assays,migration and apoptosis assays,and colony formation assays.Furthermore,RNA immunoprecipitation,dual-luciferase reporter,and fluorescence in situ hybridization assays were used to explore the molecular mechanism.Results:In this study,circAGAP1 exhibited higher expression in sunitinib-sensitive ccRCC cells and inhibited the clonogenesis,proliferation,and migration of ccRCC cells after sunitinib treatment.Mechanical studies revealed that circAGAP1 regulated the expression of sunitinib target platelet-derived growth factor receptor by acting as a microRNA sponge that suppresses miR-149-5p,miR-455-5p,and miR-15a-5p simultaneously.Overexpression of these three miRNAs reversed circAGAP1-mediated sunitinib sensitivity in ccRCC.Conclusions:In summary,our findings indicate that circAGAP1 may serve as a promising biomarker to predict sunitinib sensibility and a therapeutic target in ccRCC.展开更多
A liquid chromatography with tandem mass spectrometry（LC-MS/MS） method has been developed and validated for the measurement of sunitinib in rabbit plasma. After protein precipitation with acetonitrile, samples were ...A liquid chromatography with tandem mass spectrometry（LC-MS/MS） method has been developed and validated for the measurement of sunitinib in rabbit plasma. After protein precipitation with acetonitrile, samples were analyzed on a Zorbax Extend-C18 column（150 mm×4.6 mm, 5μm）. The mobile phase consisted of a mixture of acetonitrile and deionized water（containing 0.05% formic acid） at a ratio of 27：73（v/v）, and the flow rate was set at 0.8 mL /min. The column temperature was maintained at 30 oC. The LC eluate was detected by an electrospray ionization（ESI） source operated in the positive ion mode, and quantification was conducted using MRM of the transitions m/z 399.24→283.01 and m/z 415.19→178.00 for sunitinib and internal standard（IS, diltiazem hydrochloride）, respectively. The calibration curve was linear in the range of 2–600 ng/m L. The lower limit of quantification was 2 ng/mL. The method also exhibited satisfactory results in terms of sensitivity, specificity, accuracy（with relative error ranging from –4.0% to 1.1%）, precision（with intra- and inter-day relative standard deviations ranging from 2.8% to 9.5%）, matrix effect, recovery as well as stability. Taken together, our newly developed method was reliable to monitor sunitinib concentrations in rabbit plasma.展开更多
A sensitive, rapid, and simple liquid chromatography tandem mass spectrometry（LC-MS/MS） method for simultaneous determination of sunitinib and its active metabolites in plasma of BABL/c nude mice was developed and v...A sensitive, rapid, and simple liquid chromatography tandem mass spectrometry（LC-MS/MS） method for simultaneous determination of sunitinib and its active metabolites in plasma of BABL/c nude mice was developed and validated. Plasma samples were pre-treated by protein precipitation with pazopanib and used as an internal standard. Separation was performed on a reversed phase C18 column with a mobile phase composing of 10 m M ammonium formate p H 3.25（adjusted with formic acid） and acetonitrile（65：35, v/v） at a flow rate of 0.5 mL /min. Triple quadrupole tandem mass in multiple reaction monitoring（MRM） mode with electrospray positive ionization was used to monitor all the compounds. The current LC-MS/MS method was highly selective and sensitive with lowest limit of quantitation（LLOQ） of 0.5 ng/mL for both analytes and reliable intra- and inter-day precision and accuracy validated by relative error（RE%） and relative standard deviation（RSD%）. Linearity of calibration curve was excellent（r0.99） within a concentration range of 0.5–1000 ng/mL. This method was successfully applied to a pharmacokinetics study on BABL/c nude mice given with single dose of oral administration of sunitinib at 20 mg/kg.展开更多
Drug-loaded microspheres have been caused much attention in embotherapy in recent years. In thlS StUdy, poiyvlnyi alcohol/acrylic acid microspheres were prepared by inverse suspension polymerization method. Sunitinih ...Drug-loaded microspheres have been caused much attention in embotherapy in recent years. In thlS StUdy, poiyvlnyi alcohol/acrylic acid microspheres were prepared by inverse suspension polymerization method. Sunitinih malate （SU） was used as a model drug and loaded on microspheres through ion-exchange mechanism. We investigated the characterization of blank microspheres （B-Ms） and sunitinib-loaded microspheres （SU-Ms） in vitro, including morphology, size distribution, equilibrium water content （EWC）, elasticity, drug loading and drug release. The result showed that both B-Ms and SU-Ms were spherical with smooth surface. The particle size of B-Ms and SU-Ms were both suitable for embolization. Compared with that of B-Ms, the EWC of SU-Ms was decreased and the rigidity of SU-Ms was increased. Drug loading and entrapment efficiency of microspheres were mainly affected by the concentration of sunitinib solution than by the size of microspheres. SU-Ms exhibited a sustained release in phosphate buffer solution （PBS）. Thus, the SU-Ms may have potential application for arterial embolization.展开更多
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 Chine...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.展开更多
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...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 CDl17 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.展开更多
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. Mor...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.展开更多
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 ac...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.展开更多
G-quadruplexes are stable secondary structures formed with guanine rich sequences,which are widely distributed in genome.Chemical compounds stabilizing G-quadruplexes exhibited inhibition on tumor cells.However,the fe...G-quadruplexes are stable secondary structures formed with guanine rich sequences,which are widely distributed in genome.Chemical compounds stabilizing G-quadruplexes exhibited inhibition on tumor cells.However,the feasibility of G-quadruplex structures as drug targets needs to be validated.In this study,Sunitinib,an antitumor drug targeting tyrosine kinases was found to stabilize telomere G-quadruplex.The stabilization was further enhanced by the combined usage with Berberine,an isoquinoline alkaloid.Circular dichroism spectra showed the synergistic effect comes from inducing the conformation conversion of telomere G-quadruplex.The combination of Berberine with Sunitinib resulted in 1.7-fold enhancement in cell apoptosis rate with the percentage of apoptotic cells reaching about 70%.The confocal microscopy immunofluorescence images showed the combination of Berberine and Sunitinib induced the formation of G-quadruplex at the telomere in A549 cancer cells.This study suggested that more clinic drugs could work by targeting G-quadruplex structures.展开更多
Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has p...Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has proved that dopamine(DA)can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer(NSCLC).In this study,DA and SUN combination therapy was investigated in the treatment of pancreatic cancer,a malignant tumor with high mortality rate and very limited therapies.The cytotoxicity assay,clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival,clone formation ability and migration ability.Besides,SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft(PDX)model were constructed,further proving that DA could increase the in vivo anti-tumor efficacy of SUN,and could be reversed by SCH23390,a D1 dopamine receptor(D1DR)antagonist.Moreover,the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups.In addition,the body weight,H&E staining and blood routine test results showed that the combination therapy was safe.In summary,DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.展开更多
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 conc...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 DAPl staining. Band expressions of Fas, Fas ligand, poly （ADP-ribose） polyrnerase （PARP） and D-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.展开更多
Sunitinib malate is one of the multitargeted tyrosine kinase inhibitor,which are being used in clinic.It can inhibit more than 80 kinds of receptor`s tyrosine kinase,including epidermal growth factor receptor (EGFR),p...Sunitinib malate is one of the multitargeted tyrosine kinase inhibitor,which are being used in clinic.It can inhibit more than 80 kinds of receptor`s tyrosine kinase,including epidermal growth factor receptor (EGFR),platelet-derived growth factor receptors,vascular endothelial growth factor receptors (VEGFR),etc.And tyrosine kinase inhibitor is involved in connection with the generation and progression of many kinds of cancer including lung cancer.Several studies have evaluated the effect of Sunitinib on non-small cell lung cancer (NSCLC),by single agent,continuous daily dosing or in combination with chemotherapeutics (with docetaxel or gemcitabine plus cisplatin),which all showed certain effect.The test of Sunitinib in combination with gemcitabine plus cisplatin for advanced NSCLC shown that at the maximum tolerated dose:oral Sunitinib 37.5 mg/day intermittently (Schedule 2/1:2 weeks on treatment,1 week off treatment) schedule with intravenous infusions of gemcitabine (1000 mg/m2 days 1,8) and cisplatin (80 mg/m2 day 1),administered in 3-week cycles,66.7% patients achieved partial responses.And adverse effects were mild to moderate in severity (grades 1 to 2).Therapy was generally well tolerated.In summary,all the evidence above suggests that Sunitinib may play an important role in the treating of NSCLC.展开更多
Multidrug resistance （MDR） of breast cancer is a major cause of failure in chemotherapy. In the present study, a distearoylphosphatidyl ethanolamine-polyethylene glycol-pemetrexed （DSPE-PEG2000-PMT） conjugate was ...Multidrug resistance （MDR） of breast cancer is a major cause of failure in chemotherapy. In the present study, a distearoylphosphatidyl ethanolamine-polyethylene glycol-pemetrexed （DSPE-PEG2000-PMT） conjugate was synthesized from DSPE-PEG2000-NH2 and pemetrexed, and targeted sunitinib plus vinorelbine liposomes were developed by modifying DSPE-PEG20o0-PMT onto the surface of liposomes to overcome the MDR of breast cancer. The synthesized DSPE-PEG2000-PMT was confirmed to be consistent with the target product by matrix-assisted laser desorption/ionization time of flight mass spectrometry （MALDI-TOF-MS）. The concentrations of sunitinib and vinorelbine were measured simultaneously by high performance liquid chromatography （HPLC）. The analysis was performed on an ODS column at 30℃ at a wavelength of 215 nm with the mobile phase consisting of acetonitrile, 0.05 M KH2PO4 （pH 3.5） and triethylamine （35：65：0.3, v/v/v）. The limits of detection for sunitinib and vinorelbine were 25 ng/mL and 5 ng/mL, respectively, and the limits of quantification for both drugs were 0.25μg/mL. Two drugs were linearly correlated in the range of 0.5-25.0 μg/mL. For varying types of liposomes, the encapsulation efficiencies were 〉90%; the particle sizes were approximately 90 nm, and zeta potentials were slightly negative. The inhibitory effects were evaluated in the resistant breast cancer MCF-7/Adr cells. The results revealed that targeted sunitinib plus vinorelbine liposomes exhibited the strongest inhibitory effect to the resistant MCF-7/Adr cells among the varying formulations. Targeted coumarin liposomes were used as a fluorescent probe to evaluate the targeting effect to resistant breast cancer MCF-7/Adr cells. The results demonstrated that the targeted coumarin liposomes displayed the highest cellular uptake compared to non-targeted formulations. In conclusion, the targeted sunitinib plus vinorelbine liposomes represented a novel type of nano-formulations, which could accumulate in the resistant breast cancer cells, thereby inhibiting proliferation of the resistant cancer cells. Accordingly, the targeted sunitinib plus vinorelbine liposomes may provide a new strategy for circumventing the drug resistance in the resistant breast cancer.展开更多
Objective： Cancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colon...Objective： Cancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colonic fibroblasts. Methods： Cell cycle analysis and cell proliferation assays were performed to evaluate the inhibitory effect of sunitinib in vitro. Western-blot analysis was performed to evaluate variations in the levels of phosphorylated plateletderived growth factor receptor β （PDGFR-β）, Akt, and ERK proteins. Co-injection of SW620 cells and colonic fibreblasts in nude mice was employed to test anti-growth efficacy in vivo. Results： Sunitinib was found to effectively inhibit the growth of primary colonic fibroblasts. Low-dose sunitinib blocked the PDGF-BB-induced cell proliferation and PDGFR-β signaling. Co-injection of SW620 cells and colonic fibroblasts in nude mice generated greater tumor volumes than single injection of SW620 cells. Sunitinib treatment inhibited the SW620 cell＋colonic fibroblast tumor growth more effectively than treatment of 5-fluorouracil. Conclusions： Sunitinib mesylate inhibited the proliferation of primary human colonic fibroblasts through target-inhibited PDGFR signaling in vitro and in vivo.展开更多
文摘Objective To analyze adverse drug reactions(ADR)caused by sunitinib and provide reference for clinical safety.Methods The case reports of ADR related to sunitinib in six Chinese and English databases from 2006 to 2021 were searched to extract relevant data,and then statistical analysis was performed.Results and Conclusion A total of 147 articles were included,involving 156 cases and 283 adverse events.Adverse reactions occurred at the highest rate after 31 to 180 days of drug administration,and ADR involved organs/systems mainly in blood and lymphatic disorders(17.67%),gastrointestinal disorders(15.55%),and skin and subcutaneous tissue disorders(10.60%).The adverse effects caused by sunitinib involve multiple organs/systems throughout the body.Besides,there are many severe fatal cases.During clinical medication,patients should be monitored regularly,and drugs should be reduced or stopped timely when adverse reactions occur to reduce the risk of clinical medication.
基金supported by Shanghai Natural Science Foundation(Grant Number 22ZR1456600)Science and Technology Innovation Action Plan in Shanghai on Experimental Animal Research(Grant Number 22140903600)+1 种基金Clinical Research and Cultivation Project of Tongji Hospital in Shanghai(Grant Number ITJ(QN)2201)the National Natural Science Foundation of China(Nos.82227807,81830059)。
文摘Background:Sunitinib resistance is a major challenge in advanced renal cell carcinoma(RCC).Clinically,elucidating the underlying mechanisms and developing practical countermeasures for sunitinib resistance in RCC is desirable.In previous studies,we found that circAGAP1 expression was significantly upregulated in clear cell RCC(ccRCC)and was strongly associated with poor prognosis.However,the role of circAGAP1 in sunitinib resistance in ccRCC remains unclear.Methods:We used public databases for bioinformatics analysis to identify the binding targets of circAGAP1.Additionally,the effects of circAGAP1 on the proliferation,clonogenesis,apoptosis,and migration of ccRCC cells were analyzed using quantitative real-time PCR,cell counting kit-8 assays,migration and apoptosis assays,and colony formation assays.Furthermore,RNA immunoprecipitation,dual-luciferase reporter,and fluorescence in situ hybridization assays were used to explore the molecular mechanism.Results:In this study,circAGAP1 exhibited higher expression in sunitinib-sensitive ccRCC cells and inhibited the clonogenesis,proliferation,and migration of ccRCC cells after sunitinib treatment.Mechanical studies revealed that circAGAP1 regulated the expression of sunitinib target platelet-derived growth factor receptor by acting as a microRNA sponge that suppresses miR-149-5p,miR-455-5p,and miR-15a-5p simultaneously.Overexpression of these three miRNAs reversed circAGAP1-mediated sunitinib sensitivity in ccRCC.Conclusions:In summary,our findings indicate that circAGAP1 may serve as a promising biomarker to predict sunitinib sensibility and a therapeutic target in ccRCC.
文摘A liquid chromatography with tandem mass spectrometry（LC-MS/MS） method has been developed and validated for the measurement of sunitinib in rabbit plasma. After protein precipitation with acetonitrile, samples were analyzed on a Zorbax Extend-C18 column（150 mm×4.6 mm, 5μm）. The mobile phase consisted of a mixture of acetonitrile and deionized water（containing 0.05% formic acid） at a ratio of 27：73（v/v）, and the flow rate was set at 0.8 mL /min. The column temperature was maintained at 30 oC. The LC eluate was detected by an electrospray ionization（ESI） source operated in the positive ion mode, and quantification was conducted using MRM of the transitions m/z 399.24→283.01 and m/z 415.19→178.00 for sunitinib and internal standard（IS, diltiazem hydrochloride）, respectively. The calibration curve was linear in the range of 2–600 ng/m L. The lower limit of quantification was 2 ng/mL. The method also exhibited satisfactory results in terms of sensitivity, specificity, accuracy（with relative error ranging from –4.0% to 1.1%）, precision（with intra- and inter-day relative standard deviations ranging from 2.8% to 9.5%）, matrix effect, recovery as well as stability. Taken together, our newly developed method was reliable to monitor sunitinib concentrations in rabbit plasma.
基金National Natural Science Foundation of China(NSFC,Grant No.81473277)
文摘A sensitive, rapid, and simple liquid chromatography tandem mass spectrometry（LC-MS/MS） method for simultaneous determination of sunitinib and its active metabolites in plasma of BABL/c nude mice was developed and validated. Plasma samples were pre-treated by protein precipitation with pazopanib and used as an internal standard. Separation was performed on a reversed phase C18 column with a mobile phase composing of 10 m M ammonium formate p H 3.25（adjusted with formic acid） and acetonitrile（65：35, v/v） at a flow rate of 0.5 mL /min. Triple quadrupole tandem mass in multiple reaction monitoring（MRM） mode with electrospray positive ionization was used to monitor all the compounds. The current LC-MS/MS method was highly selective and sensitive with lowest limit of quantitation（LLOQ） of 0.5 ng/mL for both analytes and reliable intra- and inter-day precision and accuracy validated by relative error（RE%） and relative standard deviation（RSD%）. Linearity of calibration curve was excellent（r0.99） within a concentration range of 0.5–1000 ng/mL. This method was successfully applied to a pharmacokinetics study on BABL/c nude mice given with single dose of oral administration of sunitinib at 20 mg/kg.
文摘Drug-loaded microspheres have been caused much attention in embotherapy in recent years. In thlS StUdy, poiyvlnyi alcohol/acrylic acid microspheres were prepared by inverse suspension polymerization method. Sunitinih malate （SU） was used as a model drug and loaded on microspheres through ion-exchange mechanism. We investigated the characterization of blank microspheres （B-Ms） and sunitinib-loaded microspheres （SU-Ms） in vitro, including morphology, size distribution, equilibrium water content （EWC）, elasticity, drug loading and drug release. The result showed that both B-Ms and SU-Ms were spherical with smooth surface. The particle size of B-Ms and SU-Ms were both suitable for embolization. Compared with that of B-Ms, the EWC of SU-Ms was decreased and the rigidity of SU-Ms was increased. Drug loading and entrapment efficiency of microspheres were mainly affected by the concentration of sunitinib solution than by the size of microspheres. SU-Ms exhibited a sustained release in phosphate buffer solution （PBS）. Thus, the SU-Ms may have potential application for arterial embolization.
基金supported by the National Natural Science Foundation of China(Nos.81402084,81472378)the Shanghai Municipal Commission of Health and Family Planning(No.2013SY027)the Incubating Program for Clinical Research and Innovation of Renji Hospital(No.PYXJS16-008)
文摘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.
文摘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 CDl17 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.
文摘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.
基金Supported by Grant from the Deutsche Forschungsgemeinschaft(to RJ)
文摘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.
基金Huazhong Agricultural University Scientific&Technological Self-innovation Foundation(Grant No.2015RC013)The Fundamental Research Funds for the Central Universities(Grant No.2662017PY113,2662015PY208,2662015BQ048)+2 种基金National Natural Science Foundation of China(Grant No.21502060,21708011)Open fund of The State Key Laboratory of Bio-organic and Natural Products Chemistry,CAS(Grant No.SKLBNPC16343)Open fund of Beijing National Laboratory For Molecular Sciences
文摘G-quadruplexes are stable secondary structures formed with guanine rich sequences,which are widely distributed in genome.Chemical compounds stabilizing G-quadruplexes exhibited inhibition on tumor cells.However,the feasibility of G-quadruplex structures as drug targets needs to be validated.In this study,Sunitinib,an antitumor drug targeting tyrosine kinases was found to stabilize telomere G-quadruplex.The stabilization was further enhanced by the combined usage with Berberine,an isoquinoline alkaloid.Circular dichroism spectra showed the synergistic effect comes from inducing the conformation conversion of telomere G-quadruplex.The combination of Berberine with Sunitinib resulted in 1.7-fold enhancement in cell apoptosis rate with the percentage of apoptotic cells reaching about 70%.The confocal microscopy immunofluorescence images showed the combination of Berberine and Sunitinib induced the formation of G-quadruplex at the telomere in A549 cancer cells.This study suggested that more clinic drugs could work by targeting G-quadruplex structures.
基金National Natural Science Foundation of China(Grant No.81473277)Innovation Team of Ministry of Education(Grant No.BMU2017TD003)。
文摘Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has proved that dopamine(DA)can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer(NSCLC).In this study,DA and SUN combination therapy was investigated in the treatment of pancreatic cancer,a malignant tumor with high mortality rate and very limited therapies.The cytotoxicity assay,clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival,clone formation ability and migration ability.Besides,SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft(PDX)model were constructed,further proving that DA could increase the in vivo anti-tumor efficacy of SUN,and could be reversed by SCH23390,a D1 dopamine receptor(D1DR)antagonist.Moreover,the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups.In addition,the body weight,H&E staining and blood routine test results showed that the combination therapy was safe.In summary,DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.
基金Supported by the Beijing Natural Science Foundation(7102128)
文摘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 DAPl staining. Band expressions of Fas, Fas ligand, poly （ADP-ribose） polyrnerase （PARP） and D-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.
文摘Sunitinib malate is one of the multitargeted tyrosine kinase inhibitor,which are being used in clinic.It can inhibit more than 80 kinds of receptor`s tyrosine kinase,including epidermal growth factor receptor (EGFR),platelet-derived growth factor receptors,vascular endothelial growth factor receptors (VEGFR),etc.And tyrosine kinase inhibitor is involved in connection with the generation and progression of many kinds of cancer including lung cancer.Several studies have evaluated the effect of Sunitinib on non-small cell lung cancer (NSCLC),by single agent,continuous daily dosing or in combination with chemotherapeutics (with docetaxel or gemcitabine plus cisplatin),which all showed certain effect.The test of Sunitinib in combination with gemcitabine plus cisplatin for advanced NSCLC shown that at the maximum tolerated dose:oral Sunitinib 37.5 mg/day intermittently (Schedule 2/1:2 weeks on treatment,1 week off treatment) schedule with intravenous infusions of gemcitabine (1000 mg/m2 days 1,8) and cisplatin (80 mg/m2 day 1),administered in 3-week cycles,66.7% patients achieved partial responses.And adverse effects were mild to moderate in severity (grades 1 to 2).Therapy was generally well tolerated.In summary,all the evidence above suggests that Sunitinib may play an important role in the treating of NSCLC.
基金Beijing Natural Science Foundation(Grant No.7131009)the National Basic Research Program of China(Grant No.973 program,2013CB932501)+1 种基金the National Natural Science Foundation of China(Grant No.81373343)the Innovation Team of Ministry of Education(Grant No.BMU20110263)
文摘Multidrug resistance （MDR） of breast cancer is a major cause of failure in chemotherapy. In the present study, a distearoylphosphatidyl ethanolamine-polyethylene glycol-pemetrexed （DSPE-PEG2000-PMT） conjugate was synthesized from DSPE-PEG2000-NH2 and pemetrexed, and targeted sunitinib plus vinorelbine liposomes were developed by modifying DSPE-PEG20o0-PMT onto the surface of liposomes to overcome the MDR of breast cancer. The synthesized DSPE-PEG2000-PMT was confirmed to be consistent with the target product by matrix-assisted laser desorption/ionization time of flight mass spectrometry （MALDI-TOF-MS）. The concentrations of sunitinib and vinorelbine were measured simultaneously by high performance liquid chromatography （HPLC）. The analysis was performed on an ODS column at 30℃ at a wavelength of 215 nm with the mobile phase consisting of acetonitrile, 0.05 M KH2PO4 （pH 3.5） and triethylamine （35：65：0.3, v/v/v）. The limits of detection for sunitinib and vinorelbine were 25 ng/mL and 5 ng/mL, respectively, and the limits of quantification for both drugs were 0.25μg/mL. Two drugs were linearly correlated in the range of 0.5-25.0 μg/mL. For varying types of liposomes, the encapsulation efficiencies were 〉90%; the particle sizes were approximately 90 nm, and zeta potentials were slightly negative. The inhibitory effects were evaluated in the resistant breast cancer MCF-7/Adr cells. The results revealed that targeted sunitinib plus vinorelbine liposomes exhibited the strongest inhibitory effect to the resistant MCF-7/Adr cells among the varying formulations. Targeted coumarin liposomes were used as a fluorescent probe to evaluate the targeting effect to resistant breast cancer MCF-7/Adr cells. The results demonstrated that the targeted coumarin liposomes displayed the highest cellular uptake compared to non-targeted formulations. In conclusion, the targeted sunitinib plus vinorelbine liposomes represented a novel type of nano-formulations, which could accumulate in the resistant breast cancer cells, thereby inhibiting proliferation of the resistant cancer cells. Accordingly, the targeted sunitinib plus vinorelbine liposomes may provide a new strategy for circumventing the drug resistance in the resistant breast cancer.
基金supported by the National Natural Science Foundation of China(Nos.81071801 and 81272455)the Zhejiang Provincial Natural Science Foundation of China(No.R2100071)
文摘Objective： Cancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colonic fibroblasts. Methods： Cell cycle analysis and cell proliferation assays were performed to evaluate the inhibitory effect of sunitinib in vitro. Western-blot analysis was performed to evaluate variations in the levels of phosphorylated plateletderived growth factor receptor β （PDGFR-β）, Akt, and ERK proteins. Co-injection of SW620 cells and colonic fibreblasts in nude mice was employed to test anti-growth efficacy in vivo. Results： Sunitinib was found to effectively inhibit the growth of primary colonic fibroblasts. Low-dose sunitinib blocked the PDGF-BB-induced cell proliferation and PDGFR-β signaling. Co-injection of SW620 cells and colonic fibroblasts in nude mice generated greater tumor volumes than single injection of SW620 cells. Sunitinib treatment inhibited the SW620 cell＋colonic fibroblast tumor growth more effectively than treatment of 5-fluorouracil. Conclusions： Sunitinib mesylate inhibited the proliferation of primary human colonic fibroblasts through target-inhibited PDGFR signaling in vitro and in vivo.
