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BACKGROUND: Tyrosine kinase inhibitors, as well as other types of small-molecule cancer drugs, can cause severe cardiotoxicity. OBJECTIVE: To perform a heart safety re-evaluation by observing the effects of antitumor drugs on isolated heart electrocardiograph, cardiac action potential and associated ion channels and cytotoxicity. METHODS: Extracorporeal cardiac perfusion was given to the isolated rabbit heart using Langendorff perfusion: Sunitinib (0.3, 3, 10 μmol/L), Crizotinib (0.3, 1, 3 μmol/L), and Doxorubicin (1, 30 μmol/L) were perfused sequentially for 120 minutes to record electrocardiograph and left ventricular pressure. A blank control group was set for comparison. Manual patch clamp was used to record the effects of Crizotinib, Sunitinib, Doxorubicin on hERG, Cav1.2, Nav1.5 channel currents and action potential in human induced pluripotent stem cell derived cardiomyocytes. Adenosine triphosphate level in human induced pluripotent stem cell derived cardiomyocytes was detected by CellTiter-Glo luminescent cell viability assay. RESULTS AND CONCLUSION: Isolated rabbit heart using Langendorff perfusion: Compared with the blank ontrol group, Sunitinib and Crizotinib at ≥ 3 μmol/L decreased heart rate (P < 0.01) and prolonged QT/QTc interval (P < 0.01), and reduced left ventricular pressure to different extents. Manual patch clamp recording: Compared with the blank control group, Sunitinib and Crizotinib at 3 μmol/L inhibited the activities of hERG, Nav1.5 and Cav1.2 channels and significantly prolonged the duration of action potential (P < 0.01). According to the analysis of the test article, the difference between the labeled concentration and the measured concentration of the recovered solution was not significant. Cell viability assays: Compared with the blank control group, adenosine triphosphate content in human induced pluripotent stem cell derived cardiomyocytes significantly decreased after treatment with Sunitinib (IC50=4.64 μmol/L), Doxorubicin (IC50=4.21 μmol/L) and Crizotinib (IC50=2.87 μmol/L), indicating that cell viability significantly decreased (P < 0.01). To conclude, this study successfully established an early cardiac safety evaluation method for antitumor drugs, which provides good support and help for the subsequent development of antitumor drugs. [ABSTRACT FROM AUTHOR]

Objective: To establish a renal cell carcinoma sunitinib-resistant cell line and to explore the mechanism by which protein disulfide isomerase A4 (PDIA4) regulates sunitinib resistance in renal cell carcinoma. Methods: A small-dose intermittent induction method was used to establish 786-O and OS-RC-2 resistant cell lines (786-OR and OS-RC-2R), qRT-PCR and Western blot were used to detect the expression of PDIA4 in drug-resistant renal carcinoma cell lines and non-drug-resistant renal carcinoma cell lines, and lentiviral infection was used to construct a stable overexpression or knockdown renal carcinoma cell line of PDIA4. The effect of PDIA4 on the proliferation of renal cancer cells was detected by CCK-8 assay; the expression of apoptosis-related proteins BCL2, BAX, Caspase3, Cleaved-Caspase3, and Caspase9 was detected by RT-qPCR and Western blot. Results: Compared with the control group of parental cells 786-O and OS-RC-2, the PDIA4 expression levels of drug-resistant cell lines 786-OR and OS-RC-2R are significantly increased (P<0.05). Overexpression of PDIA4 promoted the growth and viability of renal cancer cells as well as decreased the sensitivity of renal cancer cells to sunitinib (P<0.05), whereas knockdown of PDIA4 inhibited the growth and viability of renal cancer cells as well as elevated the sensitivity of renal cancer cells to sunitinib (P<0.05). In addition, overexpression of PDIA4 inhibited the expression of pro-apoptotic proteins (P<0.05), while knockdown of PDIA4 promoted the expression of pro-apoptotic proteins (P<0.05). Conclusion: PDIA4 is associated with sunitinib resistance in renal cell carcinoma by the mechanism of inhibition of apoptosis causing sunitinib resistance in renal cell carcinoma, and targeting PDIA4 reverses the resistance. [ABSTRACT FROM AUTHOR]

Keloid (KD) is a pathological scar caused by excessive proliferation of fibroblasts and excessive deposition of extracellular matrix (ECM) in the skin during wound repair. It is often complicated with pain and pruritus, which can seriously affect the quality of life of patients. Although various treatments, such as injections, lasers, and surgeries, are available, the outcome is not satisfactory. Therefore, targeted therapeutic regimens, including a large molecule monoclonal antibody (Dupilumab) and the small molecule targeted drugs (Nintedanib, Sorafenib and Sunitinib), have been deployed to treat keloids. This review summarizes the progress on the treatment of keloids with these targeted drugs and their applications in the future.

Keloid (KD) is a pathological scar caused by excessive proliferation of fibroblasts and excessive deposition of extracellular matrix (ECM) in the skin during wound repair. It is often complicated with pain and pruritus, which can seriously affect the quality of life of patients・ Although various treatments, such as injections, lasers, and surgeries, are available, the outcome is not satisfactory・ Therefore, targeted therapeutic regimens, including a large molecule monoclonal antibody (Dupilumab) and the small molecule targeted drugs (Nintedanib, Sorafenib and Sunitinib), have been deployed to treat keloids・ This review summarizes the progress on the treatment of keloids with these targeted drugs and their applications in the future. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of China Tropical Medicine is the property of China Tropical Medicine Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective To investigate the clinical characteristics, treatment, and prognostic factors of pancreatic neuroendocrine tumors (pNETs) patients treated with Sunitinib. Methods The clinical data of pNETs patients from Pfizer Drug Assistance Program of Cancer Foundation of China from April 2013 to November 2017 were retrospectively analyzed. Follow-up and statistical analysis were performed. Results A total of 235 patients were enrolled, the patients′ overall survival time was between 4 and 252 months, the 3-years and 5-years survival rates were 73.8% and 60.8%, respectively. Univariate analysis showed that factors such as age, Ki-67 index and surgery were associated with the 3-years survival rates of pNETs patients (P<0.05). Multivariate analysis demonstrated that the age, Ki-67 index and surgery were independent prognostic factors for pNETs patients (P<0.05). For patients with liver metastases, univariate analysis revealed that surgery was associated with prognosis (P<0.05). The 5-years survival rate of 124 patients with extending usage of Sunitinib was 53.3%. Conclusion PNETs are rare tumors with atypical clinical symptoms and the patients often have metastasis at the initiate diagnosis. The age, Ki-67 index and surgery are associated with the prognosis of pNETs patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether spautin-1, a specific and potent autophagy inhibitor, can enhance sunitinib-induced apoptosis in renal carcinoma cells via inhibiting autophagy. Methods: Renal carcinoma cell line 786-O was used as cellular model and Western Blot was used to detect the effect of spautin-1 on sunitinib-induced autophagy; Cell Counting Kit-8 (CCK-8) was used to detect the effect of sunitinib on the proliferation of 786-O cells in the presence or absence of spautin-1. Flow cytometry was used to detect the effect of spautin-1 on sunitinib-induced apoptosis. Western Blot was used to detect the effects of spautin-1 on the PI3K/AKT/GSK3 β signaling pathway and the expression of the anti-apoptotic proteins Bcl-2 and Mcl-1. Results: Spautin-1 markedly inhibited sunitinib-induced autophagy by downregulating the autophagy protein beclin-1. Co-treatment with spautin-1 enhanced sunitinib-induced inhibition of cell proliferation. Spautin-1 enhanced sunitinib-induced apoptosis. Spautin-1 can decrease the phosphorylation levels of AKT and GSK3 in the PI3K/AKT/GSK3β signaling pathway, co-treatment of spautin-1 and sunitinib downregulated anti-apoptotic proteins including Bcl-2 and Mcl-1. Conclusion: Spautin-1 enhanced sunitinib-induced autophagy and promoted sunitinib-induced cell apoptosis by activating GSK3β in PI3K/AKT/GSK3β signaling pathway, which downregulated the expression of anti-apoptotic proteins Bcl-2 and Mcl-1. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the clinical effect of the targeted drug sunitinib in the treatment of advanced hepatocellular carcinoma (HCC). MethodsA total of 48 patients with advanced HCC who were admitted to Chang′an Hospital form September 2015 to September 2016 were enrolled and divided into control group and observation group, with 24 patients in each group. The patients in the control group were given oral sorafenib, and those in the observation group were given oral sunitinib. The patients were followed up for 1 year, and the clinical outcome, improvement in clinical symptoms, and adverse events were recorded. The t-test was used for comparison of continuous data between groups, and the Mann-Whitney U test was used for comparison of categorical data between groups. ResultsThe disease control rate (DCR) in the observation group was 68.42% (13/19), and among these 13 patients, 4 achieved effective remission and 9 had stable disease; the DCR in the control group was 76.19%, and there was no significant difference in DCR between the two groups (P＞0.05). There was a significant difference in the incidence rate of hand-foot skin reaction between the observation group and the control group (0% vs 12.5%, U=31.07, P＜0.05). The observation group had a significantly higher incidence rate of neutropenia than the control group (25% vs 16.67%, U=29.87, P＜0.05). Both groups experienced digestive tract reactions (nausea and vomiting) and abnormal liver function; since the digestive tract reactions were tolerable, no special treatment was given, and the patients with abnormal liver function were given liver-protecting drugs, so all adverse events were effectively alleviated. ConclusionSunitinib has a good clinical effect in the treatment of advanced HCC, and further studies with a larger sample size are needed to investigate the long-term clinical effect of sunitinib and combined treatment. [ABSTRACT FROM AUTHOR]

Objective To investigate the efficacy and drug related adverse reactions of sorafenib and sunitinib as first-line tyrosine-kinase inhibitors (TKIs) for patients with metastatic renal cell carcinoma (mRCC) and analyze the clinical prognostic factor for survival. Methods The data of 271 patients with metastatic renal cell carcinoma who had complete clinicopathological data were retrospectively analyzed, including 174 cases in sorafenib group and 97 cases in sunitinib group, to access patients' overall survival (OS) and progression-free survival (PFS). Prognostic values of all characteristics were determined by using univariate and multivariate Cox regression models. Results The objective response rates (ORR) of the sorafenib and sunitinib groups were 14.9% and 19.6%, respectively, and the disease control rates (DCR) were 85. 1% and 88.6%, respectively. No significant difference was found between the sorafenib and sunitinib group in ORR (P- 0.325) or DCR (P- 0.408). The most common grade 3 to 4 adverse events in the sorafenib group were hand-foot syndrome (6.7%), diarrhea (2.3%), and rash (2.3%). The most common grade 3 to 4 adverse events in the sunitinib group were neutropenia (6.2%), hand-foot syndrome (6. 2%), and thrombocytopenia (4. 6%). During the follow-up, 97 cases death occurred and 81 cases disease progression occurred in sorafenib group. The median PFS was 12 months (95% 67; 9-15 months), and the median OS was 25 months (95% CI: 21-29 months) in sorafenib group. While 74 cases death occurred and 40 cases disease progression occurred in sunitinib group, the median PFS was 12 months (95% CI: 10-12 months) and the median OS was 23 months (95% 67: 20-32 months) in sunitinib group. No significant difference was found between the sorafenib and the sunitinib group in PFS (P- 0.771) or OS (P= 0.548). Multivariate analysis showed Fuhrman grades (HR - 1.358, 95% CI: 1.004-1.835), number of metastatic sites (HR- 1.550, 95%CI; 1.143-2.101) and MSKCC risk grade (Intermediate risk group: HR = 1.621, 95% 67: 1.117-2.232; Poor risk group; HR= 2.890, 95% CI: 1.942-4.298) were independent prognostic factors for PFS. Fuhrman grades (HR-2.135, 95%67; 1.533-2.974), number of metastatic sites (HR- 1.774, 95%CI-. 1.279-2.461) and MSKCC risk grade (Intermediate risk group: HR- 1.415, 95% 67; 1.002-1.998;Poor risk group: HR-3A6X, 95%67; 2.065-4.838) were independent prognostic factors for OS. Conclusions The results of this study indicate that sorafenib and sunitinib are both effective as the first-line TKIs for mRCC patients and sorafenib has comparable efficacy to sunitinib. Rut they have differences in the incidence of adverse effects. Fuhrman grades, number of metastatic sites and MSKCC risk grade are independent prognostic factors for mRCC patients. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is a malignant tumour with quite high cancer specific mortality, and it still lacks stable and reliable markers for NSCLC's prognosis. Platelet derived grow factor (PDGF) and PDGFR has been considered to be involved in the process of cell proliferation, migration, metastasis and epithelial mesenchymal transition of cancer cell through various intracellular signal pathways. Pathology analysis showed that PDGF pathway mainly stimulates the proliferation of NSCLC tumour stroma through paracrine pattern, and some reaseach found that PDGF pathway directly promotes some NSCLC cell's proliferation. The expression of PDGF and PDGFR within NSCLC tissue correlates with status of lymphatic metastasis and patients’ prognosis. In clinical treatment of NSCLC, the great effect of PDGF pathway in angiogenesis and promoting distribution of chemotherapy by inhibition of PDGF should not be neglected. As an important pro-angiogenesis pathway, functions of PDGF in radiotherapy is dicovered by more and more fundamental research. This review focuses on the progress of PDGF pathway in NSCLC and aims to provide some new ideas for clinical and fundamental researchers.

Background and objective Advanced non-small cell lung cancer (NSCLC) is a common malignancy that is incurable. No standard treatment exists for recurrent patients. This article analyzed the efficacy and safety of sunitinib (37.5 mg qd) on a continuous daily dosing (CDD) schedule in treating recurrent advanced NSCLC. Methods We retrospectively analyzed the short-term efficacy and toxicity of sunitinib CDD in treating 17 patients who had previously undergone multiple cycles of therapy for advanced NSCLC in our hospital from January 2011 to December 2012. Treatment-related survival was also analyzed. Results Among the 17 patients, the best overall response was partial response in 1 patient (5.9%), stable disease in 7 patients (41.2%), and progressive disease in 9 patients (52.9%). The overall response rate was 5.9%, and the disease control rate was 47.1%. The median progression-free survival was 4.4 months (95%CI: 4.05-7.46). The main grade 3/4 toxicity was hand-foot skin reaction. Conclusion Sunitinib (37.5 mg QD) CDD enabled good objective response in advanced NSCLC patients who had previously received multiple cycles of treatment and was well tolerated.

Objective The aim of this study was to compare the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and the Choi criteria for evaluating the early response of advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) to sunitinib therapy. Methods 18 patients with pathologically proven advanced GEP-NENs treated with sunitinib were enrolled in the study. Pre - and post -treatment unenhanced and bi -phasic contrast -enhanced CT was performed on all patients. Changes in the target tumor size and density from pre-treatment to 1.4-3.1 months after treatment were measured for each patient. Tumor responses were identified using the RECIST 1.1 and Choi criteria. The time to tumor progression (TTP) for each patient was measured and compared between groups using the Kaplan-Meier method. Results The treatment responses using the RECIST 1.1 were partial response (PR) in 4/18 (22%), stable disease (SD) in 9/18 (50%), and progressive disease (PD) in 5/18 (28%). The median TTP of the PR group (16.6 months) was significantly longer (P=0.007) than that of the PD group (2.3 months) and not significantly longer (P=0.131) than that of the SD group (10.8 months). Using the Choi criteria, treatment responses were PR (8/18, 44%), SD (4/18, 22%), and PD (6/18, 33%). According to Choi criteria, the median TTP of PR, SD and PD group were not reached, 10.8 and 2.3 months, respectively. The median TTP of the PR group was not reached and significantly longer (P=0.026) than that of the SD (10.8 months) and PD groups (2.3 months, P<0.001). Conclusion The Choi criteria appear to be more sensitive and precise than RECIST 1.1 for assessing the early response of advanced GEP-NENs to sunitinib therapy. [ABSTRACT FROM AUTHOR]

Multi-targeted tyrosine kinase inhibitors (TKIs) play important roles in the treatment of non-small cell lung cancer (NSCLC). Recently, results of several large phase III studies have been published, showing bittersweet efficacy of multi-targeted TKIs. In the era of personalized therapy, optimal use of multi-targeted TKIs is worthy of further investigation. In this review, we summarized current clinical development and future direction of multi-targeted TKIs in NSCLC..

Objective: To investigate the inducing effect of sunitinib on the death of drug-resistant leukemia K562/ADR cells and the related signaling pathway., Methods: K562/ADR cells were treated with different concentrations of sunitinib, and the cells were collected at 24, 48, 72, and 96 hours, respectively. MTS assay was used to detect the effect of sunitinib on the proliferation of K562/ADR cells, and the appropriate sunitinib intervention time and concentration were determined. QPCR and Western blot were used to detect the mRNA and protein expression levels of apoptosis-related genes in K562/ADR cells treated with sunitinib. Four different cell death inhibitors Nec-1, VX-765, CQ and Fer-1 were used to detect the death mode of K562/ADR cells treated with sunitinib. QPCR and Western blot were used to detect the mRNA and protein expression levels of pyroptosis-related genes in K562/ADR cells treated with sunitinib., Results: Sunitinib significantly inhibited the proliferation of K562/ADR cells in a time - and concentration-dependent manner(R 48 H =0.9579, r 4 μg/ml =0.9740). The IC 50 of sunitinib was (3.96±0.14) μg/ml at 48 hours. The mRNA and protein expression levels of apoptosis-related genes Bax, BCL-2 , Caspase-3 and Caspase-9 in K562/ADR cells treated with sunitinib did not change significantly. After treatment with four different cell death inhibitors, only the pyroptosis inhibitor VX-765 could significantly reverse the inhibitory effect of sunitinib on the proliferation of K562/ADR cells ( P <0.01). The mRNA and protein expression levels of pyroptosis-related genes Caspase-1, Caspase-4, Caspase-5, NLRP3, GSDMD and IL-1β in K562/ADR cells treated with sunitinib were significantly increased ( P <0.01)., Conclusion: Sunitinib can induce pyroptosis in drug-resistant leukemia K562/ADR cells. Further study of the signaling pathways related to pyroptosis may provide experimental basis for the treatment of drug-resistant leukemia.

Objective To explore the expressions of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), and their relationship with prospective efficacy of tyrosine kinase inhibitor sunitinib in metastatic clear cell renal cell carcinoma (ccRCC). Methods Twenty patients with histologically proven metastatic ccRCC were selected between Jan., 2010 and Dec., 2010. All patients underwent radical nephrectomy and then were followed up to Dec., 2015. All patients received a standard regimen of sunitinib (a dose of 50 mg given orally once daily for 4 weeks on and 2 weeks off, 6 weeks per cycle). Tissue microarrays from primary tumor specimens of all patients were immunohistochemically stained for selected markers, including PDGF, PDGFR-α, β, VEGF-A,VEGF-C and VEGFR-2, 3. And the results of immunohistochemistry (IHC) and microvessel density (MVD) were compared with patients' survival. Results To the date of statistical analysis, 16 patients died of tumour progression. High expression of VEGFR-2 was significantly correlated with the longer progression free survival (PFS) and overall survival (OS) in Spearman correlation analysis. Cox regression analysis revealed that a strong positive of VEGFR-2 was significantly associated with both lower risk of tumor progressing (OR=0.162, 95%CI:0.031-0.839,P=0.030) and lower mortality risk (OR=0.204, 95%CI:0.041-1.015,P=0.052). Conclusions For ccRCC patients who treated with sunitinib, high expression of VEGFR-2 was significantly correlated with the longer PFS and OS, while a strong positive of VEGFR-2 was significantly associated with both lower risk of tumor progressing and lower mortality risk. VEGFR-2 could be a predictive factor for making a clinical decision in RCC targeted therapy. [ABSTRACT FROM AUTHOR]

Objective To investigate the influence of cytochrome P4503A5 (CYP3A5) and vascular endothelial growth factor receptor 3(VEGFR-3) gene polymorphism on the sunitinib treatment in gastrointestinal stromal tumors (GIST). Methods The elbow venous peripheral blood sample was taken for detecting the gene sequence of rs776746 polymorphisms of CYP3A5 gene and rs307826 polymorphisms of VEGFR3 gene by PCR direct sequencing. Sunitinib was used due to imatinib resistance after operation, or unable tolerance or sunitinib sensitivity indicated by gene detection. The curative effect and adverse reactions were fol lowed up and tracked. Results Among 25 cases, only 2 case (8.0%) were rs307826 type of VEGFR3 gene, 23 cases (92.0%) were AA type and GG type was not found; the disease control rate of AA type was significantly higher than that of AG type, the difference was statistically significant (Fisher=8.696, P=0.033); rs307826 site genotype had no relation with the age, sex, tumor site, tumor risk grade and tumor clinicopathological type (P>0.05). Among 25 cases, 12 cases (48.0%) were rs776746 AG type of CYP3A5 gene, 13 cases (52.0%) were GG type and AA type was not found; the adverse reactions in the patients with GG type were significantly slighter than those in AG type, the difference was statistically significant (Fisher=8.901, P=0.012 0); rs776746 site genotype had no relation with the age, sex, tumor site, tumor risk grade and tumor clinicopathological type (P>0.05). Conclusion The sunitinib treatment of GIST can elevate the disease control rate in the majority of patients. Detecting the polymorphism of CYP3A5 gene has an important significance to the individualized therapy, prevention and treatment of adverse reactions in GIST. [ABSTRACT FROM AUTHOR]

Ｏｂｊｅｃｔｉｖｅ　Ｔｏ ｉｎｖｅｓｔｉｇａｔｅ ｔｈｅ ｅｆｆｉｃａｃｙ ａｎｄ ｓａｆｅｔｙ ｏｆ ｓｕｎｉｔｉｎｉｂ ａｓ ｆｉｒｓｔ⁃ｌｉｎｅ ｔｈｅｒａｐｙ ｆｏｒ ｍｅｔａｓｔａｔｉｃ ｒｅｎａｌ ｃｅｌｌ ｃａｒｃｉｎｏｍａ （ｍＲＣＣ） ｏｎ ａ ２ ｗｅｅｋｓ ｏｎ／１ ｗｅｅｋ ｏｆｆ ｉｎｔｅｒｍｉｔｔｅｎｔ ｄｏｓｉｎｇ ｓｃｈｅｄｕｌｅ． Ｍｅｔｈｏｄｓ Ａ ｔｏｔａｌ ｏｆ １１ ｍＲＣＣ ｐａｔｉｅｎｔｓ ｗｅｒｅ ｅｎｒｏｌｌｅｄ ｔｏ ｒｅｃｅｉｖｅ ｓｕｎｉｔｉｎｉｂ ５０ ｍｇ／ ｄａｙ ｉｎ ２ ｗｅｅｋｓ ｏｎ／ １ ｗｅｅｋ ｏｆｆ ｓｃｈｅｄｕｌｅ ｐｅｒ ６ ｗｅｅｋｓ ｔｉｌｌ ｄｉｓｅａｓｅ ｐｒｏｇｒｅｓｓｉｏｎ ｏｒ ｉｎｔｏｌｅｒａｂｌｅ ｔｏｘｉｃｉｔｙ ｏｃｃｕｒｒｅｄ． Ｔｈｅ ｐｒｉｍａｒｙ ｅｎｄ ｐｏｉｎｔ ｗａｓ ｐｒｏｇｒｅｓｓｉｏｎ ｆｒｅｅ ｓｕｒｖｉｖａｌ （ＰＦＳ）， ｔｈｅ ｓｅｃｏｎｄａｒｙ ｅｎｄ ｐｏｉｎｔｓ ｗｅｒｅ ｏｖｅｒａｌｌ ｓｕｒｖｉｖａｌ （ＯＳ）， ｉｎｃｉｄｅｎｃｅ ｏｆ ａｄｖｅｒｓｅ ｅｆｆｅｃｔｓ ａｎｄ ｏｂｊｅｃｔｉｖｅ ｒｅｓｐｏｎｓｅ． Ｒｅｓｕｌｔｓ　Ｔｈｅ ｏｂｊｅｃｔｉｖｅ ｒｅｓｐｏｎｓｅ ｒａｔｅ ｉｎ ｔｈｅ １１ ｃａｓｅｓ ｗａｓ ４５．５％ ａｎｄ ｄｉｓｅａｓｅ ｃｏｎｔｒｏｌ ｒａｔｅ ７２．７％ （ｐａｒｔｉａｌ ｒｅｓｐｏｎｓｅ ｎ ＝５， ｓｔａｂｌｅ ｄｉｓｅａｓｅ ｎ ＝３）． Ｔｉｌｌ ｔｈｅ ｌａｓｔ ｆｏｌｌｏｗ ｕｐ ｏｎ Ｄｅｃ ２０１３， ｔｈｅ ｍｅｄｉａｎ ＰＦＳ ｗａｓ １７．０ ｍｏｎｔｈｓ （９５％ ＣＩ ７．３ ｔｏ ２６．７ ｍｏｎｔｈｓ）， ａｎｄ ｍｅｄｉａｎ ＯＳ ２６．０ ｍｏｎｔｈｓ （９５％ ＣＩ ２．２ ｔｏ ４９．８ ｍｏｎｔｈｓ）． Ｔｈｅ ｃｏｍｍｏｎ ａｄｖｅｒｓｅ ｅｖｅｎｔｓ ｉｎｃｌｕｄｅｄ ｌｅｕｃｏｐｅｎｉａ， ｔｈｒｏｍｂｏｃｙｔｏｐｅｎｉａ， ｄｉａｒｒｈｅａ， ｍｕｃｏｓｉｔｉｓ ａｎｄ ｈａｎｄ⁃ｆｏｏｔ ｓｋｉｎ ｒｅａｃｔｉｏｎ． Ｄｏｓｅ ｒｅｄｕｃｔｉｏｎ ｔｏ ３７．５ ｍｇ ｗａｓ ｓｅｅｎ ｏｎｌｙ ｉｎ ２ ｐａｔｉｅｎｔｓ ｗｉｔｈｏｕｔ ｄｉｓｃｏｎｔｉｎｕａｔｉｏｎ． Ｃｏｎｃｌｕｓｉｏｎｓ Ｓｕｎｉｔｉｎｉｂ ｏｎ ａｎ ｉｎｔｅｒｍｉｔｔｅｎｔ ｄｏｓｉｎｇ ｓｃｈｅｄｕｌｅ ２ ｗｅｅｋｓ ｏｎ ／１ ｗｅｅｋ ｏｆｆ ａｓ ｆｉｒｓｔ⁃ｌｉｎｅ ｔｈｅｒａｐｙ ｆｏｒ ｍＲＣＣ ｐａｔｉｅｎｔｓ ｓｈｏｗｓ ａ ｇｏｏｄ ｅｆｆｉｃａｃｙ ａｎｄ ｔｏｌｅｒａｎｃｅ， ｗｉｔｈ ｌｅｓｓ ｇｒａｄｅ ３⁃４ ｄｒｕｇ⁃ｒｅｌａｔｅｄ ｔｏｘｉｃｉｔｉｅｓ ａｎｄ ａ ｔｅｎｄｅｎｃｙ ｏｆ ｐｒｏｌｏｎｇｅｄ ＰＦＳ ｉｎ ｍＲＣＣ ｐａｔｉｅｎｔｓ． [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical characteristics, treatment, and prognostic factors of pancreatic neuroendocrine tumors (pNETs) patients treated with Sunitinib. Methods: The clinical data of pNETs patients from Pfizer Drug Assistance Program of Cancer Foundation of China from April 2013 to November 2017 were retrospectively analyzed. Follow-up and statistical analysis were performed. Results: A total of 235 patients were enrolled, the patients' overall survival time was between 4 and 252 months, the 3-years and 5-years survival rates were 73.8% and 60.8%, respectively. Univariate analysis showed that factors such as age, Ki-67 index and surgery were associated with the 3-years survival rates of pNETs patients ( P <0.05). Multivariate analysis demonstrated that the age, Ki-67 index and surgery were independent prognostic factors for pNETs patients ( P <0.05). For patients with liver metastases, univariate analysis revealed that surgery was associated with prognosis ( P <0.05). The 5-years survival rate of 124 patients with extending usage of Sunitinib was 53.3%. Conclusion: PNETs are rare tumors with atypical clinical symptoms and the patients often have metastasis at the initiate diagnosis. The age, Ki-67 index and surgery are associated with the prognosis of pNETs patients.

Objective: To investigate the efficacy and drug related adverse reactions of sorafenib and sunitinib as first-line tyrosine-kinase inhibitors (TKIs) for patients with metastatic renal cell carcinoma (mRCC) and analyze the clinical prognostic factor for survival. Methods: The data of 271 patients with metastatic renal cell carcinoma who had complete clinicopathological data were retrospectively analyzed, including 174 cases in sorafenib group and 97 cases in sunitinib group, to access patients' overall survival (OS) and progression-free survival (PFS). Prognostic values of all characteristics were determined by using univariate and multivariate Cox regression models. Results: The objective response rates (ORR) of the sorafenib and sunitinib groups were 14.9% and 19.6%, respectively, and the disease control rates (DCR) were 85.1% and 88.6%, respectively. No significant difference was found between the sorafenib and sunitinib group in ORR ( P =0.325) or DCR ( P =0.408). The most common grade 3 to 4 adverse events in the sorafenib group were hand-foot syndrome (6.7%), diarrhea (2.3%), and rash (2.3%). The most common grade 3 to 4 adverse events in the sunitinib group were neutropenia (6.2%), hand-foot syndrome (6.2%), and thrombocytopenia (4.6%). During the follow-up, 97 cases death occurred and 81 cases disease progression occurred in sorafenib group. The median PFS was 12 months (95% CI: 9-15 months), and the median OS was 25 months (95% CI: 21-29 months) in sorafenib group. While 74 cases death occurred and 40 cases disease progression occurred in sunitinib group, the median PFS was 12 months (95% CI: 10-12 months) and the median OS was 23 months (95% CI: 20-32 months) in sunitinib group. No significant difference was found between the sorafenib and the sunitinib group in PFS ( P =0.771) or OS ( P =0.548). Multivariate analysis showed Fuhrman grades ( HR =1.358, 95% CI: 1.004-1.835), number of metastatic sites ( HR =1.550, 95% CI: 1.143-2.101) and MSKCC risk grade (Intermediate risk group: HR =1.621, 95% CI: 1.117-2.232; Poor risk group: HR =2.890, 95% CI: 1.942-4.298) were independent prognostic factors for PFS. Fuhrman grades ( HR =2.135, 95% CI: 1.533-2.974), number of metastatic sites ( HR =1.774, 95% CI: 1.279-2.461) and MSKCC risk grade (Intermediate risk group: HR =1.415, 95% CI: 1.002-1.998; Poor risk group: HR =3.161, 95% CI: 2.065-4.838) were independent prognostic factors for OS. Conclusions: The results of this study indicate that sorafenib and sunitinib are both effective as the first-line TKIs for mRCC patients and sorafenib has comparable efficacy to sunitinib. But they have differences in the incidence of adverse effects. Fuhrman grades, number of metastatic sites and MSKCC risk grade are independent prognostic factors for mRCC patients.

Objective To investigate the expression levels of autophagy-related gene 5 (ATG5) and microtubule-associated protein 1 light chain 3 (LC3) and their effects on sunitinib resistance in human renal carcinoma cells. Methods After clinic-pathologic feature and survival analysis, 99 renal clear cell carcinoma tissues with different histological grades were used to detect the expression of ATG5 and LC3 by immunohistochemistry. Renal carcinoma cell line A-498 was infected with lentivirus-mediated ATG5 shRNA. Western blot analysis was performed to confirm the efficiency of ATG5 knockdown. Proliferation rate of A-498 cells in control group and ATG5 low expression group was determined by flow cytometry. Finally, the survival rate was detected by MTT assay after A-498 cells were treated with different concentrations of sunitinib. Results The expression levels of ATG5 and LC3 in renal clear cell carcinoma tissues were significantly higher than those in para-tumor tissues. The expression levels of ATG5 and LC3 were associated with classification, histological grade, TNM stage and survival rate, rather than gender, age, location, tumor size. Compared with the control group, the protein expressions of ATG5 and LC3 significantly decreased in A-498 cells with ATG5 low expression. The cell proliferation rate in ATG5 downregulation group was lower than that in the control group. Compared with control group, the survival rate in ATG5 low expression group were significantly reduced in a dose-dependent manner after sunitinib treatment. Conclusion Autophagy is active in renal clear cell carcinoma, and the drug sensitivity to sunitinib in renal cancer cells can be enhanced by the downregulation of ATG5.

Objective: To elucidate the historic and current diagnosis and treatment status of gastrointestinal stromal tumor (GIST) in the Chinese population based on four high volume databases., Methods: Clinicopathological data of GIST patients with follow-up information between January 1998 and December 2015 from Sun Yat-sen University Cancer Center, Union Hospital of Huazhong University of Science and Technology, Southern Medical University Nanfang Hospital and Guangdong General Hospital were retrospectively analyzed. Kaplan-Meire method was used to draw survival curve. The accumulative survival rate was calculated by life table method. Comparison of survival rate among groups was examined by Log-rank test., Results: A total of 2 610 cases were enrolled into the study, including 667(25.6%) cases from Sun Yat-sen University Cancer Center, 754(28.9%) cases from Union Hospital of Huazhong University of Science and Technology, 692(26.5%) cases from Southern Medical University Nanfang Hospital and 497 (19.0%) cases from Guangdong General Hospital. There were 1 394 male and 1 216 female cases with the ratio of 1.15 to 1.00. The age of patients was from 18 to 95 (median 58.0) years old. Three-year was used as a time stage, then 18 years were divided into 6 stages. New GIST patients increased gradually year by year. There were 13(0.5%) cases during 1998 to 2000, 68(2.6%) cases during 2001 to 2003, 256(9.8%) cases during 2004 to 2006, 517 (19.8%) cases during 2007 to 2009, 814(31.2%) cases during 2010 to 2012, and 942 (36.1%) cases during 2013 to 2015. Primary GIST sites were esophagus in 50(1.9%) cases, stomach in 1 686(64.6%) cases, duodenum in 206 (7.9%) cases, jejunum and ileum in 446 (17.1%) cases, colon and rectum in 133 (5.1%) cases, and non-gastrointestinal tract in 89 (3.4%) cases. GIST lesions of 2 404(92.1%) cases located in the primary sites and relapse/metastasis occurred in 206 cases when consulting. Among 206 relapse/metastasis cases, liver metastasis was found in 126 (61.2%) cases, abdominal cavity/pelvic cavity metastasis in 64 (31.1%) cases, liver plus abdominal cavity/pelvic cavity metastasis in 12 (5.8%) cases, and other site metastasis in 4 (1.9%) cases. Among all the patients, 352 received gene detection, including 1 (0.4%) during 2004 to 2006, 7 (1.4%) during 2007 to 2009, 150 (18.4%) during 2010 to 2012, and 194 (20.6%) during 2013 to 2015. Most of the primary oncogenic mutational site occurred in c-Kit, including 30 (8.5%) cases in exon 9, 242 (68.8%) cases in exon 11, 4 (1.1%) cases in exon 13, 2 (0.6%) cases in exon 17, while 3 (0.9%) cases in PDGFRA exon 12 and 20 (5.7%) cases in PDGFRA 18, besides, no mutations of KIT and PDGFRA were detected in 51 (14.5%) cases. A total of 2 202 cases underwent operation, including 2 038 (92.6%) of radical resection and 164 (7.4%) of palliative resection. Among 2 038 patients undergoing radical resection, 450 (22.1%) cases were very low risk, 593 (29.1%) cases were low risk, 283 (13.9%) cases were moderate risk and 712 (34.9%) cases were high risk according to NIH risk classification. Of 995 patients with moderate and high risk, 550(55.3%) cases received postoperative imatinib adjuvant therapy, whose ratio in above 6 time stages was as follows: 0, 42.8%(12/28), 19.8%(20/101), 9.8% (21/215), 65.7% (176/268) and 85.6% (321/375). Of 206 relapse/metastasis patients, 200 (97.1%) cases received imatinib as the first-line therapy, and 22 (10.7%) received sunitinib as the second-line therapy. A total of 1 743 patients had complete follow-up data and median follow-up time was 35.9 (0.1 to 173.8) months. The 5-year overall survival rates in very low, low, moderate and high risk patients were 100%, 97%, 95% and 78% respectively., Conclusion: This retrospective study provides the largest data of GIST and indicates the historic changes of clinicopathological characteristics, diagnosis and treatment of GIST for further domestic GIST research.

Objective: To investigate the efficacy and the influence factors of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma (mRCC). Methods: Clinical data of mRCC patients with sunitinib administered as the first line treatment from August 2008 to December 2015 were retrospectively reviewed. The efficacy and the influence factors of sunitinib treatment was analyzed using the Kaplan-Meier method and Cox proportional hazards models. Results: In all 166 patients who received sunitinib as first-line treatment, objective response rate was 31.9%, disease control rate was 84.3%. The median progression free survival (PFS) and overall survival (OS) were 11.0 months (95% CI: 9.0-14.0) and 28.0 months (95% CI: 19.0-33.0), respectively. Multivariate analysis showed that pathological types (clear cell carcinoma vs non clear cell carcinoma, HR : 1.889 vs 2.353), time from diagnosis to treatment(<1 year vs ≥1 year, HR : 0.293 vs 0.322) and the number of metastatic sites (1 vs ≥1, HR : 2.360 vs 4.351) were the independent prognostic factors for PFS and OS ( P <0.05). Conclusions: The efficacy of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma is similar to reports at home and abroad. The patients with renal clear cell carcinoma, time from diagnosis to treatment> 1 year, and only one metastatic site would get better PFS and OS.

Objective: To evaluate the effect of Sunitinib therapy on immune function of patient with advanced renal cell carcinoma. Methods: A total of 27 patient with advanced renal cell carcinoma who received Sunitinib therapy in Chongqing Cancer Hospital from July 2010 to July 2014 were recruited in a prospective cohort study.Nineteen were male patients and 8 were female patients aged from 36 to 75 years with mean age of (58±7)years.Twenty-five cases were renal clear cell carcinoma, the other two cases were papillary renal cell carcinoma and Xp11.2 translocation renal cell carcinoma.According to MSKCC terminal prognosis scoring recommend by NCCN: 22 cases were in low risk, 5 cases were in high risk.All the patient took Sunitinib 50 mg orally once daily for 4 weeks, followed-up by 2 weeks.Flow cytometry was used to detect the levels of CD3 + , CD8 + , CD4 + T lymphocyte, NK cell and B lymphocyte in peripheral blood of patients before taking medicine.The levels of CD3 + , CD8 + , CD4 + T lymphocyte, NK cell, B lymphocyte in peripheral blood were detected again after 4 weeks, 6 weeks, 10 weeks and the disease progression.Paired t -test was used to analyze the data comparison of two groups, mean comparison in groups was conducted with repeated measurements analysis of variance, and the pairwise comparison was performed with LSD- t method. Results: The levels of CD3 + , CD8 + T lymphocyte, NK cell, B lymphocyte were significantly increased after the therapy of Sunitinib for 1 cycle(I-J was 212±22, 163±18, 59±12, 13.8±1.4, respectively, all P <0.05). The levels of CD3 + , CD8 + T lymphocyte, NK cell, B lymphocyte were significantly increased after the therapy of Sunitinib for 2 cycles(I-J was 362±43, 299±28, 91±19, 28.1±3.9, respectively, all P <0.05), while the level of CD4 + lymphocyte was decreased, but no significant difference( F =0.873, P >0.05). CD4 + /CD8 + was significantly decreased after the therapy of Sunitinib for 1 cycle, and it went on decreasing after the therapy of Sunitinib for 2 cycles(I-J was -0.31±0.03, -0.44±0.04, respectively, all P <0.05). Disease progression occurred in 10 cases during the follow-up period.The NK cell, CD3 + , CD4 + , CD8 + T lymphocyte were significantly decreased when the disease progressed( t =2.39-5.769, all P <0.05). Conclusions: Sunitinib has effect on the immune function of patients with advanced renal cell carcinoma, and the progression of renal cell carcinoma is related to the immune function.It suggests that targeted drug therapy should be combined with biological immunotherapy, which may be the research direction for the treatment of advanced renal cell carcinoma.

Objective: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) are widely used for the treatment of metastatic renal cell carcinoma (mRCC). The aim of this study was to investigate the association between treatment-related hypertension and the therapeutic efficacy of VEGFR-TKIs., Methods: Clinical data of 155 mRCC patients treated with VEGFR-TKIs at the Cancer Hospital of Chinese Academy of Medical Sciences from 2006 to 2014 were retrospectively analyzed. All patients received first-line TKI therapy. Among them, 69 patients were treated with sunitinib, 14 cases with pazopanib, and 51 cases with fazotinib. Kaplan-Meier curves were used to evaluate the survival of the patients., Results: The median survival for the whole group (n=155) was 36.2 months. Among the 98 (63.2%) patients who developed hypertension, 9 patients (5.8%) were evaluated as grade Ⅰ, 54 (34.8%) as grade Ⅱ and 35 (22.6%) as grade Ⅲ, and there was no patient with grade Ⅳ hypertension. The occurrence of TKI-related hypertension was correlated with age and MSKCC score (P<0.05), while not significantly correlated with gender, nephrectomy, T stage, number of metastases, lung metastasis or sunitinib treatment (P>0.05 for all). For the whole group (n=155), the therapeutic efficacy rate was 43.2% (67/155), the median progression-free survival (PFS) was 12.0 months, and the median overall survival (OS) was 36.2 months. The response rate (RR) was 26.3% (15/57) in patients with normal blood pressure and 53.1% (52/98) in patients with hypertension (P=0.001). The median PFS was 7.1 months in the cases with normal blood pressure and 13.8 months in patients with hypertension (P=0.032). The response rates were 33.3% (3/9), 51.9% (28/54) and 60.0% (21/35) in patients with grade Ⅰ, Ⅱ and Ⅲ hypertension (P=0.006). The median PFS was 7.1, 9.7, and 12.0 and 19.5 months in patients with normal blood pressure, and patients with grade Ⅰ, Ⅱ and Ⅲ hypertension, respectively (P=0.039). Both univariant and multivariant analyses indicated that treatment-related hypertension is an important predictive factor for the efficacy of VEGFR-TKIs therapy., Conclusions: Hypertension might be an effective predictive factor for efficacy of VEGFR-TKIs therapy in mRCC patients. Large-sample studies are warranted to further prove these results.

Objective: To determine the mechanism of sunitinib-induced autophagy in renal cell carcinoma cells., Methods: MTS assay was applied to detect the cell viability alteration under the treatment of sunitinib (2, 8 μmol/L). The sunitinib-induced autophagy as well as cell apoptosis was measured and compared after knocking down autophagy-related protein Beclin1 and microtubule associated protein 1 light chain 3 fusion protein (LC3) by RNA interference. The transmission electron microscope was used to observe the formation of autophagosomes in ACHN cells. The fluorescence microscope was used to monitor distribution and aggregation of endogenous LC3-II. The expressions of protein such as LC3-II, the autophagic regulation molecules protein kinase B/ mammalian target of rapamycin (Akt/mTOR) and the symbol of apoptosis poly ADP-ribose polymerase (PARP) were capable to be detected by immunoblotting assay., Results: Sunitinib was able to significantly trigger cell viability loss in the renal carcinoma cell ACHN, which was both in a concentration-dependent and time-dependent manner (P<0.05). After reducing the autophagy by knocking down Beclin1 and LC3, the number of cleavage of PARP was increased remarkably, whereas there was nearly not any cleavage in the mock group. By the transmission electron microscope, there were more autophagic vacuoles in ACHN cells after being administrated with sunitininb compared with the control. And the nuclear-to-cytosol translocation as well as aggregation of LC3-II was presented after sunitinib treatment by the fluorescence microscope, which was the proof of the enhanced autophagy. According to the immunoblotting, sunitinib was able to increase the accumulation of LC3-II . At the same time, the result of sunitinib combined with chloroquine, a drug which blocked the fusion of autophagosomes and lysosomes, demonstrated that the increasing amount of LC3-II was due to the enhanced autophagy flux by sunitinib treatment in ACHN cells. However, phosphorylation of Akt as well as mTOR was decreased at the same time. The rapamycin (mTOR inhibitor) or knocking down Akt subunits could change the sunitinib-induced LC3 -II accumulation, whereas overexpression of Akt subunits decreased the autophagic flux, indicating that Akt/mTOR was the target of sunitinib in autophagy., Conclusion: Sunitinib induced autophagy via suppressing Akt/mTOR pathway, and the autophagy was involved in apopotosis.

Objective: To investigate the expression of MEK/ERK signaling pathways in renal cell carcinoma with bone metastasis, and to analyze the differences of expressions of VEGFR-2, MEK, ERK on the primary and metastasis tissue and its mechanism., Methods: The tissue samples were obtained from 7 renal cell carcinoma patients kindly provided by Department of Urology, Peking University People's Hospital from January 1, 2009 to January 1, 2010. The expression of MEK/ERK signaling pathways was detected in the 7 renal cell carcinoma patients` primary and matched metastatic tissues with ICH, The antibody concentrations were 1:200, 1:25, and 1:250, respectively. The mutation of the twentieth exon of the PDGFRA gene, the second exon of the K-ras gene, the fifteenth exon of the Braf gene and the second exon of the MEK1 gene were detected with PCR., Results: The expression intensities of VEGFR-2, MEK, and ERK were measured by H-score [intensity (1, 2, 3, or 4) multiplied by the distribution (%)]. VEGFR-2, MEK, and ERK expressions were divided into 3 groups according to the positive distribution of the tumor cells: 1, 0-5%; 2, 6%-50%; and 3, >50%, To assess intratumor heterogeneity, three distinct microscopic fields (×200) from each specimen were used to evaluate the expressions, Subsequently, the scores were averaged to obtain a single concatenated score for each tissue. VEGFR-2, MEK, and ERK expressions were assessed by 2 independent pathologists who were blinded to the clinicopathological data. The data were expressed as the mean value of the triplicate experiments. The expressions of MEK, and ERK were higher in the metastatic tissues than in the matched RCC tissues (6.10±4.10 vs. 1.33±0.51, P=0.015; 9.10±2.24 vs. 4.43± 2.84, P=0.021) while the expression of VEGFR-2 was not different between the primary and metastatic tissues (P=0.901). No mutation was detected on the twentieth exon of the PDGFRA gene, the second exon of the K-ras gene, the fifteenth exon of the Braf gene and the second exon of the MEK1 gene., Conclusion: MEK/ERK signaling pathways may play an important role in the metastasis and the resistance of sunitinib in RCC patients with bone metastasis.

Objective: To investigate the effect of sunitinib on the expressions of co-stimulatory molecule ligands, programmed death ligand 1 (PD-L1), PD-L2, CD80, CD86, B7-H4 and herpes virus entry mediator (HVEM) on peripheral blood monocyte-derived dendritic cells (DCs) from patients with renal cell carcinoma (RCC)., Methods: Monocyte-derived DCs from patients with RCC were cultured in vitro and randomly divided into three groups: sunitinib combined with lipopolysaccharide (LPS), LPS only and dimethyl sulfoxide (DMSO) treatment. Sunitinib plus LPS group was pretreated with 200 ng/mL sunitinib for 12 hours followed by stimulated with 1 μg/mL LPS for 24 hours; LPS group was pretreated with 1 μL/mL DMSO for 12 hours and then stimulated with 1 μg/mL LPS for 24 hours; DMSO group was treated with 1 μL/mL DMSO for 36 hours. Morphological changes were observed by an inverted microscope. Flow cytometry was used to detect the expressions of PD-L1, PD-L2, CD80, CD86, B7-H4 and HVEM., Results: Sunitinib-LPS co-treated and LPS-treated cells had typical dendrites, while DMSO-treated cells had no obvious dendrites. Compared with the LPS-treated group, the expressions of CD80, PD-L1 and B7-H4 on DCs significantly decreased in the sunitinib-LPS group; the expressions of PD-L1, PD-L2, CD80, CD86, B7-H4 and HVEM were lower in the DMSO group., Conclusion: Sunitinib inhibits the expressions of CD80, PD-L1 and B7-H4 on DCs induced by LPS.

Objective: To investigate the effect of sunitinib on the migration of ovarian cells and its mechanism of the negative regulation TGF-β mediated of epithelial-mesenchymal transition(EMT) by sunitinib to inhibit ovarian cancer metastasis., Methods: The migration of human ovarian cancer cells SKOV3 was evaluated by wound-healing and transwell assays. The effects of sunitinib on TGF-β-induced E-cadherin expression was assessed by Western-blotting, real time RT-PCR and immunofluorescence assay. The protein levels of Snail and the transcriptional activity of Smad in sunitinib-treated cells were examined by Western-blotting and SBE-luciferase assay., Results: Sunitinib suppressed the migration of SKOV3 cells in a concentration-dependent manner. TGF-β stimulation reduced E-cadherin protein level, which was attenuated by sunitinib. Sunitinib inhibited the up-regulation of Snail protein level induced by TGF-β treatment. The SBE reporter was constructed by linking the Smad-binding elements promoter upstream of luciferase reporter gene. A remarkable increment of transcriptional activity of Smads complexes was observed in SKOV3 cells exposed to TGF-β, which was significantly prohibited by sunitinib., Conclusion: Sunitinib can inhibit the migration of SKOV3 cells and attenuate the down-regulation of E-cadherin protein level induced by TGF-β. Sunitinib can abolish TGF-β-induced up-regulation of Snail protein and decrease the transcriptional activity of Smad complexes. The results indicate that sunitinib suppresses migration of ovarian cancer cells through negative modulation of TGF-β-mediated epithelial-mesenchymal transition.

Objective: To investigate the efficacy and safety of sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) on a 2 weeks on/1 week off intermittent dosing schedule., Methods: A total of 11 mRCC patients were enrolled to receive sunitinib 50 mg/day in 2 weeks on/1 week off schedule per 6 weeks till disease progression or intolerable toxicity occurred. The primary end point was progression free survival (PFS), the secondary end points were overall survival (OS), incidence of adverse effects and objective response., Results: The objective response rate in the 11 cases was 45.5% and disease control rate 72.7% (partial response n = 5, stable disease n = 3). Till the last follow up on Dec 2013, the median PFS was 17.0 months (95% CI 7.3 to 26.7 months), and median OS 26.0 months (95% CI 2.2 to 49.8 months). The common adverse events included leucopenia, thrombocytopenia, diarrhea, mucositis and hand-foot skin reaction. Dose reduction to 37.5 mg was seen only in 2 patients without discontinuation., Conclusions: Sunitinib on an intermittent dosing schedule 2 weeks on /1 week off as first-line therapy for mRCC patients shows a good efficacy and tolerance, with less grade 3-4 drug-related toxicities and a tendency of prolonged PFS in mRCC patients.

The emergence of small molecular tyrosine kinase inhibitors opened the era of targeted therapy of gastrointestinal stromal tumor(GIST). Survival and life of quality of patients from advanced stage are significantly improved by using targeted therapy. However, with prolonged treatment, drug resistance is becoming more and more common and directly affects the survival of patients. The current clinical management in failure of multi-line targeted therapies will be discussed in this article.

Objective: To observe the changes of programmed death-1 ligand 1 (PD-L1) and PD-L2 expressions on mouse bone marrow-derived dendritic cells (DCs) stimulated by sunitinib., Methods: DCs were randomly divided into four groups which were treated with sunitinib (100, 200, 300 ng/mL) and dimethylsulfoxide (DMSO), respectively. After 48 hours, PD-L1 and PD-L2 expression levels were analyzed by flow cytometry., Results: Compared with the control group, the expression of PD-L1 on mature DCs (mDCs) and all DCs [including mature DCs and immature DCs (imDCs)] was significantly down-regulated in sunitinib treatment groups. The PD-L1 expression percentages of imDCs, mDCs and DCs were significantly reduced in sunitinib treatment groups; the percentage of mDCs expressing PD-L2 also dropped in all treatment groups, and the percentage of DCs expressing PD-L2 decreased in 100 and 300 ng/mL sunitinib treatment groups., Conclusion: Sunitinib can significantly reduce the expressions of PD-L1 and PD-L2 on mouse DCs.

Objective: To explore the genetic polymorphisms of PDGFR associated with thrombocytopenia in Chinese patients with metastatic clear-cell renal cell carcinoma (mcc-RCC) treated with sunitinib., Methods: A total of 93 mcc-RCC patients treated with sunitinib were enrolled. Genotype analyses were performed before treatment and thrombocytopenia was recorded on the first three cycles of treatment. Genetic polymorphisms of PDGFR (rs35597368, rs1800810) were analyzed for a possible association with thrombocytopenia., Results: The genotypes of rs35597368 and rs1800810 conformed to the Hardy-Weinberg law. No significant difference existed in grade 3/4 thrombocytopenia between rs35597368 TC and TT genotypes (29.6% vs 29.4%, P = 0.313). The rs1800810 CG genotype was associated with a higher risk for grade 3/4 thrombocytopenia as compared with CC genotype (45.8% vs 34.2%, P = 0.048)., Conclusions: The risk for grade 3/4 thrombocytopenia increases in the presence of allele genotype in PDGFR 1171C/G. And a biomarker may be customized for patients with mcc-RCC treated with sunitinib.

This study was aimed to investigate the effect of SU11248 on proliferation and apoptosis of leukemia cell line K562 in vitro and its mechanism. The inhibitory effect of 3.2 µg/ml SU11248 on K562 proliferation was tested by MTT assay. The ability of SU11248 to induce apoptosis of K562 cells was examined by TUNEL and DNA ladder. The expression of C-MYC, hTERT and BCR-ABL mRNA in K562 cells was detected by RT-PCR. The protein expression of Akt and p-Akt in K562 cells was detected by Western blot. The results showed that the proliferation of K562 cells was obviously inhibited by 3.2 µg/ml SU11248 in a time-dependent manner. SU11248 could induce K562 cells apoptosis in dose-and time-dependent manner. The mRNA expression of C-MYC, hTERT and BCR-ABL was reduced significantly by SU11248 in a time-dependent manner (P < 0.05). Western blot detection showed that the expression of p-Akt protein in K562 cells decreased in dose-and time-dependent manner after SU11248 treatment, but the expression of Akt was not significantly changed. It is concluded that SU11248 can inhibit the growth of K562 cells efficiently through inducing apoptosis, its mechanism may be closely relate with the expression down-regulation of C-MYC, hTERT, BCR-ABL and the inhibition of Akt phosphorylation.

Gastrointestinal stromal tumors(GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Most of these stromal tumors are characterized by mutations in the KTT or platelet-derived growth factor receptor α (PDGFRA) genes, resulting in the constitutive activation of tyrosine kinase signaling. Tyrosine kinase inhibitors(TKI), such as imatinib and sunitinib, provide the standard first-line and second-line therapy for patients with metastatic or unresectable GIST. Imatinib resistance has been a challenging problem in clinical practice and raised great concern. This review introduces the underlying mechanisms of imatinib resistance and advances of treatment strategies. Reasonable individual treatment with the guidance of molecular biology is promising to improve the efficacy and the quality of life for GIST patients.

Targeted therapy is the first line treatment for patients with recurrent/metastatic gastrointestinal stromal tumors(GIST). Sunitinib is effective for patients who have failed imatinib, specially with c-kit exon 9 gene mutation. Tyrosine kinase inhibitors combined with partial hepatectomy may increase the overall survival of GIST patients with liver metastasis. Selective patients with recurrent or metastatic GIST can benefit from surgical resection. Regorafenib and pazopanib can provide a significant improvement in progression-free survival in patients after failure of standard treatment.

Background and Objective: Advanced non-small cell lung cancer (NSCLC) is a common malignancy that is incurable. No standard treatment exists for recurrent patients. This article analyzed the efficacy and safety of sunitinib (37.5 mg qd) on a continuous daily dosing (CDD) schedule in treating recurrent advanced NSCLC., Methods: We retrospectively analyzed the short-term efficacy and toxicity of sunitinib CDD in treating 17 patients who had previously undergone multiple cycles of therapy for advanced NSCLC in our hospital from January 2011 to December 2012. Treatment-related survival was also analyzed., Results: Among the 17 patients, the best overall response was partial response in 1 patient (5.9%), stable disease in 7 patients (41.2%), and progressive disease in 9 patients (52.9%). The overall response rate was 5.9%, and the disease control rate was 47.1%. The median progression-free survival was 4.4 months (95%CI: 4.05-7.46). The main grade 3/4 toxicity was hand-foot skin reaction., Conclusion: Sunitinib (37.5 mg QD) CDD enabled good objective response in advanced NSCLC patients who had previously received multiple cycles of treatment and was well tolerated.

Objective: To explore the effect of toxicity of sunitinib on the clinical outcome of patients with advanced renal cell carcinoma (RCC) ., Methods: A total of 136 patients with advanced RCC were treated with sunitinib from 2008 to 2011. There were 91 males and 45 females with an average age of 56 years. Their 6-week therapy cycle was 4 weeks of sunitinib 50 mg daily followed by 2-week off-treatment (schedule 4/2). The median follow-up time was 15 months. Correlation between toxicities and overall survival (OS) was evaluated in a Cox model using log-transformed levels after adjusting for MSKCC model.Log-rank test and Cox proportional hazard model were used to assess the value of drug toxicity as the prognostic factors., Results: The increased hemoglobin on cycle 1 day 14 (HR:0.950, 95%CI:0.923-0.978) and the increased lymphocytes on cycle 1 days 28 and 42 (HR:0.405, 95%CI:0.203-0.809, HR:0.394, 95%CI:0.179-0.867) were significantly associated with OS (P adj = 0.001, 0.014 and 0.022 respectively). Hypertension class III/IV (HR:0.066, 95%CI:0.008-0.582), and the number of neutrophils screening and lymphocyte count ratio (HR:2.537, 95%CI:1.182-5.404) were the survival prognosis independent predictors., Conclusion: Early hematopoietic toxicities may potentially predict the outcomes of advanced RCC after a therapy of sunitinib.

Human protein tyrosine kinases play an essential role in carcinogenesis and have been recognized as promising drug targets. By the end of 2012, eight small molecule tyrosine kinase inhibitors (TKIs) have been approved by State Food and Drug Administration of China for cancer treatment. In this paper, the pharmacokinetic characteristics (absorption, distribution, metabolism and excretion) and drug-drug interactions of the approved TKIs are reviewed. Overall, these TKIs reach their peak plasma concentrations relatively fast; are extensively distributed and highly protein bound (> 90%); are primarily metabolized by CYP3A4; most are heavily influenced by CYP3A4 inhibitors or inducers except for sorafenib; are mainly excreted with feces and only a minor fraction is eliminated with the urine; and are substrate of the efflux transporters ABCB1 (P-gp) and ABCG2 (BCRP). Additionally, many of the TKIs can inhibit some CYP450 enzymes, UGT enzymes, and transporters. Gefitinib, erlotinib, dasatinib, and sunitinib are metabolized to form reactive metabolites capable of covalently binding to biomolecules.

Objective: To explore the hematologic adverse effects in patients with renal cell carcinoma treated with sunitinib., Methods: A total of 136 patients with advanced renal cell carcinoma were treated with sunitinib at our hospital from 2008 to 2011. There were 91 males and 45 females with an average age of 55.5 years. They received sunitinib in repeated 6-week cycles consisting of 4 weeks of sunitinib 50 mg per day followed by 2 weeks of treatment (schedule 4/2). The hematologic toxicities, collected at baseline and 14, 28, 42 (after a 2-week rest period) days, were graded according to the National Cancer Institute common terminology criteria for adverse events version 3.0. The paired Wilcoxon test was used to evaluate the kinetics of hematologic adverse effects at days 14, 28, and 42 post-treatment., Results: The hematologic toxicities included leukopenia (n = 91, 66.9%), neutropenia (n = 95, 69.8%), lymphopenia (n = 58, 46.2%), thrombopenia (n = 89, 65.4%) and hypohemoglobinemia (n = 48, 35.3%). Among them, 31 cases (22.8%) had the high-grade (including grades 3 and 4) toxicity of thrombopenia. There were depressions in hematopoietic cell populations including leukocytes, neutrophils, and platelets at days 14, 28 and 42 versus the baseline level (all P < 0.05). The median hemoglobin level transiently increased at days 14 and 28 (both P < 0.01) and returned to the level of baseline at days 42 (P = 0.754)., Conclusions: The incidence of hematologic adverse effects of sunitinib slightly varies with what have been observed in previous studies. And the incidence of high-grade toxicity of thrombocytopenia is higher than that reported in studies conducted in the US and Europe.

Objective: To investigate the efficacy and safety of sunitinib on the management of gastrointestinal stromal tumors (GIST) patients with imatinib resistance., Methods: Clinical data of 48 patients with imatinib-resistant GIST received sunitinib therapy from May 2008 to April 2012 in the Union Hospital of Fujian Medical University were analyzed retrospectively. Eighteen patients received 50 mg/d of sunitinib in a protocol of 4/2 (4 weeks on and 2 weeks off) [50 mg/d (4/2)], and 30 patients received a protocol of 37.5 mg of sunitinib continuous daily dose (37.5 mg/d CDD)., Results: The median duration of sunitinib administration of all the 48 patients was 56 weeks, and the short-term efficacy was evaluated at 24 weeks after the initial treatment according to the Choi criteria. The response rate was 27.1% (13/48), including 1 case with complete response (CR), 12 cases with partial response (PR), and 21 cases with stationary disease (SD). The disease control rate was 70.8% (34/48). The mean follow-up time of 48 patients was 89 weeks. The median progression-free survival (PFS) and overall survival (OS) were 48 weeks and 92 weeks respectively. Stratified analyses indicated that the median PFS of patients previously treated by imatinib 400 mg/d and >400 mg/d were 53 weeks and 35 weeks respectively (P=0.018), and the median OS of these two groups were 157 weeks and 71 weeks respectively (P=0.003). Patients with exon 11 mutations had a significantly shorter OS compared with those with exon 9 mutations (71 weeks vs 157 weeks, P=0.008). Hand-foot syndrome was the most common adverse effect (25/48, 52.1%), followed by nausea (24/48, 50.0%), fatigue (23/48, 47.9%), neutropenia(21/48, 41.7%). The sub-group analysis of two protocols of sunitinib administration showed that the incidence of diarrhea and hand-foot syndrome were higher in 50 mg/d (4/2) group than those in 37.5 mg/d CDD group (P=0.027, P=0.048)., Conclusions: Sunitinib is effective for the patients with imatinib-resistant GIST. After 400 mg/d imatinib treatment failure, sunitinib should be prescribed instead of increased dosage of imatinib. Patients with KIT exon 9 mutations present better prognosis than those with KIT exon 11 mutations. The protocol of sunitinib 37.5 mg/d CDD possesses better safety.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the GI tract. Aberrant activation of tyrosine kinase through mutated KIT or platelet-derived growth factor receptor (PDGFRA) is the key pathogenic factor in most cases. Tyrosine kinase inhibitors (TKI) such as imatinib and sunitinib can suppress activation of tyrosine kinase receptor and has gained wide recognition as the first-line adjuvant therapy for advanced or high-risk GIST after surgery. It has become the classic model of treatment for solid tumor with molecular targeted therapy. However, the emergence of drug-resistance limits the long-term benefit of these drugs in most patients and has been a challenging clinical concern. Many factors are related to the resistance of TKI, of which KIT/PDGFRA mutation is the most important one. Genetic amplification of KIT, loss of heterozygosity, activation of an alternative downstream signaling pathways, and drug concentration are all possible factors. Therefore, reasonable individual treatment strategy and early resistance evaluation for imatinib- and sunitinib-resistant GISTs are important to patients with drug resistance in order to improve therapeutic efficacy and quality of life.

Objective: To observe the preliminary efficacies and adverse events of sunitinib in the treatment of metastatic breast cancer ulcer., Methods: From December 2008 to May 2010, patients with advanced breast cancer ulcer took a single sunitinib. The dosage was adjusted on the basis of adverse events. And clinical response was evaluated., Results: Nine patients with advanced breast cancer ulcer finished the treatment. The objective response and the clinical benefit time to progression of sunitinib were 3 and 7 patients with metastatic breast cancer ulcer, and the median time to progression (TTP) was 2.0 months. The most common adverse events included fatigue, hand-foot syndrome, neutropenia, thrombocytopenia and hypertension., Conclusion: Single-agent sunitinib treatment of refractory advanced breast cancer ulcer has marked efficacies. However, neutropenia, thrombocytopenia and hypertension are the major dose-limited toxicities.

Objective: To investigate the effect of sunitinib malate (SU11284) on proliferation of nasopharyngeal carcinoma cell line CNE-2 and explore its mechanism., Methods: Nasopharyngeal carcinoma cell line CNE-2 was treated with SU11248 in vitro, and the change in the proliferation of CNE-2 cell line was observed by MTT assay; Real-time fluorescence quantitative PCR (FQ-PCR) and Western blotting were used to detect the levels of P27(KIP1);, cyclin G1 mRNA and protein in CNE-2 cells after treated with 2.5 μg/mL SU11284 for different durations., Results: SU11248 inhibited the proliferation of CNE-2 cells in a concentration- and time-dependent manner. The 50% inhibiting concentration (IC50) was 2.5 μg/mL. Moreover, SU11248 treatment concentration-dependently decreased cyclin G1 mRNA and protein expressions (P<0.05), in contrast, it time-dependently increased P27(KIP1); mRNA and protein levels (P<0.05)., Conclusion: SU11248 may significantly inhibit the proliferation of CNE-2 cells through up-regulating P27(KIP1); and down-regulating cyclin G1.

Objective: To investigate the relationship between secondary mutations of c-kit/PDGFRα resistance to imatinib mesylate and the efficacy of sunitinib in patients with gastrointestinal stromal tumor (GIST)., Methods: Five pairs specimens were collected before and after imatinib mesylate resistance. DNA for molecular genetic investigation was extracted from formalin-fixed, paraffin-embedded tissues. Mutational analysis was performed by using PCR and direct sequencing., Results: Five pairs of specimens were collected before and after imatinib mesylate resistance from 5 GIST patients. C-kit exon 11 mutations were detected in 3 patients, which were all acquired mutations, including c-kit exon 13 V654A, c-kit exon 13 V654E and c-kit exon 17 N822K, after imatinib mesylate resistance. Furthermore, after sunitinib treatment, 3 patients had stable disease and progression free survival (PFS) were 3.5 months, 4.4 months and 3.8 months, respectively. C-kit exon 9 mutations were detected in 2 patients with no acquired mutations after imatinib mesylate resistance. And the both had partial response from sunitinib, following with 13.1 months and 12.0 months PFS respectively., Conclusion: The c-kit/PDGFRα genotypes after imatinib mesylate resistance may both relate to primary mutations and efficacy of sunitinib treatment.

Gastrointestinal stromal tumor(GIST) originates from interstitial cells of Cajal(ICCs). Tyrosine kinase inhibitors(TKI) such as imatinib and sunitinib, are effective agents besides surgery. However some GIST can become primarily or secondarily resistant to those drugs. The difference in gene mutation types and secondary gene mutation is the main cause. When the GIST is proved to be drug resistance, reasonable personal treatment strategies based on individualized medicine should be made to improve outcomes and quality of life.