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Christensen, J. G. A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Ann. Oncol. 18 (Suppl. 10), x3-x10

Pfizer Global Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
Annals of Oncology (Impact Factor: 6.58). 10/2007; 18 Suppl 10(suppl 10):x3-10. DOI: 10.1093/annonc/mdm408
Source: PubMed

ABSTRACT Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor that targets both angiogenic pathways (i.e., vascular endothelial growth factor receptor and platelet-derived growth factor receptor) and direct pro-oncogenic pathways (e.g., stem-cell factor receptor and FMS-like tyrosine kinase-3). Preclinical studies with this agent have indicated that it exhibits robust inhibitory activity against these targets. Clinical trial results have demonstrated the therapeutic potential of this agent and have implicated sunitinib targets in the pathophysiology of malignancies such as renal cell carcinoma and gastrointestinal stromal tumour. This paper reviews the preclinical data supporting the development of this agent and its translation from benchtop to bedside. It also highlights the importance of the multiple pathways that may be involved in cancer progression and the importance of these pathways in selected malignancies.

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    • "The RET tyrosine kinase becomes activated by this rearrangement, leading to constitutively activated MAPK signaling and tumorigenesis in thyroid cells [4]. Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, acts as an inhibitor of RET and exhibits some efficacy in these tumor types [53]. "
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    ABSTRACT: Thyroid cancer is an endocrine malignancy with an incidence rate that has been increasing steadily over the past 30 years. While well-differentiated subtypes have a favorable prognosis when treated with surgical resection and radioiodine, undifferentiated subtypes, such as anaplastic thyroid cancer (ATC), are far more aggressive and have a poor prognosis. Conventional therapies (surgical resection, radiation, chemotherapy, and radioiodine) have been utilized for treatment of ATC, yet these treatments have not significantly improved the overall mortality rate. As cancer is a genetic disease, genetic alterations such as mutations, fusions, activation of oncogenes, and silencing of tumor suppressors contribute to its aggressiveness. With the use of next-generation sequencing and the Cancer Genome Atlas, mutation-directed therapy is recognized as the upcoming standard of care. In this review, we highlight the known genetic landscape of ATC and the need for a comprehensive genetic characterization of this disease in order to identify additional therapeutic targets to improve patient outcomes.
    Journal of Oncology 09/2014; 2014:936285. DOI:10.1155/2014/936285
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    • "Meanwhile, the indirect inhibitors of angiogenesis interfere in the pro-angiogenic communication between the tumor cells and the endothelial cells (Folkman et al., 1998). SU5416 is a tyrosine kinase lipophilic synthetic inhibitor (TKI), indirect inhibitor of angiogenesis that blocks the phosphorylation of VEGF receptor, and has potent antiangiogenic properties in preclinical studies (Fong et al., 1999; Abdollahi et al., 2003; Christensen, 2007). On the other hand, the TNP-470 direct angiogenesis inhibitor, a fumagillin analog , has a potent cytostatic action in endothelial cells and also significant antitumor properties (Masiero et al., 1997; Folkman, 2005). "
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    ABSTRACT: The aim of this study was to evaluate the structural and molecular effects of antiangiogenic therapies and finasteride on the ventral prostate of senile mice. 90 male FVB mice were divided into: Young (18weeks old) and Senile (52weeks old) groups; Finasteride group: Finasteride (20mg/kg); SU5416 group: SU5416 (6mg/kg); TNP-470 group: TNP-470 (15mg/kg,) and SU5416+TNP-470 group: similar to the SU5416 and TNP-470 groups. After 21days, prostate ventral lobes were collected for morphological, immunohistochemical and Western Blotting analyses. The results demonstrated atrophy, occasional proliferative lesions and inflammatory cells in the prostate during senescence, which were interrupted and/or blocked by treatment with antiangiogenic drugs and finasteride. Decreased AR and Endostatin reactivities, and an increase for ER-α, ER-β and VEGF were seen in the senile group. Decreased VEGF and ER-α reactivities and increased ER-β reactivity were verified in the finasteride, SU5416 groups and especially in SU5416+TNP-470 group. The TNP-470 group showed reduced AR and ER-β protein levels. The senescence favored the occurrence of structural and/or molecular alterations suggesting the onset of malignant lesions, due to the imbalance in the signaling between the epithelium and stroma. The SU5416+TNP-470 treatment was more effective in maintaining the structural, hormonal and angiogenic factor balance in the prostate during senescence, highlighting the signaling of antiproliferation via ER-β.
    Life sciences 05/2014; DOI:10.1016/j.lfs.2014.04.027 · 2.30 Impact Factor
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    • "It is well known that the pivotal process of tumor growth and metastasis is angiogenesis. In clinical, more and more anti-angiogenesis drugs have been developed to control this process [23,24]. Angiogenesis is a complex process and its mechanisms still remain unclear. "
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    ABSTRACT: Background EPCs were isolated primarily in 1997 by Asahara et al. and recent studies indicated that bone-marrow-derived EPCs contributed little to the endothelium of tumor vessels. Tumors of the CNS system demonstrate various features of angiogenesis. Methods EPCs derived from rat bone marrow were isolated and cultured in M199 medium without any induced factors. EPCs were studied using immunohistochemical staining, Flow cytometry and culture under three-dimensional condition to determine EPCs’ characteristics in vitro. We also established an animal model by injecting EPCs marked with Hoechst 33342 into the back of BALB/c nude mice and performed hematoxylin-eosin (HE) and immunofluorescent staining to study EPCs’ features in vivo. To research effect of EPCs on glioma, animals bearing tumors model with C6 glioma were established. About 27 day after injection, we performed immunohistochemical staining and Immunofluorescence staining. Results Our results showed that EPCs derived from rat bone marrow appeared typical morphological characteristics and were positive of CD34, CD133, KDR and CD31 antigens at different time in vitro under the special M199 medium without any induced factors. The percentage of cells that expressed CD133 decreased gradually. In brief, the present study showed that EPCs derived from rat bone marrow differentiated into ECs in medium the without any induced factors and formed tubular structures in three-dimensional circumstances. Animal experiments suggested that EPCs differentiated into ECs and other else non-endothelial cells, and that EPCs contributed M199 of glioma. Discussion These findings provides some novel results about biological characteristics of EPCs in vivo and ex vivo, and an update on the effect of EPCs on glioma and which would be helpful for the overall understanding of EPCs and make EPCs to be implied on the clinical therapy.
    Cancer Cell International 06/2012; 12(1):32. DOI:10.1186/1475-2867-12-32 · 1.99 Impact Factor
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