A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities

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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    • "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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    • "Finally, increased visible lung surface nodules and lung weight were indicative of increased tumor burden in both tumor models, with representative hematoxylin and eosin (H&E) and anti-vimentin staining shown in Figure 3D. Since previously published studies had demonstrated potent tumor growth inhibition of established primary tumors in mice after sunitinib treatment (Christensen, 2007), we compared short-term and sustained sunitinib therapies in both orthotopic primary tumor and experimental metastasis models. 231/LM2-4 LUC+ cells were implanted into the mammary fat pad of nu/nu mice and treated "
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    ABSTRACT: Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible "metastatic conditioning" in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.
    Cancer cell 04/2009; 15(3):232-9. DOI:10.1016/j.ccr.2009.01.021 · 23.89 Impact Factor
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    ABSTRACT: One significant toxicity associated with the anticancer tyrosine kinase inhibitors (TKIs) is hand-foot skin reaction (HFSR). We provide an overview of HFSR, emphasizing experience-based prevention techniques and nursing management strategies from the viewpoints of a medical oncologist, a dermatologist, and an oncology nurse. Supporting data include (1) published preclinical and phase I-III clinical studies and (2) published abstracts of phase II-III clinical trials of sorafenib and sunitinib. HFSR has been reported in up to 60% of patients treated with sorafenib or sunitinib. TKI-induced HFSR may lead to dose reductions or treatment interruptions and reduced quality of life. Symptoms of TKI-associated HFSR can be managed by implementing supportive measures and aggressive dose modification. Patients educated about HFSR can work with their health-care teams to proactively detect and help manage this cutaneous toxicity, thus preventing or reducing the severity of TKI-associated HFSR. Successful prevention and management of TKI-associated HFSR can help to ensure that patients achieve optimal therapeutic outcomes. Implementation of such measures may increase the likelihood that therapy is continued for the appropriate interval at an appropriate dose for each patient. Optimal management of TKI-associated HFSR is predicated on establishing appropriate partnerships amongmedical oncologists, dermatologists, oncology nurses, and patients.
    The journal of supportive oncology 01/2011; 9(1):13-23. DOI:10.1016/j.suponc.2010.12.007
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