Sunitinib

Abstract

Sunitinib is an oral oxindole multitargeted kinase inhibitor that inhibits certain receptor tyrosine kinases (RTKs). These include vascular endothelial growth factor receptors (VEGFR type 1 and 2), platelet-derived growth factor receptors (PDGFR-alpha and PDGFR-beta), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 (FLT3), glial cell-line derived neurotrophic factor receptor (RET) and the receptor of macrophage-colony stimulating factor (CSF1R). Examination of the antitumor effect of sunitinib in a variety of cell lines in vitro suggested an antiproliferative activity that is dependent on the presence of constitutively active RTK targets. The use of sunitinib as first-line therapy in advanced renal cell carcinoma (RCC) has improved the overall survival compared with that observed after cytokine therapy, while its administration in patients with gastrointestinal stromal tumors (GISTs) after progression or intolerance to imatinib achieved an objective response of 7%. Sunitinib is currently approved for the treatment of GISTs in this setting, and as first-line therapy for the treatment of advanced RCC. The relatively long half-life of sunitinib and its major metabolite allow for a once-daily dosing schedule. An interesting antitumor activity of sunitinib was reported in phase II studies of patients with a variety of malignancies, such as hepatocellular cancer, pancreatic neuroendocrine tumors, and non-small cell lung cancer; results of phase III studies are urgently anticipated. Fatigue is one of the most common adverse effects of sunitinib, as 50-70% of patients with advanced RCC and GIST complained of this adverse effect. Other adverse effects are diarrhea, anorexia, nausea and vomiting, oral changes and bleeding events. Most toxicities are reversible and should not result in discontinuation of sunitinib. If necessary, dose adjustments or interruptions should be made. Hypothyroidism has been described in the first 2 weeks of sunitinib therapy and its incidence increases progressively with the duration of therapy. Sunitinib may exert its hypertensive activity through a direct effect on the vasculature, while its most important cardiac adverse effect is left ventricular dysfunction. A variety of skin adverse effects have been described with the use of sunitinib such as hand-foot syndrome, yellow discoloration of the skin, dry skin, subungual splinter hemorrhages, acral erythema, and generalized skin rashes. Administration of sunitinib in the adjuvant and neoadjuvant setting of patients with RCC and of its combination with chemotherapy and other targeted therapies are currently under intense investigation.

DCE-MRI of hepatocellular carcinoma: perfusion quantification with Tofts model versus shutter-speed model—initial experience

“…Zhu et al [22] found a baseline K trans distribution for HCC between 1.25 and 2.50 min −1 and k ep ranging between 1.5 and 3.0 min −1 using DCE-MRI for 34 patients enrolled in a phase II study of multitargeted kinase inhibitor sunitinib [62]. Hsu et al [23] reported baseline K trans between 0.4 and 4.5 min −1 in 31 patients with advanced HCC treated with sorafenib plus tegafur/uracil that underwent a DCE-MRI examination.…”

Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees

“…Sunitinib is a small molecule, able to inhibit a multiplicity of TK receptors including the platelet-derived growth factors PDGFRα/β, the colony stimulating factor type I (CSF-1R), the vascular endothelium growth factor (VEGFR), the stem cell factor c-KIT, and the fetal liver TK receptor 3 (FLT3) amongst others (Faivre et al, 2006; Papaetis and Syrigos, 2009). Owing to this ability to inhibit diverse multiple TK receptors, sunitinib has shown capacity to arrest angiogenesis, metastasis and tumor progression (van Erp et al, 2009).…”

Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition

“…Therefore, we wanted to investigate the effects of agents that have been shown to interfere with the activity of such receptor pathways. Sorafenib and sunitinib have been shown to inhibit the activity of a number of cytokine receptors, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (c-Kit) and FMS-like tyrosine kinase-3 (Flt-3) [13,14]. In the next set of experiments, the three AT/RT cell lines were evaluated for sensitivity to sorafenib and sunitinib by in vitro cytotoxicity assays.…”