Abstract
BackgroundIncreased exposure to multitargeted kinase inhibitor sunitinib is associated with improved outcome, emphasizing the importance of maintaining adequate dosing and drug levels. The currently approved schedule (50 mg daily, four weeks on, two weeks off) precludes further dose-intensification. Recent data suggest that sunitinib, although initially developed as an antiangiogenic agent, has direct antitumor activity.MethodsIn this study, we tested whether a chemotherapy-like schedule of pulsatile high dose sunitinib would result in improved antitumor activity.ResultsIn vitro, a single exposure to 20 μM sunitinib for 6-9 h resulted in complete inhibition of tumor cell growth and cell death conveyed through activation of caspases and autophagy upregulation. Notably, repeated exposure of tumor cells to pulses of high concentrations of sunitinib did not induce resistance. In vivo, once-weekly treatment with high dose sunitinib of tumors growing on the chorioallantoic membrane (CAM) of the chicken embryo significantly impaired tumor growth by 57 % compared to vehicle, outperforming the daily, standard scheduling.ConclusionsThese results prompted the initiation of a phase I clinical trial, where intermittent, high dose sunitinib is being investigated in patients with advanced solid tumors (registration number and date: NCT02058901, 30 September 2013, respectively). The trial is actively recruiting patients and promising preliminary indications of antitumor activity have been observed.
Highlights
Increased exposure to multitargeted kinase inhibitor sunitinib is associated with improved outcome, emphasizing the importance of maintaining adequate dosing and drug levels
High dose sunitinib inhibits tumor cell proliferation The 786-O renal cancer cell line was exposed to various concentrations of sunitinib (5, 10 and 20 μM) for time intervals ranging from 1 h to 1 week
We show that sunitinib in this pulsatile scheduling was a potent inhibitor of cell proliferation in this scheduling
Summary
Increased exposure to multitargeted kinase inhibitor sunitinib is associated with improved outcome, emphasizing the importance of maintaining adequate dosing and drug levels. The introduction of tyrosine kinase inhibitors (TKIs) elicited remarkable therapeutic responses in malignancies previously regarded as chemoresistant [2] Despite these important strides, the field of TKIs faces significant challenges, spanning from low response rates and Sunitinib malate, (SUTENT; Pfizer, New York, NY), an orally administered TKI, targets multiple receptors, including the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). The field of TKIs faces significant challenges, spanning from low response rates and Sunitinib malate, (SUTENT; Pfizer, New York, NY), an orally administered TKI, targets multiple receptors, including the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) It has already been approved for the treatment of advanced renal cell cancer (RCC), gastrointestinal. Sunitinib was developed as an antiangiogenic agent, the drug has been shown to exert direct anti-tumor activity [14]
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