Preclinical evaluation of sunitinib as single agent or in combination with chemotherapy in nasopharyngeal carcinoma
ABSTRACT Sunitinib is a multi-target receptor tyrosine kinase (RTK) inhibitor against vascular endothelial growth factor receptors, platelet-derived growth factor receptors (PDGFR), c-kit and RET. Several of these RTKs are known to be involved in the progression of nasopharyngeal carcinoma (NPC). Here, we evaluated the preclinical activities of sunitinib in NPC.
We determined the basal level of total and phosphorylated PDGFR, c-kit and RET by immunoblotting in a panel of five NPC cell lines. The effect of sunitinib on NPC cell proliferation was evaluated by MTT assay. We further studied the effect of sunitinib on NPC cell cycle progression and apoptosis. We investigated the in vitro and in vivo activities of sunitinib as single agent and in combination with cisplatin or docetaxel in NPC cell lines and tumor xenografts.
Sunitinib exhibited dose-dependent growth inhibition in all NPC cell lines tested with IC(50) between 2-7.5 μM and maximum inhibition of over 97%. Sunitinib induced apoptosis and cell cycle arrest at G(0)/G(1) phase. In vitro, sunitinib moderately enhanced the growth inhibition of cisplatin or docetaxel. Single agent sunitinib demonstrated significant growth inhibition, reduced microvessel density and caused extensive tumor necrosis in a NPC xenograft model. However, concurrent administration of sunitinib and docetaxel induced severe toxicity in mice without enhanced antitumor effect.
Single agent sunitinib demonstrated potent in vitro and in vivo growth inhibition in NPC. When combined with chemotherapy, sequential instead of concurrent administration schedule should be further explored.
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ABSTRACT: Stabilized biocompatible superparamagnetic iron oxide nanoparticles (SPIONs) were prepared by controlled coprecipitation method for hyperthermia application. ESR measurements determined that all of the interactions in the individual SPIONs (1 nm and 11 nm) were antiferromagnetic in nature because the ions contributed to the magnetization with a range of magnetic moments. In-situ monitoring of the temperature increment was performed, showing that the microwave absorption rate of the SPIONs was dispersed in an appropriate host media (polar or non-polar solvents) during microwave irradiation. Microwave absorption energy rates and heat loss of SPIONs in solvent were calculated by non-linear data fitting with an energy balance equation. The microwave absorption rates of SPIONs dispersed in solvent linearly increases when the concentration of SPIONs increases, implying that the microwave absorption rate can be tunable by changing the concentration of SPIONs.Journal of the Korean Ceramic Society 11/2011; 48(6). DOI:10.4191/kcers.2011.48.6.577 · 0.27 Impact Factor
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ABSTRACT: Nasopharyngeal carcinoma (NPC) is endemic in Southern China, and the South-East Asia including Hong Kong. We still see patients recur after primary treatment with radiotherapy or chemo-irradiation. Management of nasopharyngeal carcinoma remains one of the biggest clinical challenges. There have been breakthroughs in early detection, diagnosis, multi-modality treatment and also disease monitoring for NPC. Systemic treatment has been crucial to the management of locally advanced or metastatic NPC. With the advent of molecular targeted therapy and personalized medicine, novel therapies based on molecular targets of NPC have become the focus of research and development over the last decade. Furthermore, as NPC is tightly associated with the Epstein-Barr virus (EBV) infection, the role of tumor-associated viral antigens in NPC renders it an appealing candidate for cellular immunotherapy. This is a review of recent evolving concerted efforts and the success from our translational research with focus of the recent systemic novel targeted therapies including the potential role of immunotherapy which may offer further clinical benefit to our patients living with NPC. The scientific basis and latest published results of the relevant clinical trials are highlighted, demonstrating the ongoing battle against NPC is indeed one of the most fascinating successes in head and neck oncology.Oral Oncology 01/2014; DOI:10.1016/j.oraloncology.2014.01.002 · 3.03 Impact Factor
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ABSTRACT: The aim of this paper is to analyse sunitinib malate in vitro ability to enhance cisplatin cytotoxicity in T24, 5637, and HT1376 human urinary bladder-cancer cell lines. Cells were treated with cisplatin (3, 6, 13, and 18 μ M) and sunitinib malate (1, 2, 4, 6, and 20 μ M), either in isolation or combined, over the course of 72 hours. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, acridine orange, and monodansylcadaverine staining and flow cytometry were performed. The combination index (CI) was calculated based on the Chou and Talalay method. In isolation, cisplatin and sunitinib malate statistically (P < 0.05) decrease cell viability in all cell lines in a dose-dependent manner, with the presence of autophagic vacuoles. A cell cycle arrest in early S-phase and in G0/G1-phase was also found after exposure to cisplatin and sunitinib malate, in isolation, respectively. Treatment of urinary bladder-cancer cells with a combination of cisplatin and sunitinib malate showed a synergistic effect (CI < 1). Autophagy and apoptosis studies showed a greater incidence when the combined treatment was put into use. This hints at the possibility of a new combined therapeutic approach. If confirmed in vivo, this conjugation may provide a means of new perspectives in muscle-invasive urinary bladder cancer treatment.11/2013; 2013:791406. DOI:10.1155/2013/791406