Abstract
Angiogenesis is initiated by the activation of the vascular epidermal growth factor receptor-2 (VEGFR-2) by the vascular epidermal growth factor (VEGF) ligand. Overexpression of VEGFR-2 increases the growth of nasopharyngeal carcinomas (NPC). Apatinib (YN968D1) is a highly-selective inhibitor of VEGFR-2, but its effects on NPC have not been hitherto investigated. In the present study, CNE-2 NPC cells were xenografted into 132 nude mice, which were treated with one of 6 drug regimens of apatinib administered alone or in combination with cisplatin (DDP). The impact of treatment regimens on the growth, microvascularization, apoptosis, and metabolic response of tumors, as well as mouse survival was determined by histopathology, immunohistochemistry (VEGFR-2 and CD31), terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL), micro 18F-FDG PET/CT imaging and survival curves. Administration of apatinib alone inhibited tumor growth, reduced microvascular density, and facilitated the apoptosis of tumors. Tumors treated simultaneously with apatinib and cisplatin exhibited significantly-increased inhibition of tumor growth, prolonged survival time, decreased expression of VEGFR-2, reduced microvascular density, and frequency of apoptosis over standalone and sequential administration therapy. Tumors treated simultaneously with apatinib and cisplatin had the lowest uptake of FDG. Taken together, the simultaneous administration of apatinib and cisplatin improves the therapeutic efficacy over standalone treatments, which also led to improved efficacy over sequential administration regimens. VEGFR-2 is an important predictive marker for efficacy of apatinib treatment of NPC.
Highlights
Nasopharyngeal carcinoma (NPC) has a high incidence in southern China, Southeast Asia, and North Africa [1]
Whilst apatinib modestly inhibited the growth of CNE-2 xenografted nasopharyngeal carcinomas (NPC) tumors, treatment with a combination of apatinib and cisplatin significantly inhibited tumor growth, more so than that obtained by the two drugs administered alone(P < 0.05)
We show that vascular epidermal growth factor receptor-2 (VEGFR-2) is a predictive marker for the use of apatinib for NPC treatment, by discriminating patients who are most likely to benefit from apatinib from those that would be exposed unnecessarily to its toxicity [22]
Summary
Nasopharyngeal carcinoma (NPC) has a high incidence in southern China, Southeast Asia, and North Africa [1]. Almost 20% of NPC patients with locally-advanced disease present with distant metastases at diagnosis, which is the main cause of treatment failure of NPC [2]. Chemotherapy is an important treatment modality for patients with advanced nasopharyngeal carcinoma. ; the relativelyhigh efficacy of chemotherapies has not translated to an improvement in the survival rates of patients with advanced NPC, and the side effects of such treatments may exacerbate the prognosis [3,4]. The demand for novel drugs, and targeted therapies in particular, is high, with a view to improving the survival of, and reducing the side effects within, patients with advanced NPC undergoing chemotherapy.
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