semaxinib and Nasopharyngeal-Neoplasms

Photodynamic therapy (PDT) is a promising therapeutic modality using a tumor localizing photosensitizer and light to destroy tumor cells. A major limitation of PDT is tumor recurrence, which is partly due to neovascularization.. The objective of the present study was to determine whether combination therapy with PDT and antiangiogenic agents (i.e. SU5416 and SU6668) would be more effective in controlling tumor recurrence in a mouse model of human CNE2 poorly differentiated nasopharyngeal carcinoma compared with PDT or antiangiogenic agents administered alone.. Athymic mice bearing CNE2 tumor xenografts received daily i.p. injections of 20 mg/kg SU5416 or 100 mg/kg SU6668 for 28 consecutive days either alone or following a single hypericin-PDT treatment.. Significant inhibition of CNE2 tumor growth was observed in all treatment groups. Differences in 4x tumor growth time, the number of mice with 4x tumor growth, tumor growth inhibition as well as the percent of mice surviving were not statistically significant among individual treatment groups. However, the number of mice with 4x tumor growth observed in SU6668 monotherapy and combined PDT and SU6668 treatment groups was significantly less than that in the control group (P<0.05 and 0.01, respectively). Moreover, compared with the control group, only the combined PDT and SU6668 treatment significantly extended survival of tumor-bearing host mice (P<0.05). The semiquantitative RT-PCR results showed that the expression of HIF-1alpha, VEGF, COX-2 and bFGF were increased in PDT-treated tumor samples collected 24 h post-PDT, suggesting that PDT-induced damage to tumor microvasculature and the resultant hypoxia upregulate the expression of certain proangiogenic factors.. The effectiveness of PDT can be enhanced by antiangiogenic treatment with the synthetic RTK inhibitors. Of the two synthetic RTK inhibitors tested, SU6668 was more effective than SU5416 in enhancing tumor responsiveness to PDT.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Anthracenes; Antineoplastic Agents; Chemotherapy, Adjuvant; Drug Screening Assays, Antitumor; Gene Expression; Indoles; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Neoplasms; Neoplasm Transplantation; Neoplasms, Experimental; Oxindoles; Perylene; Photochemotherapy; Propionates; Protein-Tyrosine Kinases; Proteins; Pyrroles; Survival Rate

Juvenile nasopharyngeal angiofibroma (JNA) is a benign tumor that presents in adolescent males. Although surgical excision is the mainstay of treatment, recurrences complicate treatment. There is a need to develop less invasive approaches for management. JNA tumors are composed of fibroblasts and vascular endothelial cells. We identified fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor (VEGF) expression in JNA-derived fibroblasts. FGFR influences fibroblast proliferation and VEGF is necessary for angiogenesis. We hypothesized that targeting FGFR would mitigate JNA fibroblast proliferation, invasion, and migration, and that targeting the VEGF receptor would attenuate endothelial tubule formation.. After informed consent, fibroblasts from JNA explants of 3 patients were isolated. Fibroblasts were treated with FGFR inhibitor AZD4547, 0 to 25 μg/mL for 72 hours and proliferation was quantified using CyQuant assay. Migration and invasion of JNA were assessed using 24-hour transwell assays with subsequent fixation and quantification. Mitigation of FGFR and downstream signaling was evaluated by immunoblotting. Tubule formation was assessed in human umbilical vein endothelial cells (HUVECs) treated with vehicle control (dimethylsulfoxide [DMSO]) or semaxanib (SU5416) as well as in serum-free media (SFM) or JNA conditioned media (CM). Tubule length was compared between treatment groups.. Compared to control, AZD4547 inhibited JNA fibroblast proliferation, migration, and invasion through inhibition of FGFR and downstream signaling, specifically phosphorylation of - p44/42 mitogen activated protein kinase (p44/42 MAPK). JNA fibroblast CM significantly increased HUVEC tubule formation (p = 0.0039).. AZD4547 effectively mitigates FGFR signaling and decreases JNA fibroblast proliferation, migration, and invasion. SU5416 attenuated JNA fibroblast-induced tubule formation. AZD4547 may have therapeutic potential in the treatment of JNA.

Topics: Angiofibroma; Antineoplastic Agents; Benzamides; Cell Movement; Cell Proliferation; Cells, Cultured; Fibroblasts; Human Umbilical Vein Endothelial Cells; Humans; Indoles; Nasopharyngeal Neoplasms; Piperazines; Pyrazoles; Pyrroles; Receptors, Fibroblast Growth Factor; Receptors, Vascular Endothelial Growth Factor