Purpose-Cutaneous squamous cell carcinoma (CSCC) is the second most common nonmelanoma skin cancer. The majority of the ~250,000 cases occurring annually in the United States are small, non-aggressive, and cured by excision alone. However, a subset of these tumors which are defined by poorly differentiated histology, large tumor size, invasion of adjacent structures and/or regional metastases can prove resistant to treatment despite adjuvant radiotherapy and have increased risk of recurrence and nodal metastasis. Novel therapeutic approaches are necessary to improve outcomes for patients with aggressive CSCC.Experimental Design-We analyzed the effect of targeted therapy on the growth and survival of CSCC cell lines using an anti-IGF-IR antibody, A12, alone or in combination with an anti-EGF-R antibody, cetuximab, both in vitro and in vivo in an athymic nude mouse model of CSCC.
Results-Treatment with A12 and cetuximab inhibited the signaling pathways of IGF-IR and EGFR and inhibited proliferation and induced apoptosis of SCC cell lines in vitro.Immunohistochemical staining revealed decreased proliferating cell nuclear antigen (PCNA) and microvessel density (MVD) as well as increased apoptosis within the treated tumor xenografts. In addition, the administration of A12, alone or in combination with cetuximab inhibited the growth of tumors by 51% and 92% respectively, and significantly enhanced survival in the nude mouse model of CSCC (p = 0.044 and p < 0.001 respectively).Conclusions-These data suggest that dual treatment with monoclonal antibodies to the EGFR and IGF-IR may be therapeutically useful in the treatment of CSCC.
The intraoperative blood flow, as determined by optical rhinometry, was significantly greater with anesthesia with PR than with anesthesia with SR, 1 hour into the procedure; however, this difference did not translate into differences in the amounts of operative blood loss or in the surgical field visualization scores.
Purpose: Anaplastic thyroid cancer (ATC) is a locally aggressive type of thyroid tumor with high rate of distant metastases. With conventional treatment, the median survival ranges from 4 to 12 months; therefore, new treatment options are needed. AZD2171is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptors (VEGFR) VEGFR-1, VEGFR-2, and VEGFR-3. The objective of the study is to determine whether AZD2171 can inhibit VEGFR-2 signaling and decrease tumor growth and prolong survival of ATC in an orthotopic nude mouse model. Experimental Design: We examined the effects of AZD2171 on phosphorylation of VEGFR-2, mitogen-activated protein kinase, and AKT in human umbilical vascular endothelial cells.To determine the antiproliferative and antiapoptotic effects of AZD2171, we did 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry assays, respectively. We assessed the antitumor effects of AZD2171in a xenograft model of ATC using control, AZD2171, paclitaxel, and combination groups by measuring tumor size and survival. Results:Treatment with AZD2171led to dose-dependent inhibition ofVEGFR-2 phosphorylation and its downstream signaling in human umbilical vascular endothelial cells (IC 50 for cell proliferation, 500 nmol/L). In the ATC cell lines DRO and ARO, IC 50 was 7.5 Amol/L. AZD2171 induced apoptosis in 50% of endothelial and ATC cells at 3 and 10 Amol/L concentrations, respectively. In vivo, AZD2171 led to a significant reduction in tumor size between control and AZD2171 (P = 0.002) or AZD2171 + paclitaxel group (P = 0.002) but not the paclitaxel alone group (P = 0.11). Survival was significantly higher among AZD2171 (P < 0.001) and combination groups (P < 0.001) compared with control.Conclusions: AZD2171effectively inhibits tumor growth and prolongs survival of ATC-bearing mice. The main effect of AZD2171is mediated through angiogenesis inhibition.
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