ABSTRACT
PURPOSE: Anaplastic thyroid carcinoma is a prime target for innovative therapy because it represents one of the most lethal human neoplasms and is refractory to conventional treatments such as chemotherapy and radiotherapy. We have evaluated a novel therapeutic approach based on the oncolytic replication-selective adenovirus dl922-947. EXPERIMENTAL DESIGN: The antitumor efficacies of the E1ADeltaCR2 (dl922-947) and DeltaE1B55K (dl1520) mutants were compared in human thyroid anaplastic carcinoma cells in culture and in xenografts in vivo. To enhance the effects of dl922-947, anaplastic thyroid carcinoma tumor xenografts were treated with dl922-947 in combination with bevacizumab. RESULTS: We showed that the efficacy of dl922-947 exceeded that of dl1520 in all tested anaplastic thyroid carcinoma cells in vitro and in vivo. Furthermore, bevacizumab in combination with dl922-947 significantly reduced tumor growth compared with single treatments alone. Bevacizumab treatment significantly improved viral distribution in neoplastic tissues. CONCLUSIONS: Our data showed that dl922-947 had a higher oncolytic activity compared with dl1520 in anaplastic thyroid carcinoma cell lines and might represent a better option for virotherapy of anaplastic thyroid carcinoma. Moreover, bevacizumab increased the oncolytic effects of dl922-947 by enhancing viral distribution in tumors. The results described herein encourage the use of the dl922-947 virus in combination with bevacizumab.
Subject(s)
Adenoviridae/drug effects , Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Carcinoma/therapy , Oncolytic Virotherapy , Thyroid Neoplasms/therapy , Adenoviridae/genetics , Adenoviridae Infections/pathology , Adenoviridae Infections/therapy , Adenoviridae Infections/virology , Adenovirus E1A Proteins/deficiency , Animals , Antibodies, Monoclonal, Humanized , Bevacizumab , Carcinoma/pathology , Carcinoma/virology , Cells, Cultured , Combined Modality Therapy , Drug Synergism , Humans , Male , Mice , Mice, Nude , Thyroid Neoplasms/pathology , Thyroid Neoplasms/virology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/immunology , Vascular Endothelial Growth Factor A/metabolism , Virus Replication/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors and shows morphological features of a highly malignant, undifferentiated neoplasm. Patients with ATC have a poor prognosis with a mean survival time of 2-6 months; surgery, radiotherapy, and chemotherapy do not improve survival. Gene therapy approaches and oncolytic viruses have been tested for the treatment of ATC. To enhance the antineoplastic effects of the oncolytic adenovirus dl1520 (Onyx-015), we treated ATC cells with lovastatin (3-hydroxy-methylglutaryl-CoA reductase inhibitor), a drug used for the treatment of hypercholesterolemia, which has previously been reported to exert growth-inhibitory and apoptotic activity on ATC cells. Lovastatin treatment significantly increased the effects of dl1520 against ATC cells. The replication of dl1520 in ATC cells was enhanced by lovastatin treatment, and a significant increase of the expression of the early gene E1A 13 S and the late gene Penton was observed in lovastatin-treated cells. Furthermore, lovastatin treatment significantly enhanced the effects of dl1520 against ATC tumor xenografts. Lovastatin treatment could be exploited to increase the efficacy of oncolytic adenoviruses, and further studies are warranted to confirm the feasibility of the approach in ATC patients.
Subject(s)
Adenoviridae/drug effects , Antineoplastic Agents/therapeutic use , Carcinoma/therapy , Lovastatin/pharmacology , Lovastatin/therapeutic use , Oncolytic Virotherapy , Thyroid Neoplasms/therapy , Virus Replication/drug effects , Animals , Antineoplastic Agents/pharmacology , Carcinoma/drug therapy , Cells, Cultured , Combined Modality Therapy , Female , Humans , Mice , Mice, Nude , Oncolytic Viruses/drug effects , Viral Vaccines , Xenograft Model Antitumor AssaysABSTRACT
The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB1 receptors could induce a non-invasive phenotype in breast metastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB1 antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB1 receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB1 receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo.