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Endocrinology |
1 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; 2 Department of Immunology, Berlex Bioscience, Inc., Richmond, Richmond, California; and 3 Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, Naples, Italy
Requests for reprints: Giovanni Vitale, Department of Internal Medicine, Erasmus Medical Center, Room EE 585d, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands. Phone: 31-10-4635952; Fax: 31-10-4635430; E-mail: vanni10{at}yahoo.com.
IFN-
controls hormone secretion and symptoms in human gastroenteropancreatic neuroendocrine tumors (GEP-NET) but it rarely induces a measurable tumor size reduction. The effect of other type I IFNs, e.g., IFN-ß, has not been evaluated. We compared the antitumor effects of IFN- and IFN-ß in BON cells, a functioning human GEP-NET cell line. As determined by quantitative reverse transcription-PCR analysis and immunocytochemistry, BON cells expressed the active type I IFN receptor mRNA and protein (IFNAR-1 and IFNAR-2c subunits). After 3 and 6 days of treatment, IFN-ß significantly inhibited BON cell growth in a time- and dose-dependent manner. IC50 and maximal inhibitory effect on day 6 were 8 IU/mL and 98%, respectively. In contrast, the effect of IFN- resulted significantly in a less potent effect (IC50: 44 IU/mL, maximal inhibition: 26%). IFN- induced only cell cycle arrest, with an accumulation of the cells in S phase. IFN-ß, apart from a more potent delay in S-G2-M phase transit of the cell cycle, also induced a strong stimulation of apoptosis, evaluated by flow cytometry (Annexin V and 7-AAD) and measurement of the DNA fragmentation. Besides, only IFN-ß severely suppressed chromogranin A levels in the medium from BON cells after 6 days of treatment. In conclusion, IFN-ß is much more potent, compared with IFN-, in its inhibitory effect on GEP-NET cell proliferation in vitro through the induction of apoptosis and cell cycle arrest. Further studies are required to establish whether IFN-ß has comparable potent tumor growth inhibitory effects in vivo. (Cancer Res 2006; 66(1): 554-62)
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