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Effect of an Insulin-Like Growth Factor Binding Protein Fusion Protein on Thymidine Incorporation in Neuroblastoma and Rhabdomyosarcoma Cell Lines

Department of Internal Medicine (B.L.D., R.S.B.), The University of Iowa, and Veterans Administration Medical Center (M.B., R.S.B.), Iowa City, Iowa 52246; and Department of Medicine (L.A.B.), Austin Health/Northern Health, University of Melbourne, 3084 Melbourne, Australia

Address all correspondence and requests for reprints to: Robert S. Bar, M.D., The University of Iowa, Department of Internal Medicine, Division of Endocrinology, 3E19 Veterans Administration Medical Center, Highway 6 West, Iowa City, Iowa 52246. E-mail: robert-bar{at}uiowa.edu.

A fusion protein, FP 6/3, composed of IGF binding protein (IGFBP)-6 and IGFBP-3 was synthesized where the complete sequences of each binding protein were fused together into a single chimeric protein. The orientation of this fusion protein’s structure has the N terminus of IGFBP-3 fused to the C terminus of IGFBP-6, leaving the key binding areas of each open. FP 6/3 bound to cells via its IGFBP-3 component and retained the increased affinity for IGF-II via its IGFBP-6 component. The effect of FP 6/3 on growth was determined in cell lines from both neuroblastoma and rhabdomyosarcoma, where IGF-II is an autocrine growth factor. In studies using FP 6/3, IGFBP-3, or IGFBP-6, a growth inhibition effect was shown for all when present under coincubation conditions with IGF-II. However, with transient exposure, FP 6/3 was the only IGFBP that retained this growth-inhibition property. Under transient exposure conditions, FP 6/3 was found to be effective when exposure was limited to as few as 10 min and concentrations were as low as 1 nM. These findings with FP 6/3 suggest that it potentially could lead be used as therapy against cancers in which IGF-II is an autocrine growth factor because it brings an inhibition action directly to tumor cells.

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