The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of 111In-IGF-1 (E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin)

Introduction: Our objective was to define the relationships between tumor uptake of [In-111]-IGF-1 and [In-111]-IGF-1 (E3R), an analogue which does not bind insulin growth factor-1 (IGF-1) binding proteins (i.e., IGFBP-3), and the level of IGF-1 receptor (IGF-1R) expression on human breast cancer (BC) xenografts in athymic mice, as well as the feasibility for tumor imaging. A second objective was to correlate IGF-1R (and HER2 density) with the cytotoxicity of trastuzumab in the absence/presence of IGFBP-3 or the IGF-1R tyrosine kinase inhibitor, Ag1024. Methods: The tumor and normal tissue uptake of [In-111]-IGF-1 and [In-111]-IGF-1 (E3R) were determined at 4 h postinjection in mice implanted subcutaneously with MDA-MB-231, H2N, HR2 or MCF-7/HER2-18 human BC xenografts (8.5 x 10(4), 1.4 x 10(4),4.0 x 10(4) and 1.0 x 10(5) IGF-1R/cell, respectively). The effect of co-injection of IGF-1 (50 mu g) or IGFBP-3 (2 or 25 mu g) was studied. The relationship between tumor uptake of [In-111]-IGF-1(E3R) and IGF-1R density was examined. MicroSPECT/CT imaging was performed on mice with MCF-7/HER2-18 tumors injected with [In-111]-IGF-1(E3R). The surviving fraction of BC cells exposed to trastuzumab (67.5 mu g/ml) in the absence/presence of IGFBP-3 (1 mu g/ml) or the IGF-1R kinase inhibitor, AG1024 (1 or 5 mu g/ml), was determined. Results: [In-111]-IGF-1 was specifically taken up by MCF-7/HER2-18 xenografts; tumor uptake was decreased twofold when co-injected with IGF-1 (1.9 +/- 0.1 vs. 1.0 +/- 0.1 % 1D/g). Co-injection of IGBP-3 decreased kidney uptake of [In-111]-IGF-1 up to twofold and increased circulating radioactivity threefold. There was a strong linear correlation (r(2)=0.99) between the tumor uptake of In-111-IGF-1(E3R) and IGF-1R density. Tumor uptake ranged from 0.4 +/- 0.05 % 1D/g for H2N to 2.5 +/- 0.5 % 1D/g for MCF-7/HER2-18 xenografts. MCF-7/HER2-18 tumors were visualized by microSPECT/CT. Resistance of BC cells to trastuzumab was directly associated with IGF-1R expression, despite co-expression of HER2. The resistance of HR2 cells could be partially reversed by IGFBP-3 or AG1024. Conclusion: Imaging of IGF-1R expression using [In-111]-IGF-1 (E3R) may be useful for identifying HER2-positive tumors in BC patients that are resistant to trastuzumab through this mechanism. (C) 2008 Elsevier Inc. All rights reserved.