The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of (111)In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin).
BACKGROUND
Our objective was to define the relationships between tumor uptake of [(111)In]-IGF-1 and [(111)In]-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 [(111)In]-IGF-1 and [(111)In]-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 (8.5x10(4), 1.4x10(4), 4.0x10(4) and 1.0x10(5) IGF-1R/cell, respectively). The effect of co-injection of IGF-1 (50 microg) or IGFBP-3 (2 or 25 microg) was studied. The relationship between tumor uptake of [(111)In]-IGF-1(E3R) and IGF-1R density was examined. MicroSPECT/CT imaging was performed on mice with MCF-7/HER2-18 tumors injected with [(111)In]-IGF-1(E3R). The surviving fraction of BC cells exposed to trastuzumab (67.5 mug/ml) in the absence/presence of IGFBP-3 (1 microg/ml) or the IGF-1R kinase inhibitor, AG1024 (1 or 5 microg/ml), was determined.


RESULTS
[(111)In]-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 %ID/g). Co-injection of IGBP-3 decreased kidney uptake of [(111)In]-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 (111)In-IGF-1(E3R) and IGF-1R density. Tumor uptake ranged from 0.4+/-0.05 %ID/g for H2N to 2.5+/-0.5 %ID/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.


CONCLUSIONS
Imaging of IGF-1R expression using [(111)In]-IGF-1(E3R) may be useful for identifying HER2-positive tumors in BC patients that are resistant to trastuzumab through this mechanism.
Cornelissen
Bart
B
Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada M5S 3M2.
McLarty
Kristin
K
Kersemans
Veerle
V
Reilly
Raymond M
RM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity / Q000187:drug effects; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013223:Statistics as Topic; D014018:Tissue Distribution / Q000187:drug effects; D000068878:Trastuzumab; D014410:Tumor Stem Cell Assay
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D007334:Insulin-Like Growth Factor I; D000068878:Trastuzumab