title: Cetuximab reduces the accumulation of radiolabeled bevacizumab in cancer xenografts without decreasing VEGF expression.
abstract: Bevacizumab and cetuximab are approved for the treatment of cancer. However, in advanced colorectal cancer, addition of cetuximab to chemotherapy with bevacizumab did not improve survival. The reason for the lack of activity remains unclear. The aim of this study was to determine the effect of cetuximab on VEGF expression and targeting of bevacizumab to the tumor. Mice with subcutaneous SUM149 or WiDr xenografts were treated with cetuximab, bevacizumab, or a combination of the two. Before the start of cetuximab treatment and after 7 and 21 days of treatment, the uptake of radiolabeled bevacizumab in the tumor was measured by immunoSPECT/CT. Tumor growth of SUM149 xenografts was significantly inhibited by cetuximab, bevacizumab, or their combination, whereas growth of WiDr xenografts was not affected. Cetuximab caused a significant reduction of bevacizumab uptake in SUM149 xenografts, whereas tumor-to-blood ratios in mice with WiDr xenografts did not change. Biodistribution studies with an irrelevant antibody in the SUM149 model also showed significantly reduced tumor-to-blood ratios. Cetuximab treatment did not decrease VEGF expression. Without decreasing VEGF levels, cetuximab reduces tumor targeting of bevacizumab. This could, at least partly, explain why the combination of bevacizumab and cetuximab does not result in improved therapeutic efficacy.
authors.affiliation: Department of Radiology and Nuclear Medicine, ‡Department of Laboratory Medicine, §Department of Medical Oncology, Radboud University Medical Center , P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: Heskamp
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Janneke D M
authors.initials: JD
authors.lastname: Molkenboer-Kuenen
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Anneke
authors.initials: A
authors.lastname: Geurts-Moespot
authors.forename: Mallory S
authors.initials: MS
authors.lastname: Engelhardt
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Laarhoven
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068818:Cetuximab; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D064847:Multimodal Imaging; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000068258:Bevacizumab; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: EGFR; SPECT; VEGF; bevacizumab; cetuximab