Abstract
Susceptibility to apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is mediated through cognate death receptor signaling. We hypothesized that auto-amplification of this apparatus would enhance antitumor effects in vivo and could be optimized using the results obtained from novel imaging techniques. We therefore imaged mice bearing human colorectal cancer (Colo205) tumor xenografts with HGS-ETR1 and HGS-ETR2 agonist antibodies to TRAIL receptor-1 (TRAIL-R1) and TRAIL-R2, respectively, after radiolabeling the antibodies. Paclitaxel significantly increased in vivo expression of TRAIL-R1 and TRAIL-R2 in a time-dependent manner. The imaging results were confirmed by immunoblots for steady-state protein levels (>20-fold increase in TRAIL-R1 and TRAIL-R2 levels in tumor xenografts by 48 h after paclitaxel administration). TRAIL-R1 and TRAIL-R2 mRNA expression did not change, suggesting that these effects were posttranscriptional. Sequential treatment with paclitaxel followed by HGS-ETR1 or HGS-ETR2 after 48 h resulted in markedly enhanced antitumor activity against Colo205 mouse xenografts. Our experiments suggest that sequential taxane treatment followed by TRAIL-R agonist antibodies could be applied in the clinic, and that novel imaging techniques using radiolabeled receptor antibodies may be exploitable to optimize sequence timing and patient selection.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacokinetics
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal, Humanized
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects*
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Apoptosis / genetics
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Colorectal Neoplasms / diagnostic imaging*
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism
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Drug Synergism
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Female
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Humans
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Indium Radioisotopes
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase 1 / biosynthesis
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / biosynthesis
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Mitogen-Activated Protein Kinase 3 / metabolism
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Paclitaxel / pharmacology*
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Phosphorylation
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Radionuclide Imaging / methods
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Receptors, TNF-Related Apoptosis-Inducing Ligand / agonists
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Receptors, TNF-Related Apoptosis-Inducing Ligand / biosynthesis*
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
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Technetium
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Tumor Suppressor Protein p53 / biosynthesis
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Tumor Suppressor Protein p53 / metabolism
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Up-Regulation / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Indium Radioisotopes
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Tumor Suppressor Protein p53
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Technetium
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lexatumumab
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Paclitaxel
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mapatumumab