Abstract
The development of therapeutic inhibitors of key signaling pathways has been hampered by the inability to assess the effect of a drug on its target in the patient. 17-allylaminogeldanamycin (17-AAG) is the first Hsp90 inhibitor to be tested in a clinical trial. It causes the degradation of HER2 and other Hsp90 targets, and has antitumor activity in preclinical models. We have developed a method for imaging the inhibition of Hsp90 by 17-AAG. We labeled an F(ab')2 fragment of the anti-HER2 antibody Herceptin with 68Ga, a positron emitter, which allows the sequential positron-emission tomographic imaging of HER2 expression. We have used this method to quantify as a function of time the loss and recovery of HER2 induced by 17-AAG in animal tumors. This approach allows noninvasive imaging of the pharmacodynamics of a targeted drug and will facilitate the rational design of combination therapy based on target inhibition.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / chemistry
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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 Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Benzoquinones
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Blotting, Western
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Cell Line, Tumor
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Copper Radioisotopes
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Female
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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Heterocyclic Compounds, 1-Ring / chemistry
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Humans
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Immunoblotting
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Immunoglobulin Fab Fragments / chemistry
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Immunoglobulin Fab Fragments / pharmacology
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Indium Radioisotopes
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Isotope Labeling
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Lactams, Macrocyclic
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Mice
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Mice, Nude
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Molecular Probe Techniques
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Neoplasms / chemistry
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Neoplasms / metabolism
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Neoplasms / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Positron-Emission Tomography / methods*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Receptor, ErbB-2 / drug effects
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Receptor, ErbB-2 / metabolism*
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Rifabutin / analogs & derivatives*
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Rifabutin / pharmacology*
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Tissue Distribution
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Trastuzumab
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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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Antineoplastic Agents
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Benzoquinones
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Copper Radioisotopes
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HSP90 Heat-Shock Proteins
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Heterocyclic Compounds, 1-Ring
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Immunoglobulin Fab Fragments
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Indium Radioisotopes
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Lactams, Macrocyclic
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1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
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Rifabutin
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tanespimycin
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Receptor, ErbB-2
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Protein Serine-Threonine Kinases
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Trastuzumab