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Eur J Nucl Med Mol Imaging. 2009 Sep;36(9):1510-9. doi: 10.1007/s00259-009-1158-1. Epub 2009 May 14.

Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with (64)Cu-DOTA-trastuzumab.

Author information

1
The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd, P095, Stanford, CA 94305-5484, USA.

Abstract

PURPOSE:

17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat-shock protein 90 (Hsp90) inhibitor, has been intensively investigated for cancer therapy and is undergoing clinical trials. Human epidermal growth factor receptor 2 (HER-2) is one of the client proteins of Hsp90 and its expression is decreased upon 17-DMAG treatment. In this study, we aimed to noninvasively monitor the HER-2 response to 17-DMAG treatment in xenografted mice.

METHODS:

The sensitivity of human ovarian cancer SKOV-3 cells to 17-DMAG in vitro was measured by MTT assay. HER-2 expression in SKOV-3 cells was determined by flow cytometry. Nude mice bearing SKOV-3 tumors were treated with 17-DMAG and the therapeutic efficacy was evaluated by tumor size measurement. Both treated and control mice were imaged with microPET using (64)Cu-DOTA-trastuzumab and (18)F-FDG. Biodistribution studies and immunofluorescence staining were performed to validate the microPET results.

RESULTS:

SKOV-3 cells are sensitive to 17-DMAG treatment, in a dose-dependent manner, with an IC(50) value of 24.72 nM after 72 h incubation. The tumor growth curve supported the inhibition effect of 17-DMAG on SKOV-3 tumors. Quantitative microPET imaging showed that (64)Cu-DOTA-trastuzumab had prominent tumor accumulation in untreated SKOV-3 tumors, which was significantly reduced in 17-DMAG-treated tumors. There was no uptake difference detected by FDG PET. Immunofluorescence staining confirmed the significant reduction in tumor HER-2 level upon 17-DMAG treatment.

CONCLUSION:

The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using (64)Cu-DOTA-trastuzumab. This approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment.

PMID:
19440708
PMCID:
PMC3596115
DOI:
10.1007/s00259-009-1158-1
[Indexed for MEDLINE]
Free PMC Article

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