Abstract
Purpose
Using a “spontaneous” mammary mouse tumor model we set out to develop diagnostic approaches for non-invasive P-glycoprotein (P-gp) staging and response prediction.
Methods
99mTc-MIBI efflux rates were measured using a gamma camera in three Brca1 −/−; p53 −/− mouse mammary tumors that have different Mdr1a/b expression levels. The efflux rates were quantified in the 10–30-min period after injection. In addition to the P-gp-mediated efflux measurements in untreated tumors, efflux measurements were performed in the presence of the P-gp inhibitor tariquidar. Volumetric doxorubicin response patterns for the different tumors were determined and correlated with the efflux rates.
Results
Combined pre- and post-inhibitor treatment imaging of P-gp-mediated efflux correlated with Mdr1a/b expression: basal (0.0026, p = 0.16), 3-fold Mdr1a/b (0.0074, p = 0.02), and 17-fold Mdr1a and 46-fold Mdr1b (0.012, p = 0.002). Based on the doxorubicin response of these tumors, we generated a computer-aided diagnosis model that predicts the likelihood of drug resistance.
Conclusions
Quantified 99mTc-MIBI efflux has potential to: (1) noninvasively assign Mdr1 expression levels, (2) predict the therapeutic impact of a P-gp inhibitor, and (3) noninvasively assess the probability of drug resistance.
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Acknowledgments
This research was supported, in part, by the Technology Foundation, Applied Science Division of NWO, and the Technology Program of the Ministry of Economic Affairs (STW BGT 7528 Veni), KWF (NKI 2006-3566), and ZON-MW 945-04-512. We thank Susan Bates (NIH, Bethesda, MD) for providing tariquidar. We also thank Renato Valdes-Olmos and the technical staff of the Department of Nuclear Medicine at the NKI-AVL for their support. Lastly, we gratefully acknowledge Piet Borst for critically reading the manuscript.
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van Leeuwen, F.W.B., Buckle, T., Kersbergen, A. et al. Noninvasive functional imaging of P-glycoprotein-mediated doxorubicin resistance in a mouse model of hereditary breast cancer to predict response, and assign P-gp inhibitor sensitivity. Eur J Nucl Med Mol Imaging 36, 406–412 (2009). https://doi.org/10.1007/s00259-008-1010-z
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DOI: https://doi.org/10.1007/s00259-008-1010-z