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

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: (99m)Tc-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 (99m)Tc-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.