Imaging recognition of inhibition of multidrug resistance in human breast cancer xenografts using 99mTc-labeled sestamibi and tetrofosmin

Abstract

Background: (99m)Tc-sestamibi (MIBI) and (99m)Tc-tetrofosmin (TF) are avid transport substrates recognized by the multidrug resistance (MDR) P-glycoprotein (Pgp). This study was designed to compare the properties of MIBI and TF in assessing the inhibition of Pgp by PSC833 in severe combined immunodeficient mice bearing MCF7 human breast tumors using SPECT imaging.

Methods: Animals with drug-sensitive (MCF/WT) and drug-resistant (MCF7/AdrR) tumors were treated by PSC833 and by carrier vehicle 1 h before imaging, respectively. Dynamic images were acquired for 30 min after intravenous injection of MIBI/TF using a SPECT system, FastSPECT. The biodistribution of MIBI and TF was determined at the end of the imaging session.

Results: MCF7/WT in the absence and presence of PSC833 could be visualized by MIBI and TF imaging within 5 min and remained detectable for 30 min postinjection. MCF7/AdrR could be visualized only 2-5 min without PSC833 treatment but could be detected for 30 min with PSC833, very similar to MCF7/WT. MCF7/AdrR without PSC833 showed significantly greater radioactive washout than MCF7/WT and MCF7/AdrR with PSC833 treatment. PSC833 increased the accumulation (%ID/g) in MCF7/AdrR 3.0-fold (1.62+/-0.15 vs. 0.55+/-0.05, P<.05) for TF and 1.9-fold (1.21+/-0.04 vs. 0.64+/-0.05, P<.05) for MIBI but did not affect MCF7/WT.

Conclusions: The feasibility of MIBI and TF for assessment of MDR expression and inhibition was demonstrated in mice through FastSPECT imaging. The results indicate that TF may be at least comparable with MIBI in recognizing Pgp expression and modulation.

Fig. 1

(A) Subcutaneous MCF7/WT tumor on the right thigh (arrow) of an SCID mouse at the end of the imaging session. (B) Three-dimensional representation of a reconstructed FastSPECT data set of the animal anesthetized with isoflurane (1.0–1.5%) 10 min after injection with TF (222 MBq). The data set of 24 projections, one from each camera, was collected for 5 min. (C–E) The tumor with high radioactive uptake was visualized on coronal, transaxial and sagittal tomographic slices.

Fig. 2

(Left) FastSPECT dynamic images (serial slices of a selected coronal slice) from the mouse with an MCF7/WT tumor in Fig. 1 using TF. The time after injection is shown in the lower right corner of each image. The MCF7/WT tumor (arrow) was visualized approximately 2 min postinjection and stayed well defined for at least 30 min. (Right) Composite planar dynamic images from the tomographic coronal slices of TF images of the animal in Fig. 1. The projection data were collected for 1 min from 1 to 10 min followed by 5-min acquisition until 30 min postinjection. The T/M ratio was 1.45, as determined by biodistribution analysis at the end of the imaging session.

Fig. 3

(A) Representative dynamic tomographic images (sagittal slices) of MIBI (163 MBq) in a mouse with an MCF7/AdrR tumor without PSC833 treatment. The tumor (arrows) was visible less than 5 min after injection. The T/M ratio was 0.72. (B) Dynamic images of MIBI (95.5 MBq) from a mouse with an MCF7/AdrR tumor treated by PSC833. The tumor (arrows) was clearly visualized from 2 min after injection and remained detectable for 30 min. The T/M ratio was 1.19. Dynamic images were acquired every minute for the first 10 min, followed by acquisitions every 5 min for the next 20 min.

Fig. 4

(A) Dynamic tomographic images (sagittal slices) of TF (167 MBq) in a mouse with an MCF7/AdrR tumor in the absence of PSC833. The tumor (arrows) was visible less than 5 min after injection. The T/M ratio was 0.60. (B) TF (222 MBq) dynamic images from a mouse with an MCF7/AdrR tumor in the presence of PSC833. The tumor (arrows) was well detected from 2 min after injection and stayed well defined for at least 30 min. The T/M ratio was 1.77. The animals were imaged every minute for the first 10 min, followed by acquisitions every 5 min for the next 20 min.

Fig. 5

MIBI (A) and TF (B) washout curves from MCF7/WT and MCF7/AdrR breast tumors. In the absence of PSC833, the washout of MIBI and TF was significantly greater in MCF7/AdrR tumors compared with the tumors in the presence of PSC833. The radioactivity is plotted as a percentage of the peak activity in the tumor. *P <.05 compared with MCF7/AdrR, PSC+.