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.
OBJECTIVE
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.
van Leeuwen
Fijs W B
FW
Department of Radiology and Nuclear Medicine, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. fw.v.leeuwen@nki.nl
Buckle
Tessa
T
Kersbergen
Ariena
A
Rottenberg
Sven
S
Gilhuijs
Kenneth G A
KG
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D019398:Genes, BRCA1; D016158:Genes, p53; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D011877:Radionuclide Imaging / Q000379:methods; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3