Biphasic accumulation kinetics of [99mTc]-hexakis-2-methoxyisobutyl isonitrile in tumour cells and its modulation by lipophilic P-glycoprotein ligands.
OBJECTIVE
To study the accumulation and washout kinetics of [99mTc]-hexakis-2-methoxyisobutyl isonitrile (99mTc-MIBI) in MDR positive and MDR negative tumour cells and how this is modified by lipophilic P-glycoprotein ligands.


METHODS
The tumour cells were incubated in the presence and absence of the ligands and the uptakes of 99mTc-MIBI, rhodamine 123 and 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) were measured.


RESULTS
The accumulation of 99mTc-MIBI in the tumour cells followed biphasic kinetics. Verapamil and cyclosporin A increased the membrane fluidity and significantly enhanced the 99mTc-MIBI uptake of the MDR negative cells, while the rhodamine 123 uptake was not affected. Verapamil significantly increased the uptake of rhodamine 123 and 18FDG but did not modify that of 99mTc-MIBI in the MDR positive cells. Cyclosporin A significantly increased the 18FDG uptake of the MDR positive and negative tumour cells; these effects were ouabain-sensitive. Depolarization of the cytoplasmic membrane, acidification of the extracellular medium and the administration of CCCP decreased the accumulation of 99mTc-MIBI and rhodamine 123 uptake in the tumour cells.


CONCLUSIONS
Lipophilic P-glycoprotein ligands modified the biphasic accumulation kinetics of the 99mTc-MIBI uptakes of MDR negative and positive tumour cells in different and complex ways and could therefore mask the P-glycoprotein pump-dependent changes in tracer accumulation.
Márián
Teréz
T
PET Center, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt 98, Hungary. marian@pet.dote.hu
Balkay
László
L
Szabó
Gábor
G
Krasznai
Zoárd T
ZT
Hernádi
Zoltán
Z
Galuska
László
L
Szabó-Péli
Judit
J
Esik
Olga
O
Trón
Lajos
L
Krasznai
Zoltán
Z
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005462:Fluorine Radioisotopes; D005942:Gluconates / Q000493:pharmacokinetics; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008024:Ligands; D008560:Membrane Fluidity / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D010539:Permeability; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005462:Fluorine Radioisotopes; D005942:Gluconates; D008024:Ligands; D020112:Rhodamine 123; D016572:Cyclosporine; D017256:Technetium Tc 99m Sestamibi; C047514:2-fluoro-2-deoxy-6-phosphogluconate; D014700:Verapamil