Evaluation of 11C-colchicine for PET imaging of multiple drug resistance.
Overexpression of P-glycoprotein (P-gp) can confer multiple drug resistance (MDR) phenotype on cancer cells and tumors by reducing intracellular accumulation of various cytotoxic agents. Early diagnosis of MDR in the clinic will serve to improve the efficacy of chemotherapeutic intervention and the quality of life of patients. In this article we describe use of a positron-emitting MDR tracer, 11C-colchicine (CHC), to evaluate MDR by PET imaging. Unlike existing MDR tracers such as 99mTc-sestamibi, this compound is electroneutral, with biodistribution not affected by perturbations of membrane potential.


METHODS
In vitro studies showed that resistance to CHC is correlated to resistance to Taxol (paclitaxel). The results of biodistribution experiments were found to be consistent with previously reported experiments with CHC labeled with other isotopes. On the basis of in vitro experiments with a series of drug-resistant variants of the human neuroblastoma BE (2)-C cell line, a mathematic model of 11C-CHC distribution in tumors was formulated. Dynamic PET 11C-CHC imaging experiments were performed with nude rats xenografted with the BE (2)-C-sensitive and -resistant strains. Each scan was accompanied by a transmissions scan and a static FDG scan. These scans allowed improved image localization.


RESULTS
We observed an approximately 2-fold difference between 11C-CHC accumulation in sensitive and resistant tumors. Imaging data were analyzed using the mathematic model, and various parameters characterizing resistance could be identified and estimated. In particular, the parameter r, proportional to the level of resistance of the tumors, was obtained. We showed that the ratio of these r parameters determined from the sensitive and resistant tumors was identical to the ratio of CHC accumulation in the corresponding sensitive and resistant cell lines used for xenografting.


CONCLUSIONS
These in vivo experiments provided additional evidence for the indirect effect of P-gp action on CHC-to-tubulin binding, which in turn determines CHC uptake in tumors. The significance of these findings and future plans is discussed.
Levchenko
A
A
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Mehta
B M
BM
Lee
J B
JB
Humm
J L
JL
Augensen
F
F
Squire
O
O
Kothari
P J
PJ
Finn
R D
RD
Leonard
E F
EF
Larson
S M
SM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D003078:Colchicine; D018432:Drug Resistance, Multiple; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008962:Models, Theoretical; D009447:Neuroblastoma / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D003078:Colchicine