| Abstract: |
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. Conclusion: 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. |
| Keywords: |
protein expression; human cell; nonhuman; paclitaxel; flow cytometry; positron emission tomography; mouse; phenotype; animal; metabolism; animals; mice; animal tissue; animal experiment; tumor xenograft; tumor cells, cultured; mice, inbred balb c; cancer resistance; mathematical model; models, theoretical; bagg albino mouse; diagnostic agent; drug distribution; drug uptake; isotope labeling; xenograft; cell culture; tissue distribution; neuroblastoma; neuroblastoma cell; tumor cell line; rat; computer assisted emission tomography; transplantation, heterologous; drug clearance; rats; nude rat; rats, nude; pet; theoretical model; multidrug resistance; p-glycoprotein; colchicine; drug resistance, multiple; carbon; tomography, emission-computed; multiple drug resistance; glycoprotein p; carbon 11; carbon radioisotopes; humans; human; priority journal; article; mathematic model
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