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Published on: February 3, 2015
Evaluation of 11C-colchicine for PET imaging of multiple drug resistance
A Levchenko1, B M Mehta, J B Lee
1Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Unlabelled:
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.
Insights
Positron-emitting 11C-colchicine (CHC) PET imaging can evaluate multiple drug resistance (MDR) in tumors. This novel tracer is not affected by membrane potential, offering improved MDR assessment for cancer patients.
Area of Science:
- Nuclear Medicine
- Oncology
- Radiochemistry
Background:
- Overexpression of P-glycoprotein (P-gp) leads to multiple drug resistance (MDR) in cancer, reducing chemotherapy efficacy.
- Early MDR diagnosis is crucial for improving patient outcomes and treatment selection.
- Existing MDR tracers are affected by membrane potential, limiting their diagnostic utility.
Purpose of the Study:
- To evaluate the use of a novel positron-emitting tracer, 11C-colchicine (CHC), for assessing MDR in tumors using PET imaging.
- To demonstrate that CHC is electroneutral and its biodistribution is independent of membrane potential changes.
Main Methods:
- In vitro studies correlated CHC resistance with Taxol resistance in drug-resistant cancer cell lines.
- A mathematical model was developed for 11C-CHC distribution in tumors based on in vitro data.
- Dynamic PET imaging with 11C-CHC was performed on nude rats bearing sensitive and resistant human neuroblastoma xenografts.
Main Results:
- PET imaging revealed approximately a 2-fold difference in 11C-CHC accumulation between sensitive and resistant tumors.
- A mathematical model allowed estimation of resistance parameters (r) from imaging data.
- The ratio of estimated resistance parameters correlated directly with the ratio of CHC accumulation in corresponding cell lines.
Conclusions:
- In vivo PET imaging with 11C-CHC provides evidence for P-gp's indirect effect on CHC binding and tumor uptake.
- This method offers a promising approach for non-invasive, early diagnosis of MDR in clinical oncology.
- Further research will explore the full clinical significance and applications of 11C-CHC PET imaging.
