Using mathematical modelling to gain new insights into how tumour cells respond to hypoxia-selective PET tracers


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Rehan Ali, Cat Kelly, Alex Fletcher, Sam DiSouza, Michael Brady, Martin Christlieb

University of Oxford, UK

Abstract

Proffered paper presentation

Background
CuATSM is commonly used as a PET tracer to identify hypoxic tumour regions, however several reports have found that its uptake doesnt correlate with pimonidazole staining for some tumours and cell lines. To improve our understanding of the retention mechanisms of CuATSM, we used mathematical modelling techniques applied to in vitro experimental data.

Methods
An initial mechanism and mathematical model for the retention of CuATSM was recently proposed by Holland et al (Phys. Med. Biol. 54(2009), pp2103-2119). We used this model to develop several different mathematical models of the kinetic processes involved. These were fitted against experimental timeseries data of the uptake and washout of radiolabelled CuATSM (and its analogues) obtained at a range of oxygen levels. The model providing the best fit to the data was selected and analysed further.

Results
One of our alternative models, which incorporates an additional efflux term governing the removal of dissociated Cu(I) species from the cell, was found to significantly improve the level of fit to the experimental data. This is compatible with the known presence of the Menkes ATP7A copper efflux protein in mammalian cell membranes. Another alternative model incorporating a less specific efflux term (modelling P-glycoprotein) was found to explain unusual uptake data from rat R3327-AT cells (Nucl Med Biol, 32(2005), pp623630).

Conclusion
The fitting of theoretical models to in vitro cell uptake data has revealed a potentially new contribution to the currently accepted mechanism of the retention of hypoxic PET tracers, which is consistent with the biology of copper homeostasis and MDR. This novel consideration of efflux terms could help to explain cases of unusual CuATSM uptake. Our results suggest that efflux pathways should be characterised for the cell line under study in order to correctly interpret results from PET pharmacokinetic studies.