Pharmacokinetic Modeling of Tumor Bioluminescence Reveal Efflux as Key Hurdle in Cancer Therapy

Researchers have utilized pharmacokinetic modeling to investigate tumor bioluminescence, a powerful tool for assessing tumor burden and therapeutic response in xenograft models. However, variable substrate administration, tumor size, type, and location can lead to significant inconsistencies in bioluminescence imaging. A novel pharmacokinetic approach has been developed to address these issues, leveraging bioluminescence image data to understand drug transport in and out of tumors. The results of this study provide a quantitative physical rationale for molecular targeting of therapeutics that enhance trapping and overcome accelerated efflux kinetics.

Key Takeaways:

• Researchers employed a multicompartment pharmacokinetic model to simultaneously fit experiments for each mouse, observing that the rates of luciferin transport in and out of the tumor exhibited a clear dependence on tumor volume.
• The rate of tumor influx increased faster than the rate of efflux, resulting in a shortening of the time to peak-luciferin concentration as the tumor grows.
• The time of the peak concentration correlated poorly with tumor volume, but the peak bioluminescence signal and area under the curve both exhibited a dependence on tumor surface area.
• These observations support Starling's hypothesis relating interstitial fluid pressure in the tumor to flux across the boundary, suggesting that drug transport may depend more strongly on the surface area of the tumor than its volume.
• The study revealed that drug trapping and overcoming accelerated efflux kinetics are critical for effective cancer therapy.
• The developed pharmacokinetic approach provides a valuable tool for understanding drug transport in tumors and optimizing cancer treatment strategies.

Statistics:

• The study used data from mice implanted with a melanoma tumor cell line, with intraperitoneal injections of D-luciferin given at 5, 7, and 10 days postimplant.
• The modeling results showed a clear dependence of luciferin transport rates on tumor volume, with a shortening of the time to peak-luciferin concentration as the tumor grows.
• The peak bioluminescence signal and area under the curve exhibited a dependence on tumor surface area, rather than volume.

Sources:

• Sim, H., et al. "Pharmacokinetic modeling of tumor bioluminescence implicates efflux, and not influx, as the bigger hurdle in cancer drug therapy." Cancer Gene Therapy, 2011; 18 (5), 301-312. [10.1038/cgt.2010.88]
• University of Michigan, Biomedical Engineering and Center for Computational Medicine and Bioinformatics.
• Cancer Gene Therapy, 2011; 71(3): 686-92.