Pharmacodynamic (PD) Modelling of Anti-Proliferative Effects of Tetraiodothyroacetic Acid (Tetrac) on Human Cancer Cells
C.B. Landersdorfer (1), D. London (1), R. Meng (1), C. Lin (1), S. Lin (1), C.-U. Lim (1), L. Queimado (2), S.A. Mousa (3), G.L. Drusano (4), A. Louie (4), F.B. Davis (1), H.-Y. Lin (1), P.J. Davis (1).
(1) The Signal Transduction Laboratory, Ordway Research Institute, Albany, NY; (2) The Department of Otorhinolaryngology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK; (3) The Pharmaceutical Research Institute at Albany College of Pharmacy, Rensselaer, NY; (4) The Emerging Infections and Pharmacodynamics Laboratory, Ordway Research Institute, Albany, NY.
Objectives: Tetraiodothyroacetic acid (tetrac), a deaminated analogue of L-thyroxine (T4), competes with T4 to bind to the integrin αvβ3 receptor on the cell surface and induces apoptosis and anti-proliferation in several kinds of cancer cells. We sought to develop a PD model to characterize these effects.
Methods: Human breast cancer MDA-MB-231 cells were treated with 7 different constant concentrations of tetrac in the perfusion bellows cell culture system for 19 days and similar experiments were conducted using human glioblastoma U87MG cells treated with 3 different concentrations of tetrac for 7 days. Human colon cancer Colo-205 cells were treated with 3 different concentrations of tetrac in flasks for 18 days. Total cell counts were obtained every 1 or 2 days. All data within each study were co-modelled in NONMEM VI. Simulation-estimation experiments were run using NONMEM and S-ADAPT (MC-PEM algorithm).
Results: A mechanism-based model adequately described the proliferation of cancer cells and inhibition of proliferation by tetrac. The action of tetrac on MDA-MB cells was best described as a dual effect with both inhibition of the rate of cell growth (Imax1 0.85, IC501 5.1 μM) and inhibition of the probability of successful replication (Imax2 0.20, IC502 0.087 μM). The effect of tetrac on colon cancer cells was modelled as inhibition of the probability of successful replication (Imax 0.17, IC50 0.020 μM). Average bias was +0.1% (+0.3%) for Imax and -5% (-6%) for IC50 from 50 replicate MC-PEM (FOCE) runs with an additive error of 0.05 on log10-scale. Both effects on rate of cell growth (Imax1 0.57, IC501 0.047 μM) and probability of successful replication (Imax2 0.92, IC502 47.4 μM) were required to describe inhibition of cell proliferation of U87MG cells. Average bias was -5% (-3%) for Imax1, +26% (+19%) for IC501, +0.01% (-3%) for Imax2, and -0.4% (-4%) for IC502 in MC-PEM (FOCE) based on 50 replicates each with an additive error on log10-scale of 0.1.
Conclusions: Modelling suggests the effect of tetrac on the probability of successful replication is most important for colon cancer cells in flasks, whereas both effects are necessary to describe tetrac effects on breast cancer and glioblastoma cells in the perfusion bellows system. The perfusion bellows system with PD modelling allows simulation of concentration time profiles expected in humans in an in vitro system and can support translation from in vitro to animal models and human clinical trials.