PD modeling of three chemotherapeutic agents and human lung tumor cells

Purpose: To evaluate the effects of 3 agents on human lung tumor cells. Methods: On the day of surgery, human lung tumor cells were mechanically disaggregated and exposed to cisplatin (Cis, 2.5 and 25 μg/ml), doxorubicin (Dox, 0.6 and 6 μg/ml) and etoposide (Eto, 30 and 300 μg/ml), alone and in combination. Control and drug-exposed samples were stained with SybrGreen (DNA stain) and propidium iodide (dead cell stain), and living cells were quantitated at 0, 1, 2, 4, 6 and 24 hours by flow cytometry. Results: The data was fit to a Hill-Type pharmacodynamic model where Emax is the maximum cell death achievable, AUC is the concentration of drug(s) times the number of exposure hours, AUCm is the AUC at which half-maximal cell death is seen, and H is Hill's constant: Regimen Emax AUCm H r² Cis 33.0 146 12.0 0.465 Dox 80.0 3.46 3.00 0.758 Eto 99.0 179 2.10 0.994 Cis/Dox 55.8 0.010 5.00 0.862 Cis/Eto 100 179 1.34 0.982 Dox/Eto 99.6 119 1.94 0.999 The model fit the data well. Near-maximal cell death was seen with Eto at an achievable AUC. Least activity was seen with Cis. Cis/Dox resulted in a lower AUCm (greater potency) than either agent alone, however the Emax was lower than Dox alone. Addition of Cis to Eto did not enhance activity, while addition of Dox to Eto resulted in a lower AUCm for the combination. Conclusions: Rapid evaluation of the effects of chemotherapeutic agents, alone and in combination, was possible using flow cytometry and PD modeling. Using this approach, chemotherapeutic regimens may be evaluated and compared using exposure concentrations similar to those achieved in humans.