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Assessment of Three-Drug Combination Pharmacodynamic Interactions in Pancreatic Cancer Cells

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Abstract

The pharmacodynamic interactions among trifluoperazine (TFP), gemcitabine (GEM), and paclitaxel (PTX) were assessed in pancreatic cancer cells (PANC-1). The phenothiazine TFP was chosen for its potential activity on cancer stem cells, while GEM and PTX cause apoptosis. Effects of each drug alone and in various combinations on cell growth inhibition of PANC-1 cells were studied in vitro to determine the drug-specific parameters and assess the nature of drug interactions. Joint inhibition (JI) and competitive inhibition (CI) equations were applied with a ψ interaction term. TFP fully inhibited growth of cells (Imax = 1) with an IC50 = 9887 nM. Near-maximum inhibition was achieved for GEM (Imax = 0.825) and PTX (Imax= 0.844) with an IC50 = 17.4 nM for GEM and IC50 = 7.08 nM for PTX. Estimates of an interaction term ψ revealed that the combination of TFP-GEM was apparently synergistic; close to additivity, the combination TFP-PTX was antagonistic. The interaction of GEM-PTX was additive, and TFP-GEM-PTX was synergistic but close to additive. The combination of TFP IC60–GEM IC60–PTX IC60 seemed optimal in producing inhibition of PANC-1 cells with an inhibitory effect of 82.1–90.2%. The addition of ψ terms to traditional interaction equations allows assessment of the degree of perturbation of assumed mechanisms.

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Acknowledgments

This work was supported by Grant GM 24211 from the National Institutes of Health. We thank Dr. David D’Argenio for his help with ADAPT and Dr Gilbert Koch for advice on drug interaction modeling.

NOTE Graphs allowing rotation of Figures 2 to 5 can be found in the Supplementary Materials.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, 14214, USA

    Emilie A. G. Molins & William J. Jusko

  2. Ciblage Thérapeutique en Oncologie, Faculté de médecine Lyon-sud, Université Lyon 1, 69921, Oullins, France

    Emilie A. G. Molins

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Correspondence to William J. Jusko.

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ADAPT code

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Molins, E.A.G., Jusko, W.J. Assessment of Three-Drug Combination Pharmacodynamic Interactions in Pancreatic Cancer Cells. AAPS J 20, 80 (2018). https://doi.org/10.1208/s12248-018-0235-4

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