Pharmacodynamic Investigation of Drug Interactions in the FOLFIRINOX Regimen for Pancreatic Cancer
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The FOLFIRINOX (FFX) regimen for pancreatic ductal adenocarcinoma (PADC) is a four-drug combination consisting of leucovorin (LV), 5-fluorouracil (5-FU), irinotecan (Iri) and oxaliplatin (Ox). Although the regimen extended progression-free- and overall survival in a Phase 3 study of patients with metastatic PADC compared to those treated with gemcitabine, its toxicity profile limits the regimen to patients with high performance status, and there exists a lack of studies that investigate the pharmacodynamic (PD) actions and interactions of the combined FFX. Here, we investigated interactions of the FFX drugs in vitro using established PDAC cell lines, and applied PD analysis to determine whether drug interactions were synergistic, additive, or antagonistic. We hypothesized that proliferation of PADC cells would be inhibited in a synergistic fashion when agents of the FFX regimen were combined in vitro. MIA PaCa-2 and PANC-1 cell lines were exposed in vitro to the FFX agents alone, as well as in 2-, 3-, and 4-drug combinations. In terms of IC50 (drug concentration mediating half-maximal growth inhibition) PANC-1 cells were more resistant to each of the individual agents than MIA PaCa-2. A mathematical model incorporating a quantitative drug interaction parameter (ψ) was applied to data for cell proliferation during exposure to 2-, 3-, and 4-way combinations of the drugs. Synergy (ψ < 1) was observed for nearly all combinations in the MIA PaCa-2 cell line, whereas additivity (ψ=1) or antagonism (ψ > 1) was observed for all combinations in the PANC-1 cell line. This investigation establishes a baseline that will support future investigations into the temporal sequencing of these agents, and whether sequencing can alter toxicity of the combination without altering its efficacy against cancer cells.