ArticleJournal of pharmacokinetics and pharmacodynamics2015
Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells.
Article in Journal of pharmacokinetics and pharmacodynamics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- Practical Pharmacokinetic-Pharmacodynamic Models in Oncology.Pharmaceutics · 2025Review
- A comprehensive review of computational cell cycle models in guiding cancer treatment strategies.NPJ systems biology and applications · 2024Review
- Fibroblast growth factor receptor 1 inhibition suppresses pancreatic cancer chemoresistance and chemotherapy-driven aggressiveness.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2024Article
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- Article
- NF-κB and Pancreatic Cancer; Chapter and Verse.Cancers · 2021Review
- Synergistic Pharmacodynamic Effects of Gemcitabine and Fibroblast Growth Factor Receptor Inhibitors on Pancreatic Cancer Cell Cycle Kinetics and Proliferation.The Journal of pharmacology and experimental therapeutics · 2021Article
- Pharmacodynamic modeling of synergistic birinapant/paclitaxel interactions in pancreatic cancer cells.BMC cancer · 2020Article
- Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2',2'-difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer.Clinical and translational science · 2020Article
- Pharmacodynamic Drug-Drug Interactions.Clinical pharmacology and therapeutics · 2019Review
- Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts.Journal of pharmacokinetics and pharmacodynamics · 2018Article
- Multi-Scale Network Model Supported by Proteomics for Analysis of Combined Gemcitabine and Birinapant Effects in Pancreatic Cancer Cells.CPT: pharmacometrics & systems pharmacology · 2018Article
- Assessment of Three-Drug Combination Pharmacodynamic Interactions in Pancreatic Cancer Cells.The AAPS journal · 2018Article
- Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells.Frontiers in pharmacology · 2018Article
- Sequential Exposure of Bortezomib and Vorinostat is Synergistic in Multiple Myeloma Cells.Pharmaceutical research · 2017Article
- Array of translational systems pharmacodynamic models of anti-cancer drugs.Journal of pharmacokinetics and pharmacodynamics · 2016Review
- Assessment of non-linear combination effect terms for drug-drug interactions.Journal of pharmacokinetics and pharmacodynamics · 2016Review
- The promises of quantitative systems pharmacology modelling for drug development.Computational and structural biotechnology journal · 2016Review
- Pharmacodynamic Modeling of Cell Cycle Effects for Gemcitabine and Trabectedin Combinations in Pancreatic Cancer Cells.Frontiers in pharmacology · 2016Article
- Perspectives on the history and scientific contributions of Gerhard Levy.Journal of pharmacokinetics and pharmacodynamics · 2015Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Combination chemotherapy is standard treatment for pancreatic cancer. However, current drugs lack efficacy for most patients, and selection and evaluation of new combination regimens is empirical and time-consuming. The efficacy of gemcitabine, a standard-of-care agent, combined with birinapant, a pro-apoptotic antagonist of Inhibitor of Apoptosis Proteins (IAPs), was investigated in pancreatic cancer cells. PANC-1 cells were treated with vehicle, gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and combinations of the two drugs. Temporal changes in cell numbers, cell cycle distribution, and apoptosis were measured. A basic pharmacodynamic (PD) model based on cell numbers, and a mechanism-based PD model integrating all measurements, were developed. The basic PD model indicated that synergistic effects occurred in both cell proliferation and death processes. The mechanism-based model captured key features of drug action: temporary cell cycle arrest in S phase induced by gemcitabine alone, apoptosis induced by birinapant alone, and prolonged cell cycle arrest and enhanced apoptosis induced by the combination. A drug interaction term Ψ was employed in the models to signify interactions of the combination when data were limited. When more experimental information was utilized, Ψ values approaching 1 indicated that specific mechanisms of interactions were captured better. PD modeling identified the potential benefit of combining gemcitabine and birinapant, and characterized the key interaction pathways. An optimal treatment schedule of pretreatment with gemcitabine for 24-48 h was suggested based on model predictions and was verified experimentally. This approach provides a generalizable modeling platform for exploring combinations of cytostatic and cytotoxic agents in cancer cell culture studies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.