Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells
| LEADER | caa a22 4500 | ||
|---|---|---|---|
| 001 | 605534063 | ||
| 003 | CHVBK | ||
| 005 | 20210128100841.0 | ||
| 007 | cr unu---uuuuu | ||
| 008 | 210128e20151001xx s 000 0 eng | ||
| 024 | 7 | 0 | |a 10.1007/s10928-015-9429-x |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s10928-015-9429-x | ||
| 245 | 0 | 0 | |a Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells |h [Elektronische Daten] |c [Xu Zhu, Robert Straubinger, William Jusko] |
| 520 | 3 | |a 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, 20nM), birinapant (50, 200, 500nM), 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 24-48h 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. | |
| 540 | |a Springer Science+Business Media New York, 2015 | ||
| 690 | 7 | |a Mathematical model |2 nationallicence | |
| 690 | 7 | |a Drug combinations |2 nationallicence | |
| 690 | 7 | |a Systems pharmacology |2 nationallicence | |
| 690 | 7 | |a Pancreatic cancer |2 nationallicence | |
| 690 | 7 | |a Gemcitabine |2 nationallicence | |
| 690 | 7 | |a Birinapant |2 nationallicence | |
| 700 | 1 | |a Zhu |D Xu |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 14214, Buffalo, NY, USA |4 aut | |
| 700 | 1 | |a Straubinger |D Robert |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 14214, Buffalo, NY, USA |4 aut | |
| 700 | 1 | |a Jusko |D William |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 14214, Buffalo, NY, USA |4 aut | |
| 773 | 0 | |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/5(2015-10-01), 477-496 |x 1567-567X |q 42:5<477 |1 2015 |2 42 |o 10928 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s10928-015-9429-x |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s10928-015-9429-x |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Zhu |D Xu |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 14214, Buffalo, NY, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Straubinger |D Robert |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 14214, Buffalo, NY, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Jusko |D William |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 14214, Buffalo, NY, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/5(2015-10-01), 477-496 |x 1567-567X |q 42:5<477 |1 2015 |2 42 |o 10928 | ||