Zhu2015 - Combined gemcitabine and birinapant in pancreatic cancer cells - mechanistic PD model
This model is described in the article:
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.
This model is hosted on BioModels Database and identified by: BIOMD0000000669.
To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.
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Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells.
- Zhu X, Straubinger RM, Jusko WJ
- Journal of pharmacokinetics and pharmacodynamics , 10/ 2015 , Volume 42 , Issue 5 , pages: 477-496 , PubMed ID: 26252969
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
- 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.
Submitter of this revision: administrator
Modellers: administrator, Vijayalakshmi Chelliah
Metadata information
isDescribedBy (4 statements)
isInstanceOf (6 statements)
NCIt Combination Chemotherapy
Brenda Tissue Ontology pancreas
KEGG Drug Birinapant (USAN/INN)
NCIt Pharmacodynamic Study
hasPart (2 statements)
occursIn (1 statement)
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000669_url.xml | SBML L2V4 representation of Zhu2015 - Combined gemcitabine and birinapant in pancreatic cancer cells - mechanistic PD model | 132.43 KB | Preview | Download |
Additional files |
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| BIOMD0000000669-biopax2.owl | Auto-generated BioPAX (Level 2) | 7.64 KB | Preview | Download |
| BIOMD0000000669-biopax3.owl | Auto-generated BioPAX (Level 3) | 8.33 KB | Preview | Download |
| BIOMD0000000669.m | Auto-generated Octave file | 10.88 KB | Preview | Download |
| BIOMD0000000669.pdf | Auto-generated PDF file | 159.97 KB | Preview | Download |
| BIOMD0000000669.png | Auto-generated Reaction graph (PNG) | 4.27 KB | Preview | Download |
| BIOMD0000000669.sci | Auto-generated Scilab file | 154.00 Bytes | Preview | Download |
| BIOMD0000000669.svg | Auto-generated Reaction graph (SVG) | 845.00 Bytes | Preview | Download |
| BIOMD0000000669.vcml | Auto-generated VCML file | 900.00 Bytes | Preview | Download |
| BIOMD0000000669.xpp | Auto-generated XPP file | 8.42 KB | Preview | Download |
| BIOMD0000000669_urn.xml | Auto-generated SBML file with URNs | 132.30 KB | Preview | Download |
| MODEL1604270001_mechanistic.cps | Curated and annotated COPASI file. | 127.58 KB | Preview | Download |
| MODEL1604270001_mechanistic.sedml | SED-ML file to produce a similar figure to figure 5J of the reference publication. Concentration of germcitabine and birinapant is set to 20nM and 500nM respectively with k_delay set to 18.6 as opposed to 36.8 and Sti_apo_g and Sti_apo_b set to 0 as values for these parameters could not be found. k_tau is also not used. If raw/non-scaled values of G1, S and G2 are plotted (that is, the 'species' values and not the scaled 'quantity' values) the simulated figure is much more similar to the figure in the reference publication. However, the y-axis is labelled as 'Cell Fraction' and supposedly scaled between 0-1. | 5.48 KB | Preview | Download |
- Model originally submitted by : Vijayalakshmi Chelliah
- Submitted: Apr 27, 2016 3:54:18 PM
- Last Modified: Feb 7, 2018 2:20:31 PM
Revisions
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Version: 2
- Submitted on: Feb 7, 2018 2:20:31 PM
- Submitted by: administrator
- With comment: Current curated version of Zhu2015_mechanistic_ADAPT5
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Version: 1
- Submitted on: Apr 27, 2016 3:54:18 PM
- Submitted by: Vijayalakshmi Chelliah
- With comment: Original import of Zhu2015_mechanistic_ADAPT5.txt
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: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| G2 M phase ; G2 phase ; PANC-1 cell ; G2 Phase Process |
81656.0 mmol |
| R total collection of specimens |
236000.0 mmol |
| R other PANC-1 cell |
3540.0 mmol |
| G1 PANC-1 cell ; G1 Phase Process ; G1 phase |
113516.0 mmol |
| R live collection of specimens ; Cell Proliferation |
220660.0 mmol |
| S PANC-1 cell ; S Phase Process ; S phase |
25488.0 mmol |
| R apo PANC-1 cell ; Apoptosis |
11800.0 mmol |
| Reactions | Rate | Parameters |
|---|---|---|
| G2 = (((1-Inh_g)*k2*S-(1-Inh_3)*(1-Inh_b)*k3*G2)-(1+Sti_apo_g)*(1+Sti_apo_b)*k_apo*G2)-(1+Sti_other_g)*(1+Sti_other_b)*k_other*G2 | (((1-Inh_g)*k2*S-(1-Inh_3)*(1-Inh_b)*k3*G2)-(1+Sti_apo_g)*(1+Sti_apo_b)*k_apo*G2)-(1+Sti_other_g)*(1+Sti_other_b)*k_other*G2 | Inh_g = 0.874253042562929; Sti_apo_b = 0.0; Inh_3 = 0.483492347087237; k3 = 0.222; Inh_b = 0.135321100917431; k_apo = 0.00394; Sti_apo_g = 0.0; k_other = 2.97E-4; Sti_other_b = 2.75; k2 = 0.114; Sti_other_g = 1.34928284767356E-5 |
| R_total = G1+S+G2+R_apo+R_other | [] | [] |
| R_other = (1+Sti_other_g)*(1+Sti_other_b)*k_other*(G1+S+G2)-k_other*R_other | (1+Sti_other_g)*(1+Sti_other_b)*k_other*(G1+S+G2)-k_other*R_other | k_other = 2.97E-4; Sti_other_b = 2.75; Sti_other_g = 1.34928284767356E-5 |
| G1 = ((2*(1-Inh_3)*(1-Inh_b)*k3*G2-(1-Inh_1)*(1-Inh_b)*k1*G1)-(1+Sti_apo_g)*(1+Sti_apo_b)*k_apo*G1)-(1+Sti_other_g)*(1+Sti_other_b)*k_other*G1 | ((2*(1-Inh_3)*(1-Inh_b)*k3*G2-(1-Inh_1)*(1-Inh_b)*k1*G1)-(1+Sti_apo_g)*(1+Sti_apo_b)*k_apo*G1)-(1+Sti_other_g)*(1+Sti_other_b)*k_other*G1 | Sti_apo_b = 0.0; k_apo = 0.00394; k_other = 2.97E-4; Sti_other_g = 1.34928284767356E-5; Inh_3 = 0.483492347087237; k3 = 0.222; Inh_b = 0.135321100917431; k1 = 0.357; Sti_apo_g = 0.0; Sti_other_b = 2.75; Inh_1 = 0.642088110341617 |
| R_live = G1+S+G2 | [] | [] |
| S = (((1-Inh_1)*(1-Inh_b)*k1*G1-(1-Inh_g)*k2*S)-(1+Sti_apo_g)*(1+Sti_apo_b)*k_apo*S)-(1+Sti_other_g)*(1+Sti_other_b)*k_other*S | (((1-Inh_1)*(1-Inh_b)*k1*G1-(1-Inh_g)*k2*S)-(1+Sti_apo_g)*(1+Sti_apo_b)*k_apo*S)-(1+Sti_other_g)*(1+Sti_other_b)*k_other*S | Inh_g = 0.874253042562929; Sti_apo_b = 0.0; Inh_b = 0.135321100917431; k1 = 0.357; k_apo = 0.00394; Sti_apo_g = 0.0; k_other = 2.97E-4; Sti_other_b = 2.75; k2 = 0.114; Sti_other_g = 1.34928284767356E-5; Inh_1 = 0.642088110341617 |
| R_apo = (1+Sti_apo_g)*(1+Sti_apo_b)*k_apo*(G1+S+G2)-(1+Sti_apo_g)*(1+Sti_apo_b)*f1*k_apo*R_apo | (1+Sti_apo_g)*(1+Sti_apo_b)*k_apo*(G1+S+G2)-(1+Sti_apo_g)*(1+Sti_apo_b)*f1*k_apo*R_apo | Sti_apo_b = 0.0; k_apo = 0.00394; Sti_apo_g = 0.0; f1 = 0.467 |
(added: 07 Feb 2018, 14:13:17, updated: 07 Feb 2018, 14:13:17)