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BIOMD0000000668 - Zhu2015 - Combined gemcitabine and birinapant in pancreatic cancer cells - basic PD model

 

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Reference Publication
Publication ID: 26252969
Zhu X, Straubinger RM, Jusko WJ.
Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells.
J Pharmacokinet Pharmacodyn 2015 Oct; 42(5): 477-496
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.  [more]
Model
Original Model: BIOMD0000000668.origin
Submitter: Vijayalakshmi Chelliah
Submission ID: MODEL1604270000
Submission Date: 27 Apr 2016 14:53:09 UTC
Last Modification Date: 07 Feb 2018 13:16:38 UTC
Creation Date: 05 Feb 2018 12:05:28 UTC
Encoders:  Matthew Grant Roberts
set #1
null BioModels Database Zhu2015 - combined gemcitabine and birinapant in pancreatic cancer cells - basic PD model
null BioModels Database BIOMD0000000668
bqbiol:hasPart KEGG Drug D02368
set #2
bqbiol:hasPart KEGG Drug D10417
bqbiol:occursIn Brenda Tissue Ontology BTO:0000988
bqbiol:isDescribedBy PubMed 26252969
NCIt C191
Notes
Zhu2015 - Combined gemcitabine and birinapant in pancreatic cancer cells - basic PD model
Mathematical model to illustrate the effectiveness of combination chemotherapy involving gemcitabine and birinapant against pancreatic cancer.

This model is described in the article:

Zhu X, Straubinger RM, Jusko WJ.
J Pharmacokinet Pharmacodyn 2015 Oct; 42(5): 477-496

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: BIOMD0000000668.

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.

Model
Publication ID: 26252969 Submission Date: 27 Apr 2016 14:53:09 UTC Last Modification Date: 07 Feb 2018 13:16:38 UTC Creation Date: 05 Feb 2018 12:05:28 UTC
Mathematical expressions
Reactions
g_death_stimulus delay 1 g_death_stimulus delay 2 g_death_stimulus delay 3 g_death_stimulus delay 4
g_death_stimulus delay 4 degradation b_death_stimulus delay 1 b_death_stimulus delay 2 b_death_stimulus delay 3
b_death_stimulus delay 4 b_death_stimulus delay 4 degradation    
Rules
Assignment Rule (variable: Inh_g) Assignment Rule (variable: Inh_b) Assignment Rule (variable: Sti_g) Assignment Rule (variable: Sti_b)
Rate Rule (variable: Ra) Rate Rule (variable: Rd)    
Physical entities
Compartments Species
Pancreas Ra Rd Inh_g
Inh_b Sti_g Sti_b
Sti_g1 Sti_g2 Sti_g3
Sti_g4 Sti_b1 Sti_b2
Sti_b3 Sti_b4  
Global parameters
Ra_0 Rd_0 Rss kg
kd Imax_g Imax_b IC50_g
IC50_b Hi_g Hi_b Smax_g
Smax_b SC50_g SC50_b Hs_g
Hs_b ktau_g ktau_b Psi_i
Psi_s C_g C_b Initial for Rss
Initial for kd Initial for kg    
Reactions (10)
 
 g_death_stimulus delay 1 [Sti_g] → [Sti_g1];  
 
 g_death_stimulus delay 2 [Sti_g1] → [Sti_g2];  
 
 g_death_stimulus delay 3 [Sti_g2] → [Sti_g3];  
 
 g_death_stimulus delay 4 [Sti_g3] → [Sti_g4];  
 
 g_death_stimulus delay 4 degradation [Sti_g4] → ;  
 
 b_death_stimulus delay 1 [Sti_b] → [Sti_b1];  
 
 b_death_stimulus delay 2 [Sti_b1] → [Sti_b2];  
 
 b_death_stimulus delay 3 [Sti_b2] → [Sti_b3];  
 
 b_death_stimulus delay 4 [Sti_b3] → [Sti_b4];  
 
 b_death_stimulus delay 4 degradation [Sti_b4] → ;  
 
Rules (6)
 
 Assignment Rule (name: Inh_g) Inh_g = Imax_g*C_g^Hi_g/((Psi_i*IC50_g)^Hi_g+C_g^Hi_g)
 
 Assignment Rule (name: Inh_b) Inh_b = Imax_b*C_b^Hi_b/((Psi_i*IC50_b)^Hi_b+C_b^Hi_b)
 
 Assignment Rule (name: Sti_g) Sti_g = Smax_g*C_g^Hs_g/((Psi_s*SC50_g)^Hs_g+C_g^Hs_g)
 
 Assignment Rule (name: Sti_b) Sti_b = Smax_b*C_b^Hs_b/((Psi_s*SC50_b)^Hs_b+C_b^Hs_b)
 
 Rate Rule (name: Ra) d [ Ra] / d t= (1-Inh_g)*(1-Inh_b)*ModelValue_3*Ra*(1-Ra/ModelValue_2)-(1+Sti_g4)*(1+Sti_b4)*ModelValue_4*Ra
 
 Rate Rule (name: Rd) d [ Rd] / d t= (1+Sti_g4)*(1+Sti_b4)*ModelValue_4*Ra-ModelValue_4*Rd
 
 Pancreas Spatial dimensions: 3.0  Compartment size: 1.0
 
 Ra
Compartment: Pancreas
Initial concentration: 307000.0
 
 Rd
Compartment: Pancreas
Initial concentration: 1940.0
 
  Inh_g
Compartment: Pancreas
Initial concentration: 0.0
 
  Inh_b
Compartment: Pancreas
Initial concentration: 0.0
 
  Sti_g
Compartment: Pancreas
Initial concentration: 0.0
 
  Sti_b
Compartment: Pancreas
Initial concentration: 0.0
 
 Sti_g1
Compartment: Pancreas
Initial concentration: 0.0
 
 Sti_g2
Compartment: Pancreas
Initial concentration: 0.0
 
 Sti_g3
Compartment: Pancreas
Initial concentration: 0.0
 
 Sti_g4
Compartment: Pancreas
Initial concentration: 0.0
 
 Sti_b1
Compartment: Pancreas
Initial concentration: 0.0
 
 Sti_b2
Compartment: Pancreas
Initial concentration: 0.0
 
 Sti_b3
Compartment: Pancreas
Initial concentration: 0.0
 
 Sti_b4
Compartment: Pancreas
Initial concentration: 0.0
 
Global Parameters (26)
 
 Ra_0
Value: 307000.0
Constant
 
 Rd_0
Value: 1940.0
Constant
 
 Rss
Value: 5490000.0
Constant
 
 kg
Value: 0.0209
Constant
 
 kd
Value: 3.85E-4
Constant
 
 Imax_g
Value: 0.991
Constant
 
 Imax_b
Value: 0.375
Constant
 
 IC50_g
Value: 20.8
Constant
 
 IC50_b
Value: 145.0
Constant
 
 Hi_g
Value: 3.57
Constant
 
 Hi_b
Value: 1.06
Constant
 
 Smax_g
Value: 4.09
Constant
 
 Smax_b
Value: 17.5
Constant
 
 SC50_g
Value: 14.0
Constant
 
 SC50_b
Value: 168.0
Constant
 
 Hs_g
Value: 5.0
Constant
 
 Hs_b
Value: 0.984
Constant
 
 ktau_g
Value: 0.086
Constant
 
 ktau_b
Value: 0.611
Constant
 
 Psi_i
Value: 1.0
Constant
 
 Psi_s
Value: 1.0
Constant
 
 C_g
Constant
 
 C_b
Constant
 
 Initial for Rss
Value: 5490000.0
Constant
 
 Initial for kd
Value: 3.85E-4
Constant
 
 Initial for kg
Value: 0.0209
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000668

Curator's comment: (updated: 07 Feb 2018 13:10:49 GMT)

Similar figures of figure 4 of the reference publication have been produced with Psi_i=1 and Psi_s=1 as opposed to Psi_i=0.582 and Psi_s=0.583 for figures 4E and 4F as listed in table 1 of the reference publication.

The figures illustrate the number of proliferating (left) and dead (right) cells after 100 hours of gemcitabine (top), birinapant (middle) and combination (bottom) treatment. Black, blue, green and red curves correspond to increasing drug concentration, as used in the reference publication. The number of proliferating cells decreased after a combination of 20nM gemcitabine + 500 nM birinapant (figure 4E, bottom left, red curve).

The simulations were performed in COPASI V4.22 (Build 170) and figures were generated in MATLAB R2014.

Additional file(s)
  • COPASI file:
    Curated and annotated COPASI file.
  • SED-ML file:
    SED-ML file to produce a similar figure to figure 4a of the reference publication. Concentration of birinapant is set to zero while a parameter scan varies the concentration of gemcitabine from 0 to 20 in increments of 5 nM.
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