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        <pre>Modelling tumor growth with immune response and drug using ordinary differential equations

Mohd Rashid Admon, Normah Maan

This is a mathematical study about tumor growth from a different perspective, with the aim of predicting and/or controlling the disease. The focus is on the effect and interaction of tumor cell with immune and drug. This paper presents a mathematical model of immune response and a cycle phase specific drug using a system of ordinary differential equations. Stability analysis is used to produce stability regions for various values of certain parameters during mitosis. The stability region of the graph shows that the curve splits the tumor decay and growth regions in the absence of immune response. However, when immune response is present, the tumor growth region is decreased. When drugs are considered in the system, the stability region remains unchanged as the system with the presence of immune response but the population of tumor cells at interphase and metaphase is reduced with percentage differences of 1.27 and 1.53 respectively. The combination of immunity and drug to fight cancer provides a better method to reduce tumor population compared to immunity alone.</pre>
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                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </species>
    </listOfSpecies>
    <listOfParameters>
      <parameter constant="true" id="a1" metaid="COPASI5" name="a1" value="1">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI5">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T16:56:09Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="a4" name="a4" value="0.8"/>
      <parameter constant="true" id="d1" name="d1" value="0.29"/>
      <parameter constant="true" id="d2" name="d2" value="0.11"/>
      <parameter constant="true" id="d3" name="d3" value="0.4"/>
      <parameter constant="true" id="c1" name="c1" value="0.9"/>
      <parameter constant="true" id="c3" name="c3" value="0.9"/>
      <parameter constant="true" id="c2" name="c2" value="0.085"/>
      <parameter constant="true" id="c4" name="c4" value="0.085"/>
      <parameter constant="true" id="k" name="k" value="0.029"/>
      <parameter constant="true" id="k1" metaid="COPASI6" name="k1" value="0">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI6">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T16:48:04Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="k2" name="k2" value="0.57"/>
      <parameter constant="true" id="k3" metaid="COPASI7" name="k3" value="0">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI7">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T16:22:12Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="k4" name="k4" value="0.061"/>
      <parameter constant="true" id="alpha" name="alpha" value="0.2"/>
      <parameter constant="true" id="p" name="p" value="0.1"/>
      <parameter constant="true" id="n" name="n" value="3"/>
      <parameter constant="true" id="gamma" metaid="COPASI8" name="gamma" value="0">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI8">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T16:50:03Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="false" id="d" metaid="COPASI9" name="d" value="1.44144144144144">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI9">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T16:26:34Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
    </listOfParameters>
    <listOfRules>
      <assignmentRule variable="d">
        <math xmlns="http://www.w3.org/1998/Math/MathML">        
          <apply>
            <divide/>
            <apply>
              <times/>
              <cn> 2 </cn>
              <ci> a1 </ci>
              <ci> a4 </ci>
            </apply>
            <apply>
              <plus/>
              <ci> a1 </ci>
              <ci> d2 </ci>
            </apply>
          </apply>
        </math>
            </assignmentRule>
    </listOfRules>
    <listOfReactions>
      <reaction id="Increase_in_the_population_of_tumor_cell_during_interphase" metaid="COPASI10" name="Increase in the population of tumor cell during interphase" reversible="false">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/">
            <rdf:Description rdf:about="#COPASI10">
	<bqmodel:hasInstance>
	<rdf:Bag>
	<rdf:li rdf:resource="http://identifiers.org/ncit/C25533"/>
	</rdf:Bag>
	</bqmodel:hasInstance>
	</rdf:Description>
	
          </rdf:RDF>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI10">
                <bqmodel:isDescribedBy rdf:resource="urn:miriam:ncit:C25533"/>
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T15:57:01Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
              <listOfProducts>
          <speciesReference species="Ti" stoichiometry="1"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference species="Tm"/>
        </listOfModifiers>
        <kineticLaw>
          <math xmlns="http://www.w3.org/1998/Math/MathML">          
            <apply>
              <times/>
              <ci> compartment </ci>
              <apply>
                <ci> Function_for_increase_in_the_population_of_tumor_cell_during_interphase </ci>
                <ci> a4 </ci>
                <ci> Tm </ci>
              </apply>
            </apply>
          </math>
                </kineticLaw>
      </reaction>
      <reaction id="Decrease_in_the_population_of_tumor_cell_during_interphase" metaid="COPASI11" name="Decrease in the population of tumor cell during interphase" reversible="false">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/">
            <rdf:Description rdf:about="#COPASI11">
	<bqmodel:hasInstance>
	<rdf:Bag>
	<rdf:li rdf:resource="http://identifiers.org/ncit/C157203"/>
	</rdf:Bag>
	</bqmodel:hasInstance>
	</rdf:Description>
	
          </rdf:RDF>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI11">
                <bqmodel:isDescribedBy rdf:resource="urn:miriam:ncit:C157203"/>
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T15:58:23Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
              <listOfReactants>
          <speciesReference species="Ti" stoichiometry="1"/>
        </listOfReactants>
        <listOfModifiers>
          <modifierSpeciesReference species="I"/>
        </listOfModifiers>
        <kineticLaw>
          <math xmlns="http://www.w3.org/1998/Math/MathML">          
            <apply>
              <times/>
              <ci> compartment </ci>
              <apply>
                <ci> Function_for_decrease_in_the_population_of_tumor_cell_during_interphase </ci>
                <ci> c1 </ci>
                <ci> I </ci>
                <ci> d2 </ci>
                <ci> Ti </ci>
                <ci> a1 </ci>
              </apply>
            </apply>
          </math>
                </kineticLaw>
      </reaction>
      <reaction id="Increase_in_population_of_tumor_cell_during_mitosis" metaid="COPASI12" name="Increase in population of tumor cell during mitosis" reversible="false">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/">
            <rdf:Description rdf:about="#COPASI12">
	<bqmodel:hasInstance>
	<rdf:Bag>
	<rdf:li rdf:resource="http://identifiers.org/ncit/C25533"/>
	</rdf:Bag>
	</bqmodel:hasInstance>
	</rdf:Description>
	
          </rdf:RDF>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI12">
                <bqmodel:isDescribedBy rdf:resource="urn:miriam:ncit:C25533"/>
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T15:59:52Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
              <listOfProducts>
          <speciesReference species="Tm" stoichiometry="1"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference species="Ti"/>
        </listOfModifiers>
        <kineticLaw>
          <math xmlns="http://www.w3.org/1998/Math/MathML">          
            <apply>
              <times/>
              <ci> compartment </ci>
              <apply>
                <ci> Function_for_increase_in_the_population_of_tumor_cell_during_mitosis </ci>
                <ci> a1 </ci>
                <ci> Ti </ci>
              </apply>
            </apply>
          </math>
                </kineticLaw>
      </reaction>
      <reaction id="Decrease_in_the_population_of_tumor_cell_during_mitosis" metaid="COPASI13" name="Decrease in the population of tumor cell during mitosis" reversible="false">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/">
            <rdf:Description rdf:about="#COPASI13">
	<bqmodel:hasInstance>
	<rdf:Bag>
	<rdf:li rdf:resource="http://identifiers.org/ncit/C157203"/>
	</rdf:Bag>
	</bqmodel:hasInstance>
	</rdf:Description>
	
          </rdf:RDF>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI13">
                <bqmodel:isDescribedBy rdf:resource="urn:miriam:ncit:C157203"/>
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T16:00:54Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
              <listOfReactants>
          <speciesReference species="Tm" stoichiometry="1"/>
        </listOfReactants>
        <listOfModifiers>
          <modifierSpeciesReference species="I"/>
          <modifierSpeciesReference species="u"/>
        </listOfModifiers>
        <kineticLaw>
          <math xmlns="http://www.w3.org/1998/Math/MathML">          
            <apply>
              <times/>
              <ci> compartment </ci>
              <apply>
                <ci> Function_for_decrease_in_the_population_of_tumor_cell_during_mitosis </ci>
                <ci> d3 </ci>
                <ci> Tm </ci>
                <ci> a4 </ci>
                <ci> c3 </ci>
                <ci> I </ci>
                <ci> k1 </ci>
                <ci> k2 </ci>
                <ci> u </ci>
              </apply>
            </apply>
          </math>
                </kineticLaw>
      </reaction>
      <reaction id="induction_of_immune_response_due_to_tumor_cell_formation" metaid="COPASI14" name="induction of immune response due to tumor cell formation" reversible="false">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/">
            <rdf:Description rdf:about="#COPASI14">
	<bqmodel:hasInstance>
	<rdf:Bag>
	<rdf:li rdf:resource="http://identifiers.org/ncit/C25533"/>
	</rdf:Bag>
	</bqmodel:hasInstance>
	</rdf:Description>
	
          </rdf:RDF>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI14">
                <bqmodel:isDescribedBy rdf:resource="urn:miriam:ncit:C25533"/>
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T16:03:25Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
              <listOfProducts>
          <speciesReference species="I" stoichiometry="1"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference species="Ti"/>
          <modifierSpeciesReference species="Tm"/>
        </listOfModifiers>
        <kineticLaw>
          <math xmlns="http://www.w3.org/1998/Math/MathML">          
            <apply>
              <times/>
              <ci> compartment </ci>
              <apply>
                <ci> Function_for_formation_of_immune_response </ci>
                <ci> k </ci>
                <ci> p </ci>
                <ci> I </ci>
                <ci> Ti </ci>
                <ci> Tm </ci>
                <ci> n </ci>
                <ci> alpha </ci>
              </apply>
            </apply>
          </math>
                </kineticLaw>
      </reaction>
      <reaction id="Decrease_in_the_popoulation_of_immune_response" metaid="COPASI15" name="Decrease in the popoulation of immune response" reversible="false">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/">
            <rdf:Description rdf:about="#COPASI15">
	<bqmodel:hasInstance>
	<rdf:Bag>
	<rdf:li rdf:resource="http://identifiers.org/ncit/C157203"/>
	</rdf:Bag>
	</bqmodel:hasInstance>
	</rdf:Description>
	
          </rdf:RDF>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI15">
                <bqmodel:isDescribedBy rdf:resource="urn:miriam:ncit:C157203"/>
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T16:05:51Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
              <listOfReactants>
          <speciesReference species="I" stoichiometry="1"/>
        </listOfReactants>
        <listOfModifiers>
          <modifierSpeciesReference species="Tm"/>
          <modifierSpeciesReference species="u"/>
          <modifierSpeciesReference species="Ti"/>
        </listOfModifiers>
        <kineticLaw>
          <math xmlns="http://www.w3.org/1998/Math/MathML">          
            <apply>
              <times/>
              <ci> compartment </ci>
              <apply>
                <ci> Function_for_decrease_in_the_population_of_immune_response </ci>
                <ci> c2 </ci>
                <ci> I </ci>
                <ci> c4 </ci>
                <ci> Tm </ci>
                <ci> d1 </ci>
                <ci> k3 </ci>
                <ci> k4 </ci>
                <ci> u </ci>
                <ci> Ti </ci>
              </apply>
            </apply>
          </math>
                </kineticLaw>
      </reaction>
      <reaction id="Decrease_in_drug" metaid="COPASI16" name="Decrease in drug" reversible="false">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/">
            <rdf:Description rdf:about="#COPASI16">
	<bqmodel:hasInstance>
	<rdf:Bag>
	<rdf:li rdf:resource="http://identifiers.org/ncit/C157203"/>
	</rdf:Bag>
	</bqmodel:hasInstance>
	</rdf:Description>
	
          </rdf:RDF>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI16">
                <bqmodel:isDescribedBy rdf:resource="urn:miriam:ncit:C157203"/>
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2019-12-18T16:09:22Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
              <listOfReactants>
          <speciesReference species="u" stoichiometry="1"/>
        </listOfReactants>
        <kineticLaw>
          <math xmlns="http://www.w3.org/1998/Math/MathML">          
            <apply>
              <times/>
              <ci> compartment </ci>
              <apply>
                <ci> Function_for_decrease_in_drug </ci>
                <ci> gamma </ci>
                <ci> u </ci>
              </apply>
            </apply>
          </math>
                </kineticLaw>
      </reaction>
    </listOfReactions>
  </model>
</sbml>