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Matematika

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3, June 2015

Treatment by Using Gene Therapy

Dwi Lestari and Ratnasari Dwi Ambarwati

Abstract—This study observed a local stability of Therapy. This therapy will specifically against cancer cells,

mathematical model for cancer treatment by using gene specific area, without disturbing normal cells in the body [3].

therapy. Started with modelling the Gene Therapy for Cancer Cancer is a genetic alteration so that the gene therapy

Treatment then continued with the discussion about

equilibrium point, the model was developed by Lotka-Volterra

methods to be one type of treatment against cancer. Genetic

model. It is very important to investigate the behaviour of changes could lead to cell cycle regulation. In normal cells

equilibrium point such as the stability of that point in certain there is a balance between cell proliferation with cell death

conditions especially a local stability. Furthermore, simulation which is regulated through the cell cycle with cellular

of the model was given by taking some certain parameter checkpoint. One of the characteristics of cancer cells is the

values. loss of checkpoint control [4]. Gene therapies performed by

Index Terms—Cancer, gene therapy, Lotka Volterra,

replacing or inactivate genes that do not work, adding a

stability. functional gene, or insert a gene into the cells to make the

normal functioning of cells [5]. In contrast to the method of

immunotherapy treatment that refers to the use of cytokines,

I. INTRODUCTION namely interleukin-2 (IL-2), the method of gene therapy,

Cancer is a worldwide major cause of death. Cancer arises IL-2 eliminated from the immunotherapy model and replaced

as a result of the rapid and uncontrollable growth of abnormal E

by self-proliferation that is p [1].

cells in the human body. Cell is the smallest part of the body 1 E f

and cancer occurs from normal cells. Some types of cancers The process of gene therapy that has the characteristics of

include breast cancer, cervical cancer, brain cancer, lung controlling the speed of cancer cells growth is particular

cancer, and bone cancer. Cancer is caused by chemical interest. Seen from the mathematics point of view, gene

substances, alcoholic beverages, excessive solar radiation, therapy for cancer can be modelled mathematically in the

genetic differences, and so on [1]. Various methods are used form of differential equations systems. Based on the

to cure or inhibit the growth of cancer. The type of treatment, Lotka-Volterra model, in 1994 Kuznetsov developed the

such as surgery, radiation therapy, chemotherapy, target Lotka-Volterra model in 1994. Furthermore in 1998 [6],

therapy, immunotherapy, hormonal therapy, angiogenesis Kirschner and Panneta continued to build KP models

inhibitors, palliative care, and the last is a gene therapy. Each developed from the Kuznetsov model by adding a cytokines

therapy has side effects, eg nausea, vomiting, pressing the population as intercellular communication molecules by the

blood production, fatigue, hair loss and mouth sores. Side immune system. Gene therapy models developed from the

effects occur, as a result of chemotherapy drugs not only kill two previous models made the T-cells induce every cell to

cancer cells but also normal cells that divide rapidly. Such as, produced T-cell receptor (TCR). These cells are transferred

cell gastrointestinal tract, skin, hair and sperm [2]. Therefore, back to the cancer patient's body and will recognize and resist

other therapies developed for the treatment of cancers such as molecules found as tumor cells. TCR will activate T-cells

gene therapy. that then attack and kill cancer cells. Gene therapy models are

The latest treatment methods are still in the research stage built based on the KP models.

is gene therapy. Treatment of cancer undergoes evolutionary This study focused on the growth dynamics of effector

change as the understanding of the biological processes that cells and tumor cells because of the influence of the use of

underlie the occurrence of cancer. Surgical removal of the gene therapy. These conditions can be modeled in the form of

tumor has been documented in ancient Egypt, hormone a mathematical equation. The interaction between effector

therapy was developed in 1896, and radiation therapy was cells and tumor cells is described as a competition between

developed in 1899. Chemotherapy, immunotherapy, and new the two populations, therefore the interaction established

targeted therapies are a product of the 20th century. A new mathematical models based on the system of the predator

treatment needs to be developed and modified to improve the prey. The plot starts from the formation of the model,

effectiveness, high precision, as well as the size of survival determined the equilibrium point, analyze the local stability

skills, and improve the quality life of patients. One of the and then simulate the model.

Manuscript received December 13, 2014; revised March 3, 2015. This

work was supported in part by Internasional affairs and partnerships

Yogyakarta State University Indonesia. II. MATHEMATICAL MODEL FOR THE SPREAD OF CANCER

The authors are with the Department of Mathematics Education, Faculty

of Mathematics and natural Science, Yogyakarta State University, Indonesia

In gene therapy treatment, there are two methods in the

(e-mail: dwilestari@uny.ac.id, dwilestari.math@gmail.com, insertion of the cell, namely the insertion of in-vivo and

naasaa28@gmail.com ).

International Journal of Modeling and Optimization, Vol. 5, No. 3, June 2015

ex-vivo insertion. In-vivo insertion is the direct insertion of 1) Tumor cell growth following the logistics growth

the vector into the target area in the body, while the ex-vivo 2) Natural death occurred on effector cells

insertion is targeted cells released from the patient's body, 3) The population is not constant

forced to imitate and in transduction with vectors before In the literature [1] defined the values of the parameters are

being returned to the patient [7]. The treatments process with largely based on previous research (see Table I). These

gene therapy describe below: parameters are as follows:

1) Replace missing or mutated gene with a healthy gene. The Transfer diagram can be seen as follow:

2) Inserting genes into tumor that acts like suicide bombing

after activated by drugs.

3) Inserting genes that make tumors more vulnerable to

treatment such as chemotherapy and radiotherapy.

4) Augment the immune response to cancer by increasing

the ability of immune cells, such as T cells and dendritic

cells, to fight cancer cells.

known as KP models shown below:

Fig. 1. Gene therapy transfer diagram model.

EC

E =cT - 2 E p1 S1 (1a) Based on Fig. 1, the gene therapy model developed in the

g1 C form of differential equations systems is written as follows:

EC

T cT 2 E p1 S1 (1b)

g1 C (2)

p2 ET

C S 2 3C (1c)

g3 T with are constant. Where and

.

The notation used is

E (t ) : effector immune cell III. EQUILIBRIUM POINT

T (t ) : cancer cell

Equation (2) will reach equilibrium point on and

C(t) : effector molecules

C : antigen parameters , so the equation can be written as follows:

2 : pure death parameters

S1 : immunotheraphy parameters (2a)

(2b)

Equation (1b) shows the logistic growth of cancer cells,

with b-1 as a maximum capacity limit (maximum carrying

From Equation (2b) we obtain:

capacity). Furthermore, gene therapy models obtained by

removing the equation (1c) and replace it with cell

(3)

proliferation (self proliferation) in equation (1a).

(4)

TABLE I: PARAMETER VALUE

(5)

with :

obtained

and

with:

Here are the assumptions required to obtain mathematical Thus equilibrium point and were

models: obtained. It is analog for other following points:

203

International Journal of Modeling and Optimization, Vol. 5, No. 3, June 2015

and

with:

Eigen values were obtained from equation (8) as is the

determinant of matrix and is the trace of the matrix.

Based on definition and theorem [8], [9],

.

a) If and then the equilibrium

and :

point in the form of nodes, and if

then asymptotically stable. If then

and is unstable.

b) If , and then the

with: equilibrium point in the form of focus, and

if then asymptotically stable. If

then unstable.

. equilibrium point is written

bellow

Thus the equilibrium points and

were obtained.

and points known as the equilibrium points of

infected cancer. Therefore, those six equilibrium points,

named as:

Equation (10) can be written as follows:

, , , , (11)

and . with:

Equation (2) was being linearized to obtain the Jacobian

matrix as follows,

Eigen values obtained from equation (10) are

. (6)

1) For cancer-free equilibrium point is the determinant of the matrix and is the trace

, substituted into Equation (6) to of a matrix .

obtain cancer-free Jacobian matrix: a) If and then the equilibrium

point in the form of nodes, and if

then is asymptotically stable. If then

is unstable.

b) If , and then the

equilibrium point in the form of focus, and

The characteristic equation of (7) is: if then is asymptotically stable. If

then is unstable.

(8) substitution of into (6) can be used to obtain

the characteristic equation as bellow:

Then, equation (8) can be written as follows:

(9)

with:

(12)

Then equation (12) can be written as:

204

International Journal of Modeling and Optimization, Vol. 5, No. 3, June 2015

point in the form of nodes, and if

with:

then is asymptotically stable. If

then is unstable.

b) If , and then the

equilibrium point in the form of nodes

focus, and if then is asymptotically

stable. If then is unstable.

V. NUMERICAL SIMULATION

Three simulations were being used to see the dynamics of

effector cells and tumor cells. The initial value used in these

is the determinant of the matrix and is the trace of simulations are . Table II contained the

a matrix . values of the parameters for numerical simulations.

a) If and then the equilibrium

TABLE II: PARAMETER VALUES USED IN NUMERICAL SIMULATION [1]

point in the form of nodes, and if

then is asymptotically stable. If Parameter

Simulation

then is unstable.

b) If , and then the 1

2 764.5072

equilibrium point in the form of focus, and 3

if then is asymptotically stable. If

then is unstable. Simulation

Parameter

Analog for P4, P5 and P6 in order to obtain the eigen values

1

of characteristic equation for P4 is

2 38.004

3 2

( and ) are eligible in existence.

is the determinant of the matrix and is the trace of Stability of the simulation 1 is equilibrium point showed

a matrix . unstable result and has the type of saddle point, while is

a) If and then the equilibrium asymptotically stable and has a kind of sink focus point,

point in the form of nodes, and if which means the population of effector cells and tumor cells

then asymptotically stable. If then will grow in tandem. Based on the simulation 2, there is one

unstable. point of equilibrium (P2(25488,0)) is eligible in existence.

b) If , and then the Stability condition of the equilibrium point in simulation 2

equilibrium point in the form of nodes is asymptotically stable and has a kind of sink node point,

focus, and if then asymptotically means the effector cell population will increase while the

stable. If then unstable. tumor cell population will disappear with increasing of . On

Eigen values of the characteristic equation for the P5 is the simulation 3, there is one point of equilibrium that was

eligible in existence ( (3338,0)). Stability conditions of the

equilibrium point in simulation 3 is asymptotically stable

and has a kind of sink node point, the effector cell population

is the determinant of the matrix and is the trace will be constant at the equilibrium point, while the population

of a matrix . of tumor cells will disappear with increasing of . Fig. 2(a),

(b), and (c) showed respectively to simulation 1, 2, and

a) If and then the equilibrium

3-point equilibrium models.

point in the form of nodes, and if

then is asymptotically stable. If

then is unstable.

b) If , and then the

equilibrium point in the form of nodes

focus, and if then is asymptotically

stable. If then is unstable.

Eigen values of the characteristic equation for the P6 is

of a matrix . (a)

205

International Journal of Modeling and Optimization, Vol. 5, No. 3, June 2015

REFERENCES

[1] A. Tsygvintsev, S. Marino, and D. E. Kirshner, A Mathematical Model

of Gene Therapy for The Treatment of Cancer, Springer-Verlag,

Berlin-Heidelberg- New York, 2013.

[2] Ayahbunda. [Online]. Available:

http://www.ayahbunda.co.id/Artikel/keluarga/tips/mengatasi.efek.sam

ping.kemoterapi/001/005/193/1/1

[3] Kabarinews. [Online]. Available:

http://kabarinews.com/kesehatan-harapan-baru-pengobatan-kanker/

[4] N. L. P. I. Dharmayanti, "Study of molecular biology: Supressor gene

(p53) as gene target for cancer treatment," Wartazoa, vol. 13, no. 3,

2013.

[5] T. L. Wargasetia, "Gene therapy for cancer," Journal of Public Health,

(b)

vol. 4, no. 2, 2005.

[6] D. Kirschner and J. C. Panetta, "Modeling immunotherapy of the

tumor-immune interaction," Journal of Mathematical Biology, vol. 37,

no. 3, pp. 235-252, 1998.

[7] W. Stephanie. (2009). Gene Therapy, An Innovative Approach to

Cancer Treatment. [Online]. Available:

http://cosmos.ucdavis.edu/archives/2009/cluster1/WRAITH_STEPH.

pdf. was taken on 15 December 2013.

[8] G. J. Olsder and J. W. V. D. Woude, Mathematical Systems Theory,

Netherland: VVSD, 2004.

[9] P. Lawrence, Differential Equations and Dynamical Systems, 3rd, New

York: Springer, 2001.

(c) bachelor from Yogyakarta State University in 2007 and

Fig. 2. Simulation models (2). graduated master from Gadjah Mada University in

2010. She is a lecturer at Mathematics Education

Department, Mathematics and Natural Science Faculty,

VI. CONCLUSION Yogyakarta State University, Indonesia since 2010 until

now. Her research interests are in applied mathematics

Gene therapy models developed from Lotka-Volterra such as mathematical modelling especially

models and Kirschner and Panneta models which the effector mathematical biology.

Dwi Lestari owns was a membership of Indonesian Mathematics Society

molecule is replaced by a self proliferation of cell on immune (IndoMs) since 2011.

effector cells. Disease-free conditions for gene therapy

models are cancer-free equilibrium conditions, T=0.

Furthermore, the local stability of free cancer equilibrium

point and cancer-infected equilibrium point have to be Ratnasari Dwi Ambarwati was born in Yogyakarta,

analyzed. With the parameter value given, the simulation in 1992. She is a fresh graduate from Yogyakarta State

model of gene therapy is done. University in 2014. Her research interest is

mathematical modelling in biology.

ACKNOWLEDGMENT

The authors wish to thank International Affairs and

Partnership of Yogyakarta State University for supporting

funds. The authors also wish to thank the reviewers for theirs

helpful recommendations.

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