A Prey-Predator Model for Immune Response and Drug Resistance in Tumor Growth

G. Albano1 , V. Giorno1 , and C. Saturnino2

Dipartimento di Matematica e Informatica, Universit` di Salerno, a Via Ponte don Melillo, Fisciano (SA), Italy {pialbano,giorno}@unisa.it Dip. di Scienze Farmaceutiche , Universit` di Salerno, Via Ponte don Melillo, a Fisciano (SA), Italy saturnino@unisa.it
1

Abstract. In this paper the interaction between cancer and immunological system is analysed. The model is a modication of a one proposed by de Vladar and Gonzales. For our model the stability is analysed. Furthermore, the eect of a therapy schedule with xed concentration is investigated. Mathematically, the eect of therapy is viewed as a moderating term both for tumor cell growth rate and for T-cells death rate. In conclusion, a systematic computational analysis is associated to the obtained theoretical results. Keywords: Prey-predator model; Gompertz growth; immune surveilance.

Introduction

Many mathematical models have been proposed in literature to describe the evolution of tumors (see, for instance, [2], [5], [8]). Some of these models are based on the Gompertz law because this one approximates experimental observations of cancer growth. Furthermore, to take into account environmental uctuations, in [1] a stochastic approach generalizing Gompertz growth has been performed. The aim of this paper is to describe the interaction between the cancer and the immunological system. In this direction, in [2] de Vladar and Gonzales proposed a model that includes the principal characteristics of the T-cell-mediated reaction against cancer. This model is described by two ordinary dierential equations: x = x x ln x x y (1) y = I (x x ) y y + k
2

where x and y denote the size of tumor and of the immunocompetent cells respectively, and the parameters and are the growth and decay rates of tumor cells; is the rate of elimination of cancer cells by the activity of T-cells; I
Work performed under partial support by MIUR (PRIN 2005) G.N.C.S-INdAM.
R. Moreno-D et al. (Eds.): EUROCAST 2007, LNCS 4739, pp. 171178, 2007. az c Springer-Verlag Berlin Heidelberg 2007

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represents the production of T-cells due to the stimulation of cancer cells; 1 denotes the saturation density above which the immunological system is suppressed; is the natural death rate of T-cells and k is the constant rate of inux of T-cells from primary organs. We choose the description of de Vladar-Gonzales model since it comprises the relevant features of cancer growth under immunological activity. On the other hand, in de Vladar-Gonzales model the growth rate of immunocompetent cells depends on tumor size; when x reaches 1/ this rate, it becomes negative implying that tumor cells are able to kill the cells activated from immunological system. According to de Pillis (cf. [7]), we believe that immunocompetent cells eventually become inactivated after some number of interactions with tumor cells, but it doesnt exist any biological mechanism which allows to the tumor cells to kill T-cells. Indeed, the well known phenomenon of leukopenia, i.e. a decrease in the number of leukocytes in the blood, is associated to chemotherapy or to radiation therapy. In the second section of this work we will review the main characteristics of the model by de Vladar-Gonzales to motivate and justify our modication. In the third section we will describe the features of our model and, in the Section 4, we will study the behaviour of the system in the presence of typical treatment schedules including drug resistance. Finally, in the last section, the possibility to include random environment in the model is investigated.

de Vladar-Gonzales Model

System (1) satises an heuristic but desiderable property in tumor models: the point P0 (0, k/) is an unstable xed point for all choices of the parameters. So the model predicts that the tumor grows aggressively near the zero, therefore there is no possible condition that allows self-regression. This also implies that treatments which leave microscopic amounts of cancer cells (subclinical unobservable cancer) will permit a new tumor growth. We note that the quantity k/ is the basal density of immune-eectors in the absence of tumor cells. This model is also able to describe the dierent types of tumor behaviour observed clinically: rst, the description of dormant tumors which do not grow more than a nite size; second, the description of malignant tumors which clinically can be considered of unlimited size. 2.1 de Vladar-Gonzales Model Under Therapy

de Vladar-Gonzales consider that the eect of a therapy consists in the elimination of a proportion of cells. Therapy aects both tumor cells and T-cells in a proportion kC and kI . Mathematically the equation (1) becomes: x = x x ln x x y kC C(t) y = I (x x2 ) y y + k kI C(t), so, in the case of a therapy with xed dosage C0 (cf. [6]) the eect is a parametric perturbation on the system (1), indeed

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kC C0 , + kI C0 . Then, in accordance to clinical experience, the model predicts that treatment applications induce shrinking of the tumor to microscopical tumors and not to self-regression. We point out that the model (1) neglects one of the principal causes of the failure of chemotherapeutic treatment, i.e. the resistance development of cancer. So another description qualitatively compatible with the observations is necessary. Since we are interested in therapeutic treatment, we will consider induced resistance, i.e. that comes from the use of chemotherapy. In the following section, we will include a Richers function in de Vladar-Gonzales model to improve the description of the interaction between the immunological activity and the cancer growth. Furthermore, in the mathematical model, drug resistance will be obtained by a progressive decrease of drug intensity.

The Model
x = x x ln x x y (2) y = I x e
x

Our model is described by the following system:

y + k.

In this modied scheme the meaning of the parameter is analogous with respect to in the previous model. We are assuming that the proliferation rate of immunocompetent cells is a concave function with respect to tumor size, so immunological system is asymptotically vanished from cancer cells (see [7]). As in de Vladar-Gonzaless model, our description presents an unstable xed point at P0 (0, k ) so for tumor of small size, the acceleration of the growth is such that any interaction from the immunological system is unattainable. Moreover, if x = 0, further equilibrium points for the system (3) can be obtained as points of intersection between the two nullclines. They have the following equations: yC = log x; k yI = . (3) I x e x We observe that yI represents the immunocompetent cells size, so yI > 0 x. Hence, setting A = I x e x , from (3)it is easy to see that A < 0 x. To determine the stability of a xed point, we use the method of the eigenvalues. For each equilibrium point P (x , y ) with x = 0, the jacobian matrix associated to the system (3) is: yC J= A yI A

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where yC and yI are the derivatives of the nullclines (3) with respect to tumor size x. So the eigenvalues are: 1 A C 2 2 (A C )2 + 4 C A 1 yI . yC

(4)

Fig. 1. Phase space in the presence of one xed point corresponding to a dormant tumor: full line represents yI and dashed line is yC

Fig. 2. Phase space in the presence of one xed point corresponding to a malignant tumor: full line represents yI and dashed line is yC

Fig. 3. Phase space in the presence of three xed points: full line represents yI and dashed line is yC

A Prey-Predator Model for Immune Response and Drug Resistance

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Fig. 4. Evolution of parathyroid tumor cells (left) and immunocompetent cells (right) are plotted with x0 = y0 = 1000; I = 0.023 years1 , = 104 years1 , = 0.47 years1 , k = 1.07, = 105 years1

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Fig. 5. Evolution of parathyroid tumor cells (left) and immunocompetent cells (right) are plotted as in Figure 4 with = 105 years1

Imposing that both eigenvalues are negative we nd the condition for stable solutions. We note that < 0 since A < 0 for all (x , y ) and + < 0 yI < 1. yC (5)

In Figure 1 it is shown a conguration of the phase space with one stable xed point. Here the full line is yI and dashed line is yC . We note that the nullcline yI has a maximum in x = 1/ so we can interpret 1/ as the dimension supported by the organism (cf. Fig. 1). Then the xed point PB corresponds to a dormant tumor (if macroscopic) or simply to a microscopic equilibrium (see [3]). In

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Figure 2 it is shown another possible conguration of the phase space again with one stable xed point. Tumor size in this case is near x , the carrying capacity, so biologically this point can be interpreted as a malignant and invasive tumor. The third possible conguration of the system is shown in Figure 3 in which we have three xed points. The two xed points previously described, namely PB and PM , still exist and conserve their stable nature. The point PS , instead, is 1 unstable (saddle point) in a suitable subset of the interval ( , x ). In Figures 4 and 5 its shown the evolution of the population x and y for = 105 years1 and = 102 years1 respectively, in the case of parathyroid tumor. In the rst case we can see that tumor population evolves as in the absence of immunoeffectors with Gompertz law. In the second case a non trivial equilibrium point between tumor and immunological system is reached, so that our model predicts immune surveillance theory is plausible.

Introduction of a Therapy

The eect of a treatment schedule is evaluated on the population x and y by introducing one more term in Eq. (3). Drug resistance is obtained by a progressive decrease of aggressiveness of drug, so that a drug able to reduce tumor proliferation rate of 50% after the rst administration, at the n-th (n 2) this rate will be able to reduce it of (50 n a)% (a > 0). So, denoted by n the number of drug administrations and by ti (1 i n) the instants in which drug is administered, we have:

x=
j=0

I[t ,t ) x x ln x xy j j j+1

(6)

y = I xex y y + k c0

j I[tj ,tj+1 ) y
j=0

where the parameters j and j are non negative constants describing the aggressiveness of drug on the population x and y respectively, and so they are proportional to drug concentration (see [6]). The function I[a,b) () denotes the indicator function of the interval [a, b). We assume that the sequences {j }j0 and {j }j0 are increasing until is stopped the therapeutic schedule; after j = 1 and j = 0. In Figure 6 it is shown the evolution of tumor and immunocompetent cells in the presence of a treatment schedule with n = 5 and tj = 0.1 years. The parameters of the model are chosen as in Figure 4, in which immunological system is not able to control tumor. Furthermore we assume:
j

j + 1 for 1 j < n; 0 otherwise;

j =

j + 1 for 1 j < n; 1 otherwise.

Moreover, the nal point PF (x(tn+1 ), y(tn+1 )) can be used to estimate the evolution of the tumor after therapy, indeed by considering PF as initial point in Eq. (3) we obtain the dynamics of the populations x and y after the treatment

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Fig. 6. Evolution of parathyroid tumor cells (left) and immunocompetent cells (right) is plotted with x0 = y0 = 1000; I = 0.023 years1 , = 104 years1 , = 0.47 years1 , k = 1.07
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Fig. 7. Evolution of parathyroid tumor cells (left) and immunocompetent cells (right). We choose the parameters as in Figure 5

schedule. In Figure 7 its shown the evolution of tumor and immunocompetent cells after a treatment as in Figure 6. We can see that in this case a xed point is reached where tumor size is nite but not zero. So we conclude that a therapy with xed concentration is not able to reduce totally tumor, but an equilibrium point between immunocompetent cells and tumor in this case is reached.

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Further Work

In order to take into account random perturbations of the system (3), so as to model uctuations present in experimental data, its possible to generalize the parameters in (3) in the following way: + 1 dW1 2 + 2 dW where W1 and W2 are two independent white noises and 1 and 2 are constants describing the width of random uctuations. So, the system (3) becomes: d x = ( x x ln x x y) dt + 1 x dW1 (t) d y = (I x e x y + k) dt + 2 x dW2 (t). In order that the system (7) has an unique solution, continuous with probability one, the coecients have to verify the linear growth condition and the local Lipschitz condition. Such study will be subject of future work.

References
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