Calculating Time Intervals in Sequential Drug Treatment of Cancerous Tumors

Mochamad Adrian Prananda & Nathan Hyunsoo Lee November 27, 2013

Abstract Treatment of cancerous tumors has evolved from crude surgery to modern techniques such as resection, radiology, and chemotherapy. In this project, we present a model that uses two drugs to destroy a tumor. We determine the growth of the normal cell subpopulation, as well as the subpopulations of mutated cells that are resistant to either of the drugs. We also establish how these subpopulations are reduced in response to the two drugs. Using techniques such as separation of variables, graph analysis and programming, we form a developed model that calculates the ideal time intervals at which the two drugs are sequentially administered.

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Introduction of the Problem & Our Motivations

A defining hallmark in oncogenesisthe induction of canceris uncontrolled cell division. These proliferated cells form a mass called a tumor, and once the cells within the tumor are able to spread throughout the body via the bloodstream or lymphatic vessels, the tumor becomes malignant and cancerous [1]. Although surgery may appear to be the most viable option for the removal of the tumor, it becomes almost useless once the cancerous cells spread, or metastasize, because numerous tumors may arise even decades after the primary tumor has been removed [2]. If the tumor can be treated and eradicated before or even during metastasis, a higher chance of survival is possible for the patient. By this point, invasive procedures then become impractical. Therefore, scientists have turned to more noninvasive methods in order to treat malignant tumors. One of such methods consists of the administration of chemotherapeutic drugs. This may appear to be an effective method to treat these cancerous tumors, but there are many complications in both the administration of the drugs and the drugs themselves. Listed are few of many issues that arise during chemotherapeutic drug treatment:

Chemotherapeutic drugs used for tumor treatment are toxic to normal tissues [3]; Resistance from genetic mutations both independent of and dependent from the drug occurs naturally [4];

Interaction effects and that prevent drugs from being administered simultaneously are common [3], as well as their additive toxicity.

The complications are too many to number, but progress is being made through a tremendous amount of research in technology. As engineers that work at the University of Washington Medical Center and Fred Hutchinson Cancer Research Center, we study the field of cancer from a radiological and a pancreatic perspective. We recognize that oncologythe study of canceris crucial to discovering cures and the best treatments for the different types of cancer, as well as learning about how cancer functions and grows. Therefore, we

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have purposed this project to further investigate how to fight cancer through a very practical and mathematical means. Even though previous scientists have created more sophisticated models addressing drug therapy of tumors, we have realized that those models are near impossible to understand without a strong knowledge of oncology. With this in mind, we began our journey in creating a mathematical model that would be understood without much cancer-specific expertise and jargon and representative of basic oncology. These are the questions we plan to consider:

How does a tumor grow and proliferate over time? How do mutant cells factor into the model? How can the time intervals between administering a drug be determined, given the toxicity of a specific drug?

2
2.1

Simplifications & Variables

Simplifications
Drug delivery is not accounted for. Because drug delivery requires more extensive knowledge about vasculature of the tumor, pressures of different tissues, and the location of where a drug should be administered, we have chosen to omit the subject entirely. We assume that the drug has been properly administered and the full concentration of the dose is inserted into the tumor; this also allows us to make the assumption that the drug effects are active and felt immediately the moment at which the drug is administered. We believe that the time in which the chemotherapeutic drug will reach the tumor is insignificant relative to the time intervals between the administrations of the drug. Instead of randomly occurring, mutations that are resistant to the drug appear in a straightforward fashion that can be observed mathematically. Mutations occur randomly, and there is neither an accurate equation nor a constant method in which mutations develop. Also, mutation rates tend to increase as a drug takes its course and

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diffuses into the body system. By simplifying the way mutations occur, we may not be able to fully capture the effect of resistant mutations in our mathematical model; however, it must be understood that modeling resistance is quite controversial to this day [4]. Therefore, we believe this is a valid simplification to make in our model. The tumor is homogeneous in cell type. Specifically, in our model, homogeneity is simply defined by having the same natural birth rate and death rate. By targeting a tumor that contains only one cell type, our mathematical model can produce more accurate results. However, this is a grand simplification because almost all tumors have a mass of cancer cells that are proliferating, inactive, or obsolete [5]. To address all of these types of cells, we would have to create three different models that would connect in order to properly address a fully developed tumor. Thus, an appropriately complex model for this class would not require us to address multiple types of cells. The population growth model applies to tumor cell proliferation. Cell proliferation can be modeled using two constants: the proliferation rate and the carrying capacity at the location of the tumor [5]. Using these constants, we can use the population growth model to describe tumor cell proliferation. We believe this assumption is justified because a population of cells is no different than a population of any other species; the cell-specific constants alter the population growth model to better fit the proposed problem. Because the drugs are toxic, the follow equation [3] is always fulfilled:
!! !!

!! ! ! !! !

! !!"#$% !!! ! !! !

Our model specifically suggests the timing of drug administration by looking at the growth of resistant mutant cells and optimizing the effect of the drugs. We believe that the optimal concentration can be found through clinical trials and analysis of data, both of which are unavailable to us. Thus, we have chosen to leave out the concentration aspect from our model and accept this simplification.

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Mutant cells can only be resistant to a single drug.

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Although the above statement is not necessarily factual, the capability of a cell being resistant to both administered drugs would require another complicated factor in our model. With this simplification, we can better control the growth and death of the mutant cell population. Ideally, we want to destroy mutant cells with the administration of any two drugs; thus, our model does not completely satisfy real-life situations and, instead, presents the results for an ideal situation. Drug-specific constants can be determined by experimental data pertaining to that drug and used as inputs in the final mathematical model. It is quite difficult to find pertinent data of specific drugs, and without data it is impossible determine viable constants to be used in our mathematical model. Thus, we assume that professional scientists and oncologists can acquire the correct constants through methods that are beyond our knowledge and feasibility. This also makes our model more versatile and relevant to many types of drugs, drug combinations, and tumors, which is one of our goals in this project. The natural birth rate is always greater than the natural death rate (L > D). The proliferation of tumor cells requires a growing behavior; therefore, there will be a natural positive difference between the production and the termination of cells. The death rate due to drug toxicity is always greater than the growth rate of cells. This is an obvious assumption because the drugs must have a destructive effect over the tumor cells. Therefore, the growth rate of normal tumor cells and mutant tumor cells is negative in the presence of a drug, portrayed through the cell populations decreasing values.

2.2

Variables

Natural development of normal tumor cells t N (t) Time (days) Normal tumor cell population as a function of time (number of cells)

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L D K Birth rate of tumor cells7 (percent of cell population in decimal form)

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Death rate of tumor cells not from drugs (percent of cell population in decimal form) Carrying capacity of cancer models (number of cells)

Drug administration A B R A( t ) R B( t ) Death rate of N(t) induced by drug A (percent of cell population in decimal form) Death rate of N(t) induced by drug B (percent of cell population in decimal form) Mutant tumor cell population resistant to drug A as a function of time (number of cells) Mutant tumor cell population resistant to drug B as a function of time (number of cells)

RA-B(t) RA reduced by drug B as a function of time (number of cells) RB-A(t) RB reduced by drug A as a function of time (number of cells) DAM DBM Death rate of RB induced by drug A (percent of cell population in decimal form) Death rate of RA induced by drug B (percent of cell population in decimal form)

Modeling of time intervals T (o ) o r Time intervals of drug administration as a function of the order of administration (days) Order of administration (1st, 2nd, 3rd,) Parameter to determine the slope of time intervals over order of intervals (days/o2)

3
3.1

Mathematical Models
Simplest Model of Tumor Growth (Prior to Drug Administration)

The purpose of this section is to show how normal tumor cells multiply and when drugs should be administered to begin reducing the cell population. In the real world, tumors behave in a very unpredictable way. Since the biology of human body is very complex, it is difficult to play directly with numerous parameters at once. However, we first want to understand how a normal tumor grows. In early stages, a tumor grows rapidly and then slows until a maximum cell population is reached6. The closest equation that we can use is the logistic population growth model. We assume that the normal tumor cell

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population N(t) grows exponentially, accounting for the parameters L, D and K. From these three parameters, we can model cancer as a logistic growth equation:
!" ! !"

! !!! ! !

!! ! !
!

(1)

3.2

More Sophisticated Tumor Models (Subsequent to Drug Administration)

Upon understanding the mechanism of normal tumor cell growth, we recognize another aspect of tumor growth: the mutant tumor cell population R(t). These mutant cells correlate closely with the drugs we administer. However, the mutant cells behave more rigorously than the tumor cells, and, in real-life situations, different kinds of mutant cells exist even in a single tumor. In our model, mutant cells can be resistant to one of the administered drugs. For the sake of simplicity, let us consider two types of drugs: drug A and B. Both drugs kill normal tumor cells N(t) when N(t) reaches a steady state. In addition, let us consider mutant cells RA(t) that are resistant to drug A and mutant cells RB(t) that are resistant to drug B. The changes in these populations can be modeled with exponential growth and decay. Because mutant cancer cells can metastasize [6], mutant cancer can increase exponentially; this behavior is what makes cancer cells so deadly and uncontrollable. From these facts, we derive the following equations:

Treatments with Drug A The development of mutant cells resistant to drug A

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! ! ! ! !!

(2)

The treatment of normal tumor cells with drug A

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! !!!!! !

(3)

The treatment of mutant cells resistant to drug B with drug A

! ! !!! !"

! ! ! ! ! !!" !!!!

(4)

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Treatments with Drug B The development of mutant cells resistant to drug B
! !! !"

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! ! ! ! !!

(5)

The treatment of normal tumor cells with drug B

!" !"

! !!!!! !

(6)

The treatment of mutant cells resistant to drug A with drug B

! ! !!! !"

! ! ! ! ! !!" !!!!

(7)

DAM and DBM are greater than A and B, respectively, because mutant cells are more sensitive to the effects of the drug they are not resistant to. Cells that harbor mutations that do not affect resistance to a drug are more susceptible to that specific drug-induced damage [6].

3.2.1

Improvisation

Since exponential models are simple by this point, we wish to determine when we should administer drugs A and B. Upon further research, we find that sequential administration of drugs A and B could effectively reduce the total population. The reason behind this idea is growth of mutant cells resistant to either drug A or B. We must destroy the optimal amount of normal tumor cells while accounting for the growth of mutant cells resistant to the drug being used, then we must begin to use the other drug to destroy the mass of mutant cells that emerged while destroying normal tumor cells as well. This produces a sequential schedule of administration. We do not want the mutant cells to grow to 80% of the normal tumor cell population; this situation may allow the mutant cells to metastasize. Therefore, we can reasonably say that a drug should be administered when the mutant cells grow to 50% of the normal tumor cell population at a given time. When drug A is administered, the mutant cells resistant to drug B can be killed while killing numerous normal tumor cells. Then, when the population of mutant cells resistant to drug A increases, we can

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immediately kill that subpopulation with drug B. This method is repeated until the mutant cells exponential growths become very dismal.

3.3

Time Interval Modeling

We wish to model how time intervals T(o) (in days) will behave over the order of drug administration (1st interval, 2nd interval,). This model will determine how often we have to administer drugs to the system so that R(t) and N(t) cells can be killed as effectively as possible. Our sequential schedule states that the 1st administration uses drug A, the 2nd administration uses drug B, the 3rd administration uses drug A, and so on. Thus, T(1) is the time interval between the first administrations of drug A and drug B. We hypothesized that the time intervals could be modeled exponentially, where the parameter r is a decay rate because we believe that administration of the drugs would occur more often as the order of drug administration increased. Thus, the exponential equation can be modeled by:
! ! ! !! ! !"

! !!

(8)

4
4.1

Solutions
Analytical Solutions

Using Mathematica, we used the function DSolve to solve eq. (1):

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! !!! ! ! ! ! !

!! ! !
!

! ! !"!!" ! !"!!" !! !"

! ! !

!! ! ! !" !! ! !" !! !"

, where !! ! ! !"

(1)

To model natural growth, we must assume that L D must be greater than zero; thus, when L > D, then N(t) ! " as t ! ", which models exponential growth.

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To develop our analytical solutions and identify estimated values of the constants, 1) We used the separation of variables technique for all of the following equations.

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2) We determined an if-then statement that must be true in order to model reality by comparing possible values of the given constants and identifying the resulting long-term behaviors. We have shown our work for eq. (2); the same steps were completed for each equation.
! !! !" ! !! !! ! !! !!

! !! ! ! !!! ! ! ! ! !! ! ! ! ! ! !!"

!" !! ! ! ! ! ! ! !! !! ! ! !! ! !!!!!! , where !! ! !! ! If L > D, then RB(t) ! " as t ! ", which models exponential growth. !!! ! ! !! !
!

(2)

! !! !!! !

, where !! ! !!! !!!

(3)

If L > D and L D < DA, then N A(t) ! 0 as t ! ", which models exponential decay. !!!! ! ! !! ! !!!!!!!" !! , where !! ! !!!! !!! If L > D and L D < DAM, then RB A(t) ! 0 as t ! ", which models exponential decay.
!

(4)

!! ! ! !! ! !!!!!! , where !! ! !! !!! If L < D, then RA(t) ! " as t ! ", which models exponential growth. !!! ! ! !! !
!

(5)

! !! !!! !

, where !! ! !!! !!!

(6)

If L > D and L D < DB, then N B(t) ! 0 as t ! ", which models exponential decay. !!!! ! ! !! ! !!!!!!!" !! , where !! ! !!!! !!! If L > D and L D < DBM, then RA B(t) ! 0 as t ! ", which models exponential decay.
!

(7)

! ! ! !! ! !!!!!! , where C8 = T(1) If r < 0, then T(o) ! 0 as t ! ", which models exponential decay.

(8)

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In this class, we have studied differential equations extensively. We have learned about the appropriate use of constants and how to best formulate differential equations from a given situation. All of equations above are first-order ordinary differential equations (ODEs), and we have applied the techniques we learned in this class to solve them. Furthermore, we also learned to assess the behavior of a solution in the long run; this concept is represented by evaluating the solutions as time goes to infinity with different values of the constants.

4.2

Numerical Solutions

The numerical solutions for the three different models are derived in Matlab based on the analytical solutions. The parameters are within reasonable values [7].

4.2.1

Proliferation of Normal Tumor Cells

For our first trial, we set L = 0.5, D = 0.3 and K = 500000, with the initial condition N(0) = 1. Therefore, L is the increase in population at the rate of 50% of current population over time, D is the decrease in population at the rate of 30% of current population over time, and K is the limiting tumor population (that is, 500,000 cells). The initial population is one cell because cells can divide extremely fast even from a single cell [5]. Using ode45 and the function

logistic.m containing eq. (1), we obtained the following trajectory:

Figure 1. Normal tumor cell growth model with L = 0.5, D = 0.1, K = 500000

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Lets try other parameter values. If we set L = 0.9, D = 0.1, and K = 500,000, with the initial condition N(0) = 1, we will acquire the following trajectory behavior:

Figure 2. Normal tumor cell growth model with L = 0.9, D = 0.1, K = 500000

4.2.2

Response to Drug Administration

When the normal cells reach the carrying capacity, we must administer drugs immediately [5].

However, mutant cells respond differently to the drugs. To model the sequential treatment schedule, we set L = 0.5, D = 0.1, A = 0.42, B = 0.42, DAM = 0.421, DBM = 0.422, with initial conditions of RB(0) = 1, RA(0) = 1, N(0) = K = 900,000. The value of every rate is less than one [6]. We used four functions in our code: wA.m, which governs RA(t) (eq. (1)) and N(t) (eq. (2)) when drug A is administered; wA_drug.m, which governs RB(t) (eq. (3)) when drug A is administered; wB.m, which governs RB(t) (eq. (4)) and N(t) (eq. (5)) when drug B is administered; and wB_drug.m, which governs RA(t) (eq. (6)) when drug B is administered. Also, we used the main function popul_intern.m to govern the functions. To obtain solutions that describe how mutant and normal cells behave during drug administration, we can set a logical loop expressed by the pseudo-code below to attain the graph using Matlab:
Set parameters L, D, K, A, B, D_AM, D_BM, and initial conditions Set time interval recorder

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% one cycle = administration of one drug for every 2 cycles % when drug A is administered solve R_A(t), N(t) due to drug A check when R_A(t) = 0.5*N(t) plot both R_A(t) and N(t) with shifted time affected by drug B % for first cycle, R_B still not mutant due to % drug A % for first cycle, time is not shifted yet solve using ode45 for R_B(t) decrease due to A shift time to when R_A(t) = 0.5*N(t) record time interval (from shifted time) reset initial condition for N and R_A(t) depending on last known condition % when drug B is administered solve using ode45 R_B(t) and N(t) due to drug B check when R_B = 0.5*N(t) plot both R_B(t) and N(t) with shifted time affected by drug A solve for R_A(t) decrease to B shift time to when R_B(t) = 0.5*N(t) record time interval (from shifted time) reset initial condition for R_A, R_B, and N depending on last known condition end loop

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Unfortunately, we were not able to make the loop work because of its high complexity. However, we were able to code three cycles for RA(t) and two for RB(t), a total of five cycles for N(t), which means that five drug administrations were issued in the given amount of time. When we ran the file, we found sometimes possible values of RA(t) and RB(t) that is close to 50% of N(t). And, we take the median of these values to look for the closest value to 50% of N(t). However, sometimes the median value is not in RA(t) and RB(t) array values. To solve this problem, we used another file closest.m to help finding the closest value of RA(t) and RB(t) to the median.

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From the provided parameter values, equations and functions, we present a numerical graph for our model:

!"#$%& !"#$%'% !"#$%&%

Figure 3. Sequential treatment schedule for about 55 days, with arrows showing three of the five drug administrations

In this specific model, we only presented one set of parameters because we want to use this specific set of parameters to analyze the time intervals over the order of drug administrations. Since this model is very related to the following model, we want to keep everything consistent.

4.2.3

Time Interval Modeling

Using the previous model, we save the time intervals between each drug issuance as shown in the pseudocode while we run the loop logic. Then, we pair each interval to the order of administration (1st, 2nd, 3rd interval). From the same code and parameter values of the previous model, we acquire the following data: Order of Interval Time Interval 1st 29.3547 days 2nd 27.8955 days 3rd 5.3968 days 4th 2.1587 days 5th 1.0545 days Table 1. The values of time intervals between drug administrations

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We can now use eq. (8) and the data above to find both r and C8; take, for example, the values of the 1st and 5th intervals: 29.3547 days and 1.0545 days, respectively. To find C8: !"!!"#$ ! !! ! !
!!!

!! ! !"!!"#$!!"#$ To find r: !!!"#" ! !"!!"#$! !!!!!! !" !!!"#" ! !! ! !"!!"#$

! ! ! !!!!"#!!"#$!!!"#$"!!" !!"#$%$&'(!'$)%!! Thus, the complete equation is as follows: ! ! ! !!"!!"#$! !!!!"#!!!!!

Figure 4. Comparison of the actual data versus the exponential fit of the time interval data The fitted exponential curve mainly follows most of the data from the table except for the 2nd interval, and this discrepancy is discussed in the following section.

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5
5.1

Results
Natural Development of Normal Tumor Cells

In Fig. 1 and Fig. 2, the two solutions differ slightly. Here, we can see that if the birth rate of cells is much greater than the death rate, the cell population can increase quickly at dramatic pace, and the population stays at a steady state of 500,000 cellsa smaller tumorwhen time goes to infinity. When we set L = 0.5 and D = 0.3, it takes about 80 days for the cells to reach the steady state; the difference between L and D is much smaller than the second solution in Fig. 2. When we set L = 0.9 and D = 0.1, it takes only 10 days for the cells to reach the steady state. This model answers our question regarding how normal tumor cells proliferate. We also know that no matter what the initial condition is, the normal cell population will always reach K in the ideal situation. The faster the growth is, the more dangerous the cells are, because this provides room for mutant cells to develop [8]. In a real-life situation, we must administer a drug as soon as we can before the tumor reaches carrying capacity [4]. Our values are reasonable in comparison to the values used in previous research papers (104 to 106 cells in a tumor) [7].

5.2

Drug Administration Sessions

When the normal tumor cells population has already reached its carrying capacity, and mutant cells proliferate naturally and in response to drugs, we can administer the drugs in a sequential manner that can eradicate the cancerous cells. When we administer the drugs sequentially, we notice a decrease in amplitude for both RA(t) (from 250,000 to about 100,000) and RB(t) (from 150,000 to 100,000), and a decreasing value of N(t) (from 900,000 to 300,000); these are all desired results. We can say that our model calculates the death of both mutant cells and normal cells to a certain point, answering one of our questions from the introduction, because the values of RA(t) and RB(t) seemed to reach a steady state value of 100,000 cells as seen from the graph. However, we do know what the model would look like in the long run because we were only able to program up to five cycles.

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Here, we used two points, the 1st and 5th intervals, to find the fitted exponential curve for the model. After obtaining the data, we saw that the time intervals decrease as the order of administration increases. Also, the fitted curve actually suits the model very well. The fitted curve in Fig. 4 fits almost all of the points, except on the 2nd interval where our model is slightly off. We believe this discrepancy occurs because the time interval between the first administrations of drug A and drug B varies greatly due to different growth constants varied by 0.1% (looking at DAM and DBM). However, the near-perfect fitting of most of the points shows that our model is potentially applicable to real life. This model answers our question of how often should drugs should be administered. Compared to previous papers, the time intervals of administration in our model are reasonable (about every three days to one month) [3,4].

Limitations, Improvements & Future Work

Our results show that the time intervals between administration of the drugs decreases at every issuance of each drug. This does not seem to be the case in reality. Instead, one drug may be given every two weeks, while another drug is given each day; the time intervals between administrations may remain uniform even after several months. Therefore, a possible venture in the future may consist of comparing the two methods and analyzing why one method may be more effective than the other. More future work may be accomplished through a more sophisticated and viable software than Matlab. Matlab prevented us from seeing the long-run behavior of our model because we could not code a successful loop that would sustain our equations. Through lengthy and repetitive coding, we were able to generate five cycles of drug administration. However, we do not deem this amount of data to be a success, and we want to find another program that would provide the necessary means to create a viable loop. With simplification come limitations, and our model is no exception. One of the greatest limitations of our model consists of its reliability on the homogeneous condition of a tumor. As stated before, a typical tumor is a spherical mass of cells that are either multiplying, idle or dead5. Our model

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only addresses treatment of the proliferating population of tumor cells, not the cells that are already idle or dead. We do not necessarily know how the idle and dead cells can be removed or if they have to be removed, but they should be considered as part of the total population of tumor cells. Furthermore, our model does not take into account other sources of natural resistance. For example, compact grouping of exterior tumor cells may reduce penetration of the drug into the interior of the tumor tissue [9]. Thus, less tumor cells would be killed by the same concentration of a drug. Another characteristic of tumors that may decrease the efficacy of a chemotherapeutic drug is the vasculature collapse within the tumor microenvironment [2]. Many, if not all, drugs must travel through blood vessels, and disorganization of the vascular architecture within a tumor prevents drugs from being potent throughout the tumor [10]. These are only two of the sources of natural resistance that occur in typical tumors that we did not address, which accentuates the limitations of our proposed model. Because of the complexity of cancer and its treatments, many improvements can be made to our model to yield more accurate results. For example, to model a more authentic manifestation of mutated cells, we would have to consider the arbitrary characteristic of mutations. Upon further research, we discovered the concept of stochastic differential equations (SDEs). Replacing the ODEs of the mutant cells with SDEs may produce more realistic results because mutations occur randomly. By using SDEs, we could generate time intervals that would better represent the optimal schedule for drug administration. Another improvement we could make in our model is to provide the optimal concentration of each drug during a certain time interval. Because timing is only half of the required information for proper drug administration, our model could be enhanced to calculate the appropriate dosage. We took the equation
!! !!

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! !!"#$% !!! ! !! ! for granted in our model; however, we can add a

component that addresses how to determine CFixed and how the toxicities of each drug work together. This addition would validate our model if it produced dosages that were realistic and similar to real-life data. Deeper knowledge of oncology and human biology, as well as access to drug-specific clinical trial data, would allow us to complete more future work and improve our model. Having said that,

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acquiring such assets will take long periods of time, further education and much effort on our part. We acknowledge that our model is relatively basic in comparison to previously made models, but the potential to further develop our model is apparent and extremely possible.

Conclusion

Developing a model to calculate the time intervals of sequential drug administrations proved to be a difficult problem. We created eight ODEs that represented the growth of normal and mutated subpopulations of tumor cells, responses to the administrations of a certain drug, and the relationship between time intervals versus the number of administrations. Using techniques like separation of variables and behavioral analysis, as well as software programs like Matlab and Mathematica, we were able to solve these ODEs and combine them to form a graph that would describe when to administer the drugs over time. As we had originally hypothesized, our results showed that the time intervals decreased as the number of administrations increased; our model was also able to calculate the exact days at which the drugs should be administered. However, our model does not take other natural resistances into account. The lack of functional blood vessels and a tumors compact nature are two of the many characteristics of tumors that our model does not acknowledge. With improvements and future work, our model could provide oncologists and doctors with an effective and important tool.

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[1] [2] Freeman S. Biological science. 4th ed. San Francisco (CA): Pearson Education, Inc.; 2011. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell [Internet]. 2011 Mar 4;144:646-74. [3] [4] Wheldon TE. Mathematical models in cancer research. Bristol: A. Hilger; 1988. 247 p. Panetta J. A mathematical model of drug resistance: heterogeneous tumors. Math Biosciences [Internet]. 1997 Dec 31;147(1):41-61. [5] Jackson TL, Byrne HM. A mathematical model to study the effects of drug resistance and vasculature on the response of solid tumors to chemotherapy. Math Biosciences [Internet]. 1999 Nov 23;164(2000):17-38. [6] Atsumi Y, Inase A, Osawa T, Sugihara E, Sakasai R, Fujimori H, Teraoka H, Saya H, Kanno M, Tashio F et al. The Arf/p53 protein module, which induces apoptosis, down-regulates histone H2AX to allow normal cells to survive in the presence of anti-cancer drugs. J of Bio Chem [Internet]. 2013 May 10;288(19):13269-77. [7] Laird AK. Dynamics of tumor growth. Division of Bio and Med Res [Internet]. 1964 Jun 8:490502. [8] Tomasetti C, Levy D. An elementary approach to modeling drug resistance in cancer. Math Biosciences and Engineering [Internet]. 2010 Oct;7(4):905-918. [9] Grantab R, Sivananthan S, Tannock IF. The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells. Can Res [Internet]. 2006 Jan 15;66(2):1033-39. [10] Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nature Rev [Internet]. 2006 Aug;6:583-592.