Data to establish the optimal standard regimen and predicting the response to docetaxel therapy

This paper contains data to establish the optimal standard regimen and predicting the response to docetaxel therapy (Moawad, 2014) [1]. Docetaxel has been in use for over a decade without demonstrating data indicates a predictable response in the treatment of cancer. Data of puzzling response to docetaxel therapy was due to its cell cycle specific effect. Although several administered schedules were investigated, the relative therapeutic advantage of high versus low doses has not been identified yet. Also the antitumor target of docetaxel has not yet been identified to optimize therapy by predicting the response of patients prior to therapy to provide a protection against treatment failure. In the present paper, we demonstrate the data used to optimize docetaxel therapy and investigate the possibility of predicting for the first time the antitumor target of docetaxel.


a b s t r a c t
This paper contains data to establish the optimal standard regimen and predicting the response to docetaxel therapy (Moawad, 2014) [1]. Docetaxel has been in use for over a decade without demonstrating data indicates a predictable response in the treatment of cancer. Data of puzzling response to docetaxel therapy was due to its cell cycle specific effect. Although several administered schedules were investigated, the relative therapeutic advantage of high versus low doses has not been identified yet. Also the antitumor target of docetaxel has not yet been identified to optimize therapy by predicting the response of patients prior to therapy to provide a protection against treatment failure. In the present paper, we demonstrate the data used to optimize docetaxel therapy and investigate the possibility of predicting for the first time the antitumor target of docetaxel.
& 2015 The Author. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Table   Subject area Medical oncology More specific subject area Docetaxel therapycancer stagingidentifying the effectiveness of antitumor drugs. Type of data

Value of the data
• Although docetaxel has been in use for over a decade, optimal dosing and scheduling are still the most important issues regarding the use of docetaxel [2][3][4][5][6][7][8][9]. • In the same time, predicting patient's response has become a necessity to preserve patient's right against treatment failure or non-optimal treatments [10][11][12][13][14][15][16][17]. • The acquired data was for identifying the energy yield by docetaxel doses to investigate the possibility of predicting for the first time the antitumor target of docetaxel. • Assessment of the efficient regimen for optimizing cell-cycle specific therapy would be based on achieving an accumulated doubling time-energy conversion in the tumor cells by the regimen doses [1,12]. • The higher the energy yields by the same docetaxel dose the more effectiveness of the applied regimen and vice versa. • Then, efficiency of those applied standard and metronomic regimens on different types of tumor models would be determined to assess the specifications of the personalized treatment schedule [10][11][12][13][14].
• The correlation and regression between the energy yield by the applied docetaxel doses in optimal schedules (dependent variable) and value of those doses (independent variable) would be investigated. If both variables were perfectly correlated, the target of our thesis would be achieved. • In such a case, a dose-energy model with perfect fit for docetaxel would be constructed to administer the optimal (personalized) dose in an efficient schedule as conducted before in earlier studies [10][11][12][13][14]. • Accordingly, the therapeutic response of cancer to docetaxel could be predicted prior to therapy by identifying each of patient's histologic grade (H G Control )-in vitro or in vivo-and energy yield by the proposed dose using the constructed dose-energy model of docetaxel [10][11][12][13][14][15][16][17][18][19][20].

Docetaxel cancer growth inhibition
Data shows that schedule of the applied regimen is responsible for the puzzling response to therapy due to the cell cycle specific effect of docetaxel.

Clinical model of staging and grading cancer
The processes of tumor formation and cancer therapy are based mainly on the concept of doubling time-energy conversion (DT-EC) in which the conversion of doubling time into growth energy takes place [10][11][12][13][14][15][16][17][18][19][20][21]. The fundamental principle for cell cycle duration in relation to the physical energy condition of a cell has been derived and confirmed [17,21]. In which, the duration of the mitosis stage is defined by cell doubling time or division time and denoted by t D . While the growth energy ðE G Þ of the biological cell in terms of t D was expressed by the DT-EC formula: which is known also by Emad formula referring to the unit used in identifying the converted energy [17][18][19][20][21][22][23][24][25][26]. The Emad unit of each of the biological cell growth energy and the radionuclide Iodine-131ð 131 IÞ decaying energy were taken equivalent, where 131 I is the commonest safely used radionuclide [17,21]. Thus the conversion factor from Emad unit to Mega electron volt (MeV) unit is as follows : This concept for DT-EC in the biological systems was established to asses the limits of energy that is suitable for energy conversion processes.
Monitoring the mechanical behavior of the tumor response to therapy is assessed by determining the growth/or shrinkage constants of those tumors of different volumes along the corresponding periods [21][22][23][24]. The growth constant ( ln2 tD , where t D is the tumor doubling time in seconds)/or shrinkage constant ( ln2 t 1=2 , where t 1=2 is the tumor half-life time in seconds) of the tumor at a certain time expresses the rate of the difference between mitosis and apoptosis with respect to the total number of the tumor cells (M-A) that characterize the tumor response at that time [10][11][12][13][14][15][16][17]. If rate of mitosis is greater than that of apoptosis, tumor grows by the growth constant, and vice versa if rate of mitosis is less than that of apoptosis, tumor shrinks by the shrinkage constant [10][11][12][13][14].

Identifying effectiveness and optimal regimens of cell cycle specific antitumor drugs
Accordingly from Eq. (5), the alteration in the treated tumor H G compared to that of the control tumor induced by the drug dose would be equivalent to the energy yield by the drug dose according to the following model [10][11][12][13][14][15][16][17][18][19][20]: Assessment of the efficient regimen for optimizing therapy would be based on achieving an accumulated doubling time-energy conversion in the tumor cells by the doses of the regimen [10][11][12][13][14][15][16][17].
For cell cycle specific antitumor drugsas docetaxel -, the higher the energy yields by the same drug dose the more effectiveness of the applied regimen and vice versa [12].
In addition, as much as the time period (t) from initiating therapy passes in the optimal cell cycle specific treatments the induced tumor doubling time ðt D Þ intraday should be steadily increased.
Thus, the criterion of the efficient regimen of docetaxel treatment can be determined by comparing the tumor t D intraday on time of dose delivery to time periods from the start of therapy to the time of dose delivery in the studied regimen.

Experimental design, materials and methods
Monitoring the growth constant in each of the treated and control groups for tumor models was identified by applying the exponential growth model shown in Eq. (3) on the progress induced in tumor volume illustrated in Table 1. In case of shrinking, the tumor's shrinkage portion was replaced by the growing portion before undergoing apoptosis as determined from Eq. (4) in the exponential growth model shown in Eq. (3) to identify the virtual growth constant.
H G of all treated and control groups has been identified by applying DT-EC formula on their determined growth constants and knowing their numbers of the inoculated cells in the transplanted tumor of those xenografted models from Table 1 as shown in Eq. (5).
Determining the energy yield by the docetaxel dose that equivalent to the alteration in the treated tumor H G compared to that of the control tumor for each tumor model as shown in Eq. (6).
Data of the energy yield by docetaxel doses in the treated groups demonstrates puzzling response to docetaxel therapy illustrated in Fig. 1 and 2.
In same tumor model, data shows the metronomic regimens of low doses could be more efficient than the standard regimens of high doses. Fig. 1 shows two regimens of docetaxel were applied on the same tumor model ((2.5 Â 10 5 ) HeyA8 cells). The lower dose (147 mg/L) in metronomic regimen was more effective than the higher one (840 mg/L) in standard regimen. Li et al. [5] (1 Â Although data shows that the therapeutic effect of same dose of docetaxel in different tumor models is unpredictable, data shows also that the therapeutic effect of same dose was identical in some standard regimens applied on different tumor types. Consequently, the response to those regimens of the identical therapeutic effect could be predicted. In Fig. 2, the therapeutic effect of same dose of docetaxel (840 mg/L) in different standard regimens applied on five different tumor types was identical in three of them and different in the others.
In addition, tumor doubling time intraday on time of dose delivery of the applied regimens on tumor models shown in Table 1 has been identified using Eq. (3) to be compared by the time period from the start of therapy to the time of next dose delivery in the studied regimens.
Data of the induced tumor doubling time on time of dose delivery compared by the period from starting therapy to time of the next dose delivery would clarify when the therapeutic effect of same docetaxel doses would be optimized, identical and consequently predictable for its consistency, or on the contrary when it would be puzzling and randomized and consequently unpredictable in the treated groups as illustrated in Figs. 3 and 4.  By completing analysis to the acquired data for all tumor models shown in Table 1, steps described in Section 2 can be performed and then, one can establish the optimal standard regimen and predicting the response to docetaxel therapy.

Conflict of interest
The author declares no conflict of interest.