The dynamics of cell proliferation.
The article provides a mathematical description based on the theory of differential equations, for the proliferation of malignant cells (cancer). A model is developed which enables us to describe and predict the dynamics of cell proliferation much better than by using ordinary curve fitting procedures. By using differential equations the ability to foresee the dynamics of cell proliferation is in general much better than by using polynomial extrapolations. Complex time relations can be revealed. The mass of each living cell and the number of living cells are described as functions of time, accounting for each living cell's age since cell-birth. The linkage between micro-dynamics and the population dynamics is furnished by coupling the mass increase of each living cell up against the mitosis rate. A comparison is made by in vitro experiments with cancer cells exposed to digitoxin, a new promising anti-cancer drug. Theoretical results for the total number of cells (living or dead) is found to be in good agreement with experiments for the cell line considered, assuming different concentrations of digitoxin. It is shown that for the chosen cell line, the proliferation is halted by an increased time from birth to mitosis of the cells. The delay is probably connected with changes in the Ca concentration inside the cell. The enhanced time between the birth and mitosis of a cell leads effectively to smaller mitosis rates and thereby smaller proliferation rates. This mechanism is different from the earlier results on digitoxin for different cell lines where an increased rate of apoptosis was reported. But we find it reasonable that cell lines can react differently to digitoxin. A development from enhanced time between birth and mitosis to apoptosis can be furnished, dependent of the sensitivity of the cell lines. This mechanism is in general very different from the mechanism appealed to by standard chemotherapy and radiotherapy where the death ratios of the cells are mainly affected. Thus the analysis supports the view that a quite different mechanism is invoked when using digitoxin. This is important, since by appealing to different types of mechanism in parallel during cancer treatment, more selectivity in the targeting of benign versus malignant cells can be invoked. This increases the probability of successful treatment. The critical digitoxin level concentration, i.e. the concentration level where the number of living cells is not increasing, is approximately 50 ng/ml for the cell line we investigated in this article. Therapeutic plasma concentration of digitoxin when treating cardiac congestion is about 15-33 ng/ml, but individual tolerances are large. The effect of digitoxin during cancer treatment is therefore very promising. The dynamic model constitutes a new powerful tool, supported by empirics, describing the mechanism or process by which the number of malignant cells during anti-cancer treatment can be studied and reduced.
Moxnes
John F
JF
Department for Protection and Material, Norwegian Defence Research Establishment, PO Box 25, N-2007, Kjeller, Norway. john-f.moxnes@ffi.no
Haux
Johan
J
Hausken
Kjell
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004074:Digitoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008433:Mathematics; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012680:Sensitivity and Specificity; D013997:Time Factors
D000970:Antineoplastic Agents; D004074:Digitoxin; D002118:Calcium