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The adverse effects of chemotherapy on normal cells of the body create substantial clinical problems for many cancer patients. However, relatively little is known about the effects, other than promotion of cell death, of such agents on the function of normal precursor cells critical in tissue homeostasis and repair. We have combined mathematical and experimental analyses to identify the effects of sublethal doses of chemotherapy on glial precursor cells of the central nervous system. We modeled the temporal development of a population of precursor and terminally differentiated cells exposed to sublethal doses of carmustine (BCNU), a classic alkylating chemotherapeutic agent used in treatment of gliomas and non-Hodgkin's lymphomas, as a multitype age-dependent branching process. We fitted our model to data from in vitro clonal experiments using the method of pseudo-likelihood. This approach identifies several novel drug effects, including modification of the cell cycle length, the time between division and differentiation, and alteration in the probability of undergoing self-renewal division in precursor cells. These changes of precursor cell function in the chemotherapy-exposed brain may have profound clinic implications.

Mathematical and Experimental Approaches to Identify and Predict the Effects of Chemotherapy on Neuroglial Precursors