Mathematical and experimental approaches to identify and predict the effects of chemotherapy on neuroglial precursors

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. We applied our computational approach to analyze the effects of BCNU on clonal cultures of oligodendrocyte progenitor cells-one of the best-characterized neural progenitor cells in the mammalian brain. Our analysis reveals that transient exposures to BCNU increased the cell cycle length of progenitor cells and decreased their time to differentiation, while also decreasing the likelihood that they will undergo self-renewing divisions. By investigating the behavior of our mathematical model, we demonstrate that precursor cell populations should recover spontaneously from transient modifications of the timing of division and of differentiation, but such recovery will not happen after alteration of cell fate. These studies identify means by which precursor cell function can be critically compromised by transient exposure to chemotherapy with long-term consequences on the progenitor cell pool even in the absence of drug-induced apoptosis. These analyses also provide novel tools that apply broadly to identify effects of chemotherapeutic agents and other physiological stressors.