Research Article: Cyclophosphamide and the taste system: Effects of dose fractionation and amifostine on taste cell renewal

Date Published: April 4, 2019

Publisher: Public Library of Science

Author(s): Eugene R. Delay, Sarah H. Socia, Jessica L. Girardin, Benjamin C. Jewkes, John H. King, Rona J. Delay, Giuseppe Biagini.


Chemotherapy often causes side effects that include disturbances in taste functions. Cyclophosphamide (CYP) is a chemotherapy drug that, after a single dose, elevates murine taste thresholds at times related to drug-induced losses of taste sensory cells and disruptions of proliferating cells that renew taste sensory cells. Pretreatment with amifostine can protect the taste system from many of these effects. This study compared the effects of a single dose (75 mg/kg) of CYP with effects generated by fractionated dosing of CYP (5 doses of 15 mg/kg), a dosing approach often used during chemotherapy, on the taste system of mice using immunohistochemistry. Dose fractionation prolonged the suppressive effects of CYP on cell proliferation responsible for renewal of taste sensory cells. Fractionation also reduced the total number of cells and the proportion of Type II cells within taste buds. The post-injection time of these losses coincided with the life span of Type I and II taste cells combined with lack of replacement cells. Fractionated dosing also decreased Type III cells more than a single dose, but loss of these cells may be due to factors related to the general health and/or cell renewal of taste buds rather than the life span of Type III cells. In general, pretreatment with amifostine appeared to protect taste cell renewal and the population of cells within taste buds from the cytotoxic effects of CYP with few observable adverse effects due to repeated administration. These findings may have important implications for patients undergoing chemotherapy.

Partial Text

Patients undergoing chemotherapy often report that their sense of taste has been adversely affected by their treatment [1, 2]. This usually involves a loss of sensitivity for one or more basic tastes but can also manifest as dysgeusia or as hypersensitivity [3–6]. In chemotherapy patients, disturbances in taste can have a negative impact on nutritional intake, reduce energy intake at a time when an increase in energy is necessary, and ultimately result in a poorer clinical prognosis [7–10]. Frequently, the clinical approach to chemotherapy is to divide the therapeutic dose into parts to be administered over time, an approach often called dose fractionation [11–13]. Fractionated dosing assumes that rapidly proliferating cancerous cells are exposed to the chemotherapy drug over a longer period to increase its effectiveness. Because each dose is smaller than the full dose, side effects may be lessened or eliminated. By extension, however, one would expect normal tissues requiring rapid cell renewal to be adversely affected by dose fractionation. The taste system is known for the short life spans of taste sensory cells and relatively rapid cell renewal of these cells. One goal of this study was to determine if dose fractionation of a chemotherapy drug, cyclophosphamide (CYP), might change the way the drug affected the taste system.

The findings of this study provide new insights into how the taste system may be impacted by different dosing regimens a patient might encounter during chemotherapy. They also give us new insights into the temporal patterns of the effects of CYP on cellular losses and cell renewal in the taste system. One of the most important insights is how important the dosing regimen is for cell proliferation and cell renewal. Both CYP dosing regimens effectively suppressed cell cycling to about the same level immediately after the last injection of CYP. Ki67 expression in mice given a single large dose of CYP remained suppressed up to four days post injection but then appeared to increase to control levels by the sixth day. In contrast, Ki67 expression in mice given CYP by dose fractionation remained suppressed much longer. After fractionated dosing of CYP, Ki67 expression began to increase after six days but more gradually, eventually reaching control levels 10 days after the last injection. While neither dosing regimens stopped cell proliferation completely, both were able to slow this process down to the point where cell renewal did not appear to keep up with the loss of cells when they reached the end of their life span.




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