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.

Radiotherapy is one of the most common treatments for head and neck cancers, with an almost obligate side effect of altered taste (Conger AD. 1973. Loss and recovery of taste acuity in patients irradiated to the oral cavity. Radiat Res. 53:338-347.). In mice, targeted irradiation of the head and neck causes transient repression of proliferation of basal epithelial cells responsible for taste cell replacement, leading to a temporary depletion of taste sensory cells within taste buds, including Type II taste cells involved in detection of sweet stimuli (Nguyen HM, Reyland ME, Barlow LA. 2012. Mechanisms of taste bud cell loss after head and neck irradiation. J Neurosci. 32:3474-3484.). These findings suggest that irradiation may elevate sucrose detection thresholds, peaking at 7 days postirradiation when loss of Type II cells is greatest. To test this hypothesis, sucrose detection thresholds (concentration detected in 50% of presentations) were measured in mice for 15 days after treatment of: 1) irradiation while anesthetized, 2) anesthetic alone, or 3) saline. Mice were trained to distinguish water from several concentrations of sucrose. Mice were irradiated with one 8 Gy dose (RADSOURCE-2000 X-ray Irradiator) to the nose and mouth while under 2,2,2-tribromethanol anesthesia (Avertin). Unexpectedly, mice given anesthesia showed a small elevation in sucrose thresholds compared to saline-injected mice, but irradiated mice show significantly elevated sucrose thresholds compared to either control group, an effect that peaked at 6-8 days postirradiation. The timing of loss and recovery of sucrose sensitivity generally coincides with the reported maximal reduction and recovery of Type II taste cells (Nguyen HM, Reyland ME, Barlow LA. 2012. Mechanisms of taste bud cell loss after head and neck irradiation. J Neurosci. 32:3474-3484.). Thus, even a single dose of irradiation can significantly alter detection of carbohydrates, an important consideration for patients undergoing radiotherapy.

Chemotherapy is one of the most common treatments for cancer; however, a side effect is often altered taste. This study examined how cyclophosphamide, a chemotherapy drug, affects salt taste in mice. On the basis of previous findings, it was predicted that cyclophosphamide-induced disruptions in salt taste would be observed near days 2-4, 8-12, and 22-24 posttreatment, and that multiple, smaller doses would cause more severe disruptions to taste. To test these predictions, two experiments were performed, one using brief access testing to measure appetitive qualities, and another using operant conditioning to measure detection thresholds. After a single 100 mg/kg cyclophosphamide injection, peak alterations in brief access lick rates were seen near days 5-8 and 15 posttreatment, whereas peak alterations in detection thresholds were seen days 6, 14, and 20 posttreatment. After five 20 mg/kg injections of cyclophosphamide, brief access lick rates revealed disruptions only on postinjection day 8 whereas thresholds appeared to cycle, gradually increased to and decreased from peak elevations on posttreatment days 4, 10, 15, 20, and 23. Although salt taste functions were disrupted by cyclophosphamide, the patterns of these disruptions were less severe and shorter than expected from cell morphology studies, suggesting a functional adjustment to maintain behavioral accuracy. Fractionation of cyclophosphamide dosing had minimum effect on brief access responses but caused longer, cyclic-like disruptions of detection thresholds compared to single-dose administration.