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

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.

化疗常可引发包括味觉功能紊乱在内的多种不良反应。环磷酰胺（Cyclophosphamide, CYP）作为一种化疗药物，单次给药后会升高小鼠的味觉阈值，该效应有时与药物诱导的味觉感觉细胞丢失、以及负责更新味觉感觉细胞的增殖细胞功能受损相关。氨磷汀（amifostine）预处理可使味觉系统免受上述多数不良反应的损伤。本研究采用免疫组织化学（immunohistochemistry）技术，对比了单次给药（75 mg/kg）的环磷酰胺与临床化疗中常用的分次给药（fractionated dosing）方案（即分5次给药，每次15 mg/kg）的环磷酰胺对小鼠味觉系统的影响。研究结果显示，分次给药可延长环磷酰胺对负责味觉感觉细胞更新的细胞增殖的抑制作用。此外，分次给药还会降低味蕾（taste buds）内细胞总数与II型细胞（Type II cells）的占比。上述细胞丢失的注射后时间窗，与I型和II型味觉细胞的寿命相吻合，且此时缺乏可替代的新生细胞。相较于单次给药，分次给药对III型细胞（Type III cells）的减少程度更为显著，但这类细胞的丢失可能与味蕾的整体健康状态和/或细胞更新相关因素有关，而非仅取决于III型味觉细胞的自身寿命。总体而言，氨磷汀预处理似乎可保护味觉细胞更新过程及味蕾内细胞群体免受环磷酰胺的细胞毒性作用（cytotoxic effects）损伤，且重复给药未观察到明显的不良反应。本研究结果或将对接受化疗的患者具有重要临床参考价值。