Cyclophosphamide (CYP), widely used to treat cancer, will serve as a prototypical agent to study novel questions about how chemotherapy drugs disrupt taste, how cell populations within taste buds are renewed, and how we might protect these cells from the effects of chemotherapy drugs. Taste loss caused by chemotherapy frequently reduces food intake and results in malnutrition, lower quality of life, poorer recovery, and increased mortality. Prior research has focused mostly on how nausea and other side effects of these drugs form conditioned food aversions that reduce food consumption, or how these drugs disrupt salivary function. However, no one has asked how these drugs affect taste epithilium. CYP damages DNA during mitosis and thus targets cells engaged in high rates of mitosis such as cancer or adult progenitor cells of tissues with high rates of self-renewal. A noncancerous cell attacked by CYP is arrested in its cell cycle until its DNA is repaired, or the cell dies. In behavioral studies, one dose of CYP disrupted the ability of mice to discriminate between two similar tastes for up to 5 days post injection and again at 8-12 days post injection. Taste sensory cells have life spans of 8-12 days. When they die, they are replaced by cells derived from progenitor cells around the base of taste buds. Our initial findings suggest CYP kills or damages progenitor cells in taste epithelium and when surviving taste cells die 8-12 days later, there are insufficient replacement cells to maintain normal taste functions until the cell-renewal cycle is restarted. The proposed research has 3 Specific Aims to test our hypothesis that CYP induces cell death in taste buds and arrests mitotic activity of progenitor cells that normally replace taste sensory cells. Both effects disrupt taste functions but at different times after drug treatment.
Aim 1 will assess the extent to which CYP alters taste functions of mice by testing their sensitivity and taste acuity for sweet, sour, bitter, and salt.
Aim 2 will determine f CYP disrupts taste by killing taste cells and stopping the taste cell replacement cycle. Other cell markers will be used to determine when progenitor cells restart their cell cycles to generate replacement taste cells, and when specific taste cell types become functional.
Aim 3 will test if amifostine can prevent taste loss and explore how it prevents taste cell death induced by CYP. Although this research is focused on chemotherapy drugs and taste, it uses a novel combination of behavioral and cellular assays that capitalize on the short life span of taste cells to study ho taste buds are repopulated, normally and after injury. This research will lay the foundation for future studies that more closely examine mechanisms underlying the effects of chemotherapy drugs, the processes underlying taste cell renewal, and possible mechanisms that can protect taste cells from the deleterious effects of cancer treatments, a significant health issue associated with the treatment of cancer. More broadly, this model can be used to study other forms of injury such as irradiation and is applicable for studying other tissues with rapid cell turnover.
A critical side effect of chemotherapy drugs is a disturbance in taste that can cause poorer dietary intake, malnutrition, and slowed recovery. Prevailing theory is that nausea caused by these drugs leads to food aversions, but our data suggest that a common chemotherapy drug, cyclophosphamide, may disrupt taste cell renewal and regeneration in taste buds. Understanding how cyclophosphamide causes this effect will yield insights into how disturbances in taste may be prevented in cancer patients.