Elucidation of the Taste Disorder Outbreak Mechanism With the Anticancer Drug Dosage

Patients undergoing cancer chemotherapy typically experience multiple adverse events. Of these, dysgeusia, which is frequently observed in such patients, has been reported to be one of the most distressing, along with fatigue, nausea, vomiting, and hair loss. Dysgeusia affects the daily quality of life of these patients, leading to malnutrition, weight loss and, in severe cases, difficulty in maintaining the chemotherapy regimen and possibly significant morbidity. Although dysgeusia in patients undergoing cancer chemotherapy has been frequently observed, little is known about its generation mechanisms. The aim of this study was to reveal taste disorder-related peripheral mechanisms using the two-bottle preference test (TBPT) and histological examination of tongues by hematoxylin-eosin staining and immunohistochemistry with protein-gene product 9.5.

In the TBPT, one bottle was filled with the 0.01 mM quinine hydrochloride, as a bitter compound, and the other was filled with water. A 0.5 % carboxymethyl cellulose sodium solution was used as the vehicle to suspend S-1 (tegafur/gimeracil/oteracil 123potassium). S-1 doses of 50 and 100 mg/kg/day are lethal to male Wistar rats, and thus the appropriate dose of S-1 (2, 10, 20 mg/kg/day) was administered by a sonde for 3 weeks. During this time the dose administration schedule was one dose per day for 5 consecutive days, followed by a pause the 6th and 7th day of each week. The 2 mg/kg/day dose of S-1 corresponds to the clinical dose administered to cancer patients. The part of the tongue containing the circumvallate papillae was excised the following TBPT. Statistical significance of differences between means was determined using the unpaired t test or the Mann–Whitney U test. A P value of <0.05 was considered to be statistically significant. Correlations between the rate of the area of nerve fibers and the rate of increase in average preference rate, as well as between the degeneration rate of nerve cells and the rate of increase in average preference rate were tested by Pearson’s r, with significance identified by P <0.05.

There were no observalbe morphological changes in the mucosal epithelial basal cells and taste buds of the circumvallate papillae in those rats administered S-1 compared to the control group. The average number of taste buds and taste cells after S-1 administration in all S-1 (2, 10, 20 mg/kg/day) groups was not significantly different from that in control group. The rate of increase in terms of the average preference rate for the quinine vs. all intake (quinine plus water) was significant from the initial S-1 period to the final one, compared with that in control rats, suggesting the possibility of a worsening sensation for the bitter taste. In S-1 rats, the area of taste nerve fibers were significantly decreased and the rate of degeneration of intra-tongue ganglionic nerve cells was significantly increased. These changes were significantly correlated with the rate of increase in average preference rate of the quinine.

These results suggest the possibility that the taste disorder observed in rats which were administered S-1 is related to the degeneration of taste nerve fibers and intra-tongue ganglionic nerve cells. Neuropathy of the gustatory nerve at the periphery may be involved in taste disorders induced by an anticancer drug.

References

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Zabernigg A, Gamper E-M, Giesinger JM et al (2010) Taste alterations in cancer patients receiving chemotherapy: a neglected side effect? Oncologist 15:913–920