Abstract
Hand-foot syndrome (HFS) is one of the common side effects of chemotherapy by cytotoxic agents such as fluoropyrimidines, and multi kinase inhibitors, starting with dysesthesia, erythema, and as it progresses, it is accompanied by hyperkeratosis, swelling, and pain. Discomfort of HFS has a major impact on patient’s quality of life, but the mechanism of HFS still remains unknown. In order to seek prevention measures by elucidating the mechanism of HFS, we established and characterized an animal model of HFS with tegafur.
Eight-week male SD rats were administered 170 mg/kg tegafur orally by gavage for 35 days. Parameters evaluated: clinical signs, body weight, sensitivity to mechanical pressure (Randall selitto test), locomotor activity, drug concentration (the skins of hindlimb and abdomen), histopathologic examination (the skins of hindlimb and abdomen).
Around Day 20 of treatment, animals showed dryness/fissuring of the skin of footpad of hindlimbs, and then exacerbated to thickening of the skin of footpad, which eventually resulted in cracking with bleeding. These findings were also observed in forelimbs. With the progression of the HFS-like findings, the animals showed decreases in the threshold of paw pressures and in the amount of locomotor activity. In the histopathology, dyskeratinization, desquamation, spongiosis, and associated inflammation were observed in the skin of feet. 5-FU concentration in the skin was higher in the hindlimb than that in the abdomen. The current data show that the clinical and histopathological features of our rat model well resembles human HFS. Furthermore, it is suggested that the dermal accumulation of 5-FU in the skin of footpad may be one of contributing factors in the pathophysiology. Our animal model will be a useful model to investigate the treatment and prevention for HFS.
