Abstract：
Hand-foot syndrome (HFS) is a common side effect of fluoropyrimidine anticancer drugs and often becomes a dose-limiting manifestation of toxicity once it occurs. The precise mechanism of HFS remains unclear, and effective measures to prevent or relieve it are currently limited. To investigate the pathogenesis of HFS and effective measures for treating or preventing it, establishment of animal models is crucial. Here, we gave male SD rats 170 mg/kg of tegafur (prodrug of 5-FU) daily for 35 days and evaluated their clinical and histopathological characteristics and pain-related behavioral tests. TUNEL-positive apoptotic cells and 5-FU concentrations in the plantar skin were also evaluated to investigate the mode of toxicity. Tegafur treatment induced hypersensitivity to mechanical pressure on the plantar surface beginning in Week 3, with decreased locomotor activity. Focal desquamation of the plantar skin was observed almost concomitantly and gradually worsened to palmar and plantar skin thickening with severe desquamation, cracks, or both. Histopathological lesions in the plantar skin at treatment end included desquamation and thickening, with epidermal cell swelling and spongiosis and focal inflammation in the dermis. The time-course of development and the characteristics of the tegafur-induced skin lesions were highly similar to those in human fluoropyrimidine-induced HFS, indicating that a HFS rat model was successfully established. Localized high concentrations of 5-FU in the palmar and plantar skin, with increased apoptosis, are likely involved in the mode of toxicity. Our model should clarify the pathogenesis of HFS, providing new insights into the best supportive care and prevention.
摘要：
手足综合征（HFS）是氟嘧啶抗癌药物的常见副作用，一旦发生，通常会成为毒性的剂量限制表现。HFS的确切机制尚不清楚，预防或缓解这种情况的有效措施目前有限。探讨HFS的发病机制及预防治疗的有效措施,动物模型的建立至关重要。这里,我们每天给予雄性SD大鼠170mg/kg替加氟（5-FU的前药），持续35天，并评估其临床和组织病理学特征以及与疼痛相关的行为测试。还评估了TUNEL阳性凋亡细胞和足底皮肤中的5-FU浓度以研究毒性模式。替加氟治疗在第3周开始引起对足底表面机械压力的超敏反应，运动活动减少。足底皮肤的局灶性脱屑几乎同时观察到，并逐渐恶化到手掌和足底皮肤增厚，伴有严重脱屑，裂缝,或者两者兼而有之。治疗结束时足底皮肤的组织病理学病变包括脱皮和增厚，真皮表皮细胞肿胀、海绵状和局灶性炎症。替加氟诱导的皮肤病变的发展时间和特征与人氟嘧啶诱导的HFS高度相似，说明成功建立了HFS大鼠模型。手掌和足底皮肤局部高浓度的5-FU，随着细胞凋亡的增加，可能与毒性模式有关。我们的模型应该阐明HFS的发病机制，为最佳支持性护理和预防提供新的见解。
