WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Hand-foot syndrome (HFS) is a limiting toxicity of the widely used fluorouracil (5FU) prodrug capecitabine.• The pharmacological origin of HFS has not been elucidated.• The expression of capecitabine-metabolizing enzymes thymidine phosphorylase (TP, activating pathway) and dihydropyrimidine dehydrogenase (DPD, catabolic pathway) in the skin of the palm (target tissue for HFS) is unknown. WHAT THIS STUDY ADDS• This pilot study, conducted in healthy volunteers, clearly demonstrated that TP expression is significantly greater in the palm compared with the lower back (control area).• This suggests TP-facilitated enhanced production of 5FU in the palm that could explain the occurrence of HFS.• This result may support strategies to prevent HFS. AIMSThe oral fluoropyrimidine prodrug capecitabine is widely used in oncology. Capecitabine was designed to generate 5FU via the thymidine phosphorylase (TP) enzyme, preferentially expressed in tumoral tissues. Hand-foot syndrome (HFS) is a limiting toxicity of capecitabine. A pilot study on healthy volunteers was conducted in order to test the hypothesis that the occurrence of HFS could be related to tissue-specific expression of drug-metabolizing enzymes in the skin of the palm and sole. To this end, the expression of TP (activating pathway), dihydropyrimidine dehydrogenase (DPD, catabolic pathway) and cell proliferation (Ki67) were measured in the skin of the palm (target tissue for HFS) and of the lower back (control area). METHODSTwo paired 4-mm diameter punch biopsy specimens (palm and back) were taken in 12 healthy volunteers. Immunohistochemical analyses were performed on frozen tissues. RESULTSProliferation rate (Ki67 staining) was significantly higher in epidermal basal cells of the palm compared with the back (P = 0.008). Also, TP and DPD expression were significantly greater in the palm relative to the back (P = 0.039 and 0.012, respectively). TP and Ki67 expression were positively and significantly correlated in the palm. CONCLUSIONSThe high proliferation rate of epidermal basal cells in the palm could make them more sensitive to the local action of cytotoxic drugs. TP-facilitated local production of 5FU in the palm during capecitabine treatment could explain the occurrence of HFS. This observation may support future strategies to limit the occurrence of HFS during capecitabine therapy.

The MCC system was well managed by both patients and caregivers. These results show that it has the potential to improve medical assistance by virtue of a constant access to medical advice and reduce unnecessary hospital admissions.

2019 Background: Use of the oral fluoropyrimidine capecitabine, which generates 5FU in tumor tissues, is currently expanding. HFS is frequently associated with administration of capecitabine. However, the underlying pharmacological mechanism of HFS is still not elucidated. In a previous experimental study, we ruled out a possible implication of 5FU catabolites (FUH2 and FBAL) in the etiology of HFS (Anti-Cancer Drugs 15: 969, 2004). The aim of this study was to investigate expression levels of thymidine phosphorylase (TP, the main activating enzyme of capecitabine) and dihydropyrimidine dehydrogenase (DPD, the rate-limiting enzyme of 5FU catabolism) in skin samples from the palm area of the hand (target zone) and from the back (control zone). Methods: Paired-skin biopsies have been planned in 12 healthy volunteers, in agreement with the local ethical committee. Expressions of TP, DPD, and Ki67 (cell proliferation marker) were analyzed by a two-step immunohistochemical method using specific monoclonal antibodies (from Calbiochem for TP, Roche for DPD and Dako for Ki67) and immunoperoxydase revelation (kit ABC Vectastain). Results: Data from the first four subjects indicate no significant difference in the strong Ki67 staining between control and target zones. TP was markedly expressed in the basal layer of the epidermis (BLE), with similar staining in control and target zones. Interestingly, in 3 cases out of 4, DPD was strongly expressed (2+, 3+) in the BLE of the control zone and much less (0, 1+) in the paired-target zone. Definitive data on 12 subjects will be presented. Conclusions: This preliminary original observation suggests that capecitabine may be locally activated in the skin due to high TP expression. The relative absence of DPD expression in the palm area may explain the specificity of HFS, which may result from a lack of local 5FU catabolism. These new data open the way to a possible pharmacological approach to limit HFS. No significant financial relationships to disclose.

No abstract