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.