Candidate mechanisms for capecitabine‐related hand–foot syndrome

Abstract

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.

A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome

“…This could also take place in normal tissues. In particular, cell cytotoxicity could be accentuated by the elevated proliferation rate observed in the skin of the palm and sole, rendering them more sensitive to the cytotoxic effects of the 5-FU (21). This model may explain the capecitabine-related HFS variability found in treated patients.…”

Significant Association between Hand-Foot Syndrome and Efficacy of Capecitabine in Patients with Metastatic Breast Cancer

“…Regarding interindividual differences in HFS susceptibility, it is likely that differences in activities of CDA, TP and DYPD 4,19,20) or inducibility of cyclooxygenase 2 21) in the palmar and plantar tissues might be responsible. A recent study identified a single nucleotide polymorphism (SNP) in the promoter region of the CDA gene that is related to capecitabine-induced HFS.…”

S-1-associated hand-foot syndrome as a prognostic factor in patients with metastatic breast cancer

“…One possible reason is the difference of DPD activity between skin sites. Expression of DPD metabolizing 5-FU is significantly greater in the palm than the back 22) . Further research is required regarding the difference between ethnic groups and mechanism of HFS.…”