5-Fluorouracil (5-FU) is an antimetabolite that acts during the S phase of the 
cell cycle. The active metabolite, 5-fluorodeoxyuridine monophosphate inhibits 
thymidylate synthase (TS), thus preventing DNA synthesis, which leads to 
imbalanced cell growth and ultimately cell death. 5-FU and its oral prodrug 
capecitabine are used in the treatment of a number of solid tumors, including 
colorectal, breast, gastric, pancreatic, prostate, and bladder cancers. Common 
side effects include leukopenia, diarrhea, stomatitis, nausea, vomiting, and 
alopecia. Hand-foot syndrome (HFS) is a relatively common side effect of 
cytotoxic chemotherapy. It is more frequently associated with 5-FU, 
capecitabine, and cytarabine. This article reports on the case of a 55-year-old 
black man with metastatic colorectal carcinoma that was refractory to 
recommended treatment measures who developed grade 3 HFS after treatment with 
modified FOLFOX6 (leucovorin [LV]/5-FU/oxaliplatin) and bFOL (bolus 
5-FU/LV/oxaliplatin) regimens. Treatment was discontinued despite excellent 
response to chemotherapy. The patient had progression of disease on IROX 
(irinotecan/oxaliplatin) and irinotecan/cetuximab regimens. He was started on 
gemcitabine/capecitabine and developed HFS again, which was controlled with 
aggressive skin care and vitamin B6 treatment. Full sequencing of the 
dihydropyrimidine dehydrogenase (DPYD) gene and analysis of the human TS gene 
(TYMS) promoter region was performed. Pharmacogenetic testing revealed 2R/2R 
genotype of TYMS gene, which is associated with up to a 2.5-fold risk of 
toxicity to 5-FU therapy. Hand-foot syndrome has proven to be a dose-limiting 
toxicity of 5-FU, especially of capecitabine, leading to significant morbidity. 
Hand-foot syndrome seems to be dose dependent, and both peak drug concentration 
and total cumulative dose determine its occurrence. Genetic variations such as 
polymorphic abnormality of TYMS are potential causative factors for a 
significant portion of serious adverse reactions to 5-FU-based therapy.