Cardiotoxicity of 5-fluorouracil and capecitabine in a pancreatic cancer patient with a novel mutation in the dihydropyrimidine dehydrogenase gene.
BACKGROUND
5-fluorouracil (5-FU) is an antimetabolite that acts during the S phase of the cell cycle. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the pathway that catabolises the pyrimidines. 5-fluorouracil 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. Cardiotoxicity is a relatively uncommon side effect of 5-fluorouracil and capecitabine.


METHODS
This article reports the case of a 63-year-old male with locally invasive pancreatic cancer who developed recurrent chest pain and ischemic electrocardiogram changes after treatment with 5-fluorouracil and capecitabine. Full sequencing of the dihydropyrimidine dehydrogenase (DPYD) gene and analysis of the thymidylate synthetase (TYMS) gene promoter region was performed. Pharmacogenetic testing revealed p453L (1358C>T) type DPYD germ line mutation. This mutation has not been reported previously in association with 5-fluorouracil induced cardiotoxicity.


CONCLUSIONS
Cardiotoxicity associated with 5-fluorouracil and capecitabine administration is infrequently reported in the literature and appears to be dose and schedule dependent. Genetic variations such as polymorphic abnormality of DPYD are potential causative factors for a significant portion of serious adverse reactions to 5-fluorouracil-based therapy.
Shahrokni
Armin
A
Rajebi
Mohammad Reza
MR
Harold
Laurie
L
Saif
Muhammad Wasif
MW
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000069287:Capecitabine; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000503:physiopathology; D004252:DNA Mutational Analysis; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D004452:Echocardiography / Q000187:drug effects; D005472:Fluorouracil / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D016133:Polymerase Chain Reaction; D011355:Prodrugs / Q000009:adverse effects / Q000627:therapeutic use; D011665:Pulmonary Valve Insufficiency / Q000139:chemically induced / Q000503:physiopathology; D013940:Thymidylate Synthase / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil