CASE REPORT

5-Fluorouracil/irinotecan induced lethal toxicity as a result of a combined pharmacogenetic syndrome: report of a case

M Steiner¹, M Seule¹, B Steiner², I Bauer³, M Freund², C H Köhne² and P Schuff-Werner¹

¹ Institute of Clinical Chemistry and Laboratory Medicine, University of Rostock, Ernst-Heydemann-Str. 6, D-18057 Rostock, Germany
² Division of Haematology/Oncology, Department of Internal Medicine, University of Rostock
³ Division of Medical Genetics, Children’s Hospital, University of Rostock

Correspondence to:
Correspondence to:
Dr M Steiner
Medical Faculty, Institute of Clinical Chemistry and Laboratory Medicine, University of Rostock, Ernst-Heydemann-Str. 6, D-18057 Rostock, Germany; michael.steiner{at}med.uni-rostock.de

Combination cancer chemotherapy induced toxicity can be associated with combined pharmacogenetic syndromes. Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme involved in the catabolic detoxification of 5-fluorouracil (5FU). A heterozygous G > A transition at the 5' splicing donor consensus sequence in intron 14 leading to exon 14 skipping (IVS14+1 G > A, DPYD*2A) with partial loss of enzyme activity may be partly responsible for 5FU induced toxicity, whereas irinotecan associated toxicity may in part be explained by an aberrant UGT1A1 promoter (TA)_n genotype underlying Gilbert’s syndrome with reduced liver glucuronidation activity. This report describes a 44 year old white woman who suffered from severe gastrointestinal and haematological toxicity while undergoing 5FU_24h/folinic acid/irinotecan treatment for adenocarcinoma of the sigmoid colon. Despite appropriate supportive treatment, her condition rapidly deteriorated and led to death. Molecular analysis revealed a hitherto undescribed combined pharmacogenetic syndrome, consisting of heterozygosity for the DPD IVS14+1 G > A mutation and UGT1A1 (TA)_6/7 heterozygosity, which probably contributed to the fatal outcome in this patient.

Abbreviations: DPD, dihydropyrimidine dehydrogenase; FA, folinic acid; 5FU, 5-fluorouracil

Keywords: dihydropyrimidine dehydrogenase; 5-fluorouracil; Gilbert’s syndrome; irinotecan; pharmacogenetics

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• Hahn, K. K., Wolff, J. J., Kolesar, J. M. (2006). Pharmacogenetics and irinotecan therapy. Am J Health Syst Pharm 63: 2211-2217 [Abstract] [Full Text]