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Pancytopenia and Severe Gastrointestinal Toxicities Associated with 5-Fluorouracil in a Patient with Thymidylate Synthase (TYMS) Polymorphism.
Cureus 2016; 8(9):e798C

Abstract

5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in solid tumors, including colon, gastric and breast cancers. The pharmacogenetic syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency leading to severe toxicity after administration of 5-flourouracil (5-FU) and capecitabine has been well-recognized. However, the data about the association of the target enzyme, thymidylate synthase (TYMS) with the toxicity of these agents is limited. A 50-year-old Caucasian woman with T2N2M0 Stage IIIB squamous cell rectal cancer after local surgical excision initiated 5-FU therapy with mitomycin-C and radiation therapy in the adjuvant setting. Following the first treatment with 5-FU, she developed grade III mucositis and grade IV neutropenia which delayed her second dose of therapy. Following her second dose of 5-FU, she again developed grade III mucositis, grade II diarrhea, pancytopenia, fever, and rectal bleeding requiring hospitalization. She was treated with blood and platelet transfusion, pegfilgrastim, IV antibiotics, and supportive therapy. Due to her severe clinical toxicity following chemotherapy involving 5-FU, we tested her for both DPD deficiency andTYMS polymorphisms. The patient was found to be homozygous for the TYMS polymorphism 5'TSER genotype 2R/2R*f, which has been associated with increased 5-FU drug sensitivity and susceptibility to 5-FU toxicity. Our case report further underlines the fact that TYMS polymorphism not only predicts response to 5-FU by relating to intratumoral-TYMS mRNA expression but also the toxicity in these patients receiving fluoropyrimidines. In brief, TYMS genotype variations present a dilemma in 5-FU-driven cancer therapy- overexpression leads to decreased drug sensitivity and poor prognosis, while underexpression leads to the manifestation of toxic drug effects that may halt therapy altogether. Future prospective translational studies in a larger population are warranted to validate its role as a predictive and prognostic factor.

Authors+Show Affiliations

Internal Medicine, Tufts Medical Center, Tufts University School of Medicine.Tufts Medical Center, Tufts University School of Medicine.Hematology/Oncology, Tufts Medical Center, Tufts University School of Medicine.

Pub Type(s)

Case Reports

Language

eng

PubMed ID

27774364

Citation

Wang, Bo, et al. "Pancytopenia and Severe Gastrointestinal Toxicities Associated With 5-Fluorouracil in a Patient With Thymidylate Synthase (TYMS) Polymorphism." Cureus, vol. 8, no. 9, 2016, pp. e798.
Wang B, Walsh SJ, Saif MW. Pancytopenia and Severe Gastrointestinal Toxicities Associated with 5-Fluorouracil in a Patient with Thymidylate Synthase (TYMS) Polymorphism. Cureus. 2016;8(9):e798.
Wang, B., Walsh, S. J., & Saif, M. W. (2016). Pancytopenia and Severe Gastrointestinal Toxicities Associated with 5-Fluorouracil in a Patient with Thymidylate Synthase (TYMS) Polymorphism. Cureus, 8(9), pp. e798.
Wang B, Walsh SJ, Saif MW. Pancytopenia and Severe Gastrointestinal Toxicities Associated With 5-Fluorouracil in a Patient With Thymidylate Synthase (TYMS) Polymorphism. Cureus. 2016 Sep 21;8(9):e798. PubMed PMID: 27774364.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pancytopenia and Severe Gastrointestinal Toxicities Associated with 5-Fluorouracil in a Patient with Thymidylate Synthase (TYMS) Polymorphism. AU - Wang,Bo, AU - Walsh,Shannon J, AU - Saif,Muhammad W, Y1 - 2016/09/21/ PY - 2016/10/25/pubmed PY - 2016/10/25/medline PY - 2016/10/25/entrez KW - 5-fu KW - mucositis KW - neutropenia KW - rectal cancer KW - thrombocytopenia KW - toxicity KW - tyms SP - e798 EP - e798 JF - Cureus JO - Cureus VL - 8 IS - 9 N2 - 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in solid tumors, including colon, gastric and breast cancers. The pharmacogenetic syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency leading to severe toxicity after administration of 5-flourouracil (5-FU) and capecitabine has been well-recognized. However, the data about the association of the target enzyme, thymidylate synthase (TYMS) with the toxicity of these agents is limited. A 50-year-old Caucasian woman with T2N2M0 Stage IIIB squamous cell rectal cancer after local surgical excision initiated 5-FU therapy with mitomycin-C and radiation therapy in the adjuvant setting. Following the first treatment with 5-FU, she developed grade III mucositis and grade IV neutropenia which delayed her second dose of therapy. Following her second dose of 5-FU, she again developed grade III mucositis, grade II diarrhea, pancytopenia, fever, and rectal bleeding requiring hospitalization. She was treated with blood and platelet transfusion, pegfilgrastim, IV antibiotics, and supportive therapy. Due to her severe clinical toxicity following chemotherapy involving 5-FU, we tested her for both DPD deficiency andTYMS polymorphisms. The patient was found to be homozygous for the TYMS polymorphism 5'TSER genotype 2R/2R*f, which has been associated with increased 5-FU drug sensitivity and susceptibility to 5-FU toxicity. Our case report further underlines the fact that TYMS polymorphism not only predicts response to 5-FU by relating to intratumoral-TYMS mRNA expression but also the toxicity in these patients receiving fluoropyrimidines. In brief, TYMS genotype variations present a dilemma in 5-FU-driven cancer therapy- overexpression leads to decreased drug sensitivity and poor prognosis, while underexpression leads to the manifestation of toxic drug effects that may halt therapy altogether. Future prospective translational studies in a larger population are warranted to validate its role as a predictive and prognostic factor. SN - 2168-8184 UR - https://www.unboundmedicine.com/medline/citation/27774364/Pancytopenia_and_Severe_Gastrointestinal_Toxicities_Associated_with_5_Fluorouracil_in_a_Patient_with_Thymidylate_Synthase__TYMS__Polymorphism_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27774364/ DB - PRIME DP - Unbound Medicine ER -