Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency



5-Fluorouracil (5-FU), an analog of uracil, is one of the most commonly used chemotherapeutic agents and like other agents has a narrow therapeutic index limited by toxicity. Compared to previous attempts, uridine triacetate (Vistogard) has shown to increase the potential efficacy of 5-FU by allowing administering a higher dose and decreasing the toxicity. Recently, Vistogard received orphan drug designation from the FDA as an antidote in the treatment of 5-FU poisoning and from the European Medicines Agency as a treatment for 5-FU overdose. However, no data have been published to date in humans who were rescued by this agent following severe toxicity associated with 5-FU due to dihydropyrimidine dehydrogenase (DPYD) deficiency, the enzyme which is responsible for the elimination of approximately 80 % of the administered dose of 5-FU.

Patients and methods

We identified two patients with advanced pancreatic cancer who were referred to us for testing of DPYD status following severe toxicity associated with 5-FU administered at a dose of 1400 mg/m2 weekly bolus high-dose 5-FU followed by oral uridine triacetate as a part of a clinical trail. One patient developed grade 3 thrombocytopenia and grade 3 skin rash that resolved with discontinuation of 5-FU and supportive care, while second patient developed grade 4 thrombocytopenia, grade 3 coagulopathy and grade 3 neurological toxicity with a fatal outcome. DPYD status was evaluated as we have previously published.


The first patient was found to have an abnormally low DPYD activity of 0.087-nmol/min/mg protein by radioisotopic assay (reference normal range 0.182–0.688 nmol/min/mg protein). Because of pancytopenia, DPYD enzyme activity could not be assessed in patient 2; genotypic analysis of DPYD during autopsy revealed the presence of the heterozygous mutation, IVS14+1 G>A, DPYD*2A, now recognized as the most common cause of DPYD deficiency.


These two patients present the first two cases of DPYD deficiency that had either delay in severe toxicity or recovered from severe toxicity as they received oral Vistogard as a part of the conical trial. Toxicity was delayed in both patients by a mean of 3.5 weeks (range 3–4 weeks), indicating that Vistogard might be able to delay 5-FU toxicity despite higher doses than standard bolus dose of 5-FU used in gastrointestinal malignancies and the appearance of a potentially less toxic adverse effect of 5-FU at an unusual site (cutaneous) in one patient. The role of uridine triacetate with 5-FU in DPYD-deficient patients needs further investigation.

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  1. 1.

    Allegra CJ, Grem JL (1997) Antimetabolites. In: DeVita VT Jr, Hellman S, Rosenberg SA (eds) Cancer: principles and practice of oncology, 5th edn. Lippincott-Raven, Philadelphia, pp 432–451

    Google Scholar 

  2. 2.

    Sobrero AF, Aschele C, Bertino JR (1997) Fluorouracil in colorectal cancer: a tale of two drugs—Implications for biochemical modulation. J Clin Oncol 15:368–381

    CAS  PubMed  Google Scholar 

  3. 3.

    Grem JL (1996) 5-Fluoropyrimidines. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy: principles and practice. Lippincott-Raven, Philadelphia, pp 149–211

    Google Scholar 

  4. 4.

    Ezzeldin H, Diasio R (2004) Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer 4:181–189

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Johnson MR, Diasio R (2001) Importance of dihydropyrimidine dehydrogenase (DYPD) deficiency in patients exhibiting toxicity following treatment with 5-fluorouracil. Adv Enzyme Regul 41:151–157

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H, DeAbreu RA, Maring JG, Vreken P, Van Gennip AH (2000) Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity; identification of new mutations in the DPD gene. Clin Cancer Res 12:4705–4712

    Google Scholar 

  7. 7.

    Diasio RB, Beavers TL, Carpenter JT (1988) Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Investig 81:47–51

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Johnson MR, Hageboutros A, Wang K, High L, Smith JB, Diasio RB (1999) Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient following treatment with topical 5-fluorouracil. Clin Cancer Res 5:2006–2011

    CAS  PubMed  Google Scholar 

  9. 9.

    Martin DS, Stolfi RL, Sawyer RC, Spiegelman S, Young CW (1982) High-dose 5 fluorouracil with delayed “uridine” rescue in mice. Cancer Res 42:3964–3970

    CAS  PubMed  Google Scholar 

  10. 10.

    Klubes P, Cerna I, Meldon MA (1982) Uridine rescue from the lethal toxicity of 5-fluorouracil in mice. Cancer Chemother Pharmacol 8:17–21

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Martin DS, Stolfi RL, Sawyer RC (1989) Use of oral uridine as a substitute for parenteral uridine rescue of 5-fluorouracil therapy, with and without the uridine phosphorylase inhibitor 5-benzylacyclouridine. Cancer Chemother Pharmacol 24:9–14

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Klubes P, Leyland-Jones B (1989) Enhancement of the antitumor activity of 5-fluorouracil by uridine rescue. Pharmacol Ther 41:289–302

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Nord LD, Stolfi RL, Martin DS (1992) Biochemical modulation of 5-fluorouracil with leucovorin or delayed uridine rescue: correlation of antitumor activity with dosage and FUra incorporation into RNA. Pharmacol 43:2543–2549

    CAS  Google Scholar 

  14. 14.

    Leyva A, van Groeningen CJ, Kraal I, Gall H, Peters GJ, Lankelma J, Pinedo HM (1984) Phase I and pharmacokinetic studies of high-dose uridine intended for rescue from 5-fluorouracil toxicity. Cancer Res 44:5928–5933

    CAS  PubMed  Google Scholar 

  15. 15.

    Van Groeningen CJ, Peters GJ, Nadal JC, Laurensse E, Pinedo HM (1991) Clinical and pharmacologic study of orally administered uridine. J Natl Cancer Inst 83:437–441

    Article  PubMed  Google Scholar 

  16. 16.

    Kemeny N, Martin D, Schneider A, Williams L, Colofiore J, Sawyer R (1993) Uridine allows dose escalation of 5-fluorouracil when given with N-phosphonacetyl-l-aspartate, methotrexate, and leucovorin. Cancer 71:1875–1881

    Article  PubMed  Google Scholar 

  17. 17.

    Schwartz GK, Christman K, Saltz L, Casper E, Quan V, Bertino J, Martin DS, Colofiore J, Kelsen D (1996) A phase I trial of a modified, intensive FAMTX regimen (high dose 5-fluorouracil + doxorubicin + high-dose methotrexate + leucovorin) with oral uridine rescue. Cancer 78:1988–1995

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Saif MW, von Borstel R (2005) 5-Fluorouracil dose escalation enabled with PN401 (triacetyluridine): toxicity reduction and increased antitumor activity in mice. Cancer Chemother Pharmacol 27:1–7

    Google Scholar 

  19. 19.

    Kelsen DP, Martin D, O’Neil J, Schwartz G, Saltz L, Sung MT, von Borstel R, Bertino J (1997) Phase I trial of PN401, an oral prodrug of uridine, to prevent toxicity from fluorouracil in patients with advanced cancer. J Clin Oncol 15:1511–1517

    CAS  PubMed  Google Scholar 

  20. 20.

    Bamat MK, Tremmel R, O’Neil JD et al (2010) Uridine triacetate: an orally administered, lifesaving antidote for 5-FU overdose [ASCO abstract 9084]. J Clin Oncol 28(suppl 15)

  21. 21.

    Von Borstel R, O’Neil JD, Saydoff JA, Bamat MK (2010) Uridine triacetate for lethal 5-FU toxicity due to dihydropyrimidine dehydrogenase (DPD) deficiency. J Clin Oncol 28(Suppl 15):e13505

    Google Scholar 

  22. 22.

    Johnson MR, Yan J, Shao L, Albin N, Diasio RB (1997) Semi-automated radioassay for determination of dihydropyrimidine dehydrogenase (DPD) activity. Screening cancer patients for DPD deficiency, a condition associated with 5-fluorouracil toxicity. J Chromatogr B Biomed Sci Appl 696:183–191

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Lu Z, Zhang R, Diasio RB (1993) Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res 53:5433–5438

    CAS  PubMed  Google Scholar 

  24. 24.

    Ezzeldin H, Okamoto Y, Johnson MR, Diasio RB (2002) A high-throughput denaturing high-performance liquid chromatography method for the identification of variant alleles associated with dihydropyrimidine dehydrogenase deficiency. Anal Biochem 306:63–73

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Saif MW, Ezzeldin H, Vance K, Sellers S, Diasio RB (2007) DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol 60(4):503–507

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Ma WW, Saif WM, El-Rayes BF, Fakih M, Cartwright TH, Posey J, von Borstel R, Bamat MK (2016) Clinical trial experience with uridine triacetate for 5-fluorouracil toxicity. J Clin Oncol 34(Suppl 4S):655

    Google Scholar 

  27. 27.

    Hildalgo M, Villalona-Calero MA, Eckhardt SG, Drengler RL, Rodriguez G, Hammond LA, Diab SG, Weiss G, Garner AM, Campbell E, Davidson K, Louie A, O’Neil JD, von Borstel R, Von Hoff DD, Rowinsky EK (2000) Phase I and pharmacologic study of PN401 and fluorouracil in patients with advanced solid malignancies. J Clin Oncol 18(1):167–177

    Google Scholar 

  28. 28.

    Ashour OM, Naguib FN, Panzica RP (2000) Al Safarjalani ON, el Kouni MH. Modulation of 5-fluorouracil host toxicity by 5-(benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2′,3′,5′-tri-O-acetyluridine, a prodrug of uridine. Biochem Pharmacol 60:427–431

    CAS  Article  PubMed  Google Scholar 

  29. 29.

  30. 30.

    Harris BE, Song R, Soong SJ, Diasio RB (1990) Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res 50:197–201

    CAS  PubMed  Google Scholar 

  31. 31.

    Saif MW (2013) Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among Caucasian and non-Caucasian patients with 5-FU-and capecitabine-related toxicity using full sequencing of DPYD. Cancer Genom Proteom 10(2):89–92

    CAS  Google Scholar 

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This work was supported in part by NIH Grant CA 62164.

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Correspondence to Muhammad Wasif Saif.

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Saif, M.W., Diasio, R.B. Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency. Cancer Chemother Pharmacol 78, 151–156 (2016).

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  • 5-Fluorouracil
  • Fluoropyrimidines
  • PN401
  • Uridine
  • DPYD gene