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. 1999 Feb;79(3-4):627–630. doi: 10.1038/sj.bjc.6690098

Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity

G Milano 1, M C Etienne 1, V Pierrefite 1, M Barberi-Heyob 2, R Deporte-Fety 3, N Renée 1
PMCID: PMC2362417  PMID: 10027340

Abstract

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. We report lymphocytic DPD data concerning a group of 53 patients (23 men, 30 women, mean age 58, range 36–73), treated by 5-FU-based chemotherapy in different French institutions and who developed unanticipated 5-FU-related toxicity. Lymphocyte samples (standard collection procedure) were sent to us for DPD determination (biochemical method). Among the whole group of 53 patients, 19 had a significant DPD deficiency (DD; below 150 fmol min−1 mg−1 protein, i.e. less than 70% of the mean value observed from previous population study). There was a greater majority of women in the DD group (15 out of 19, 79%) compared with the remaining 34 patients (15 out of 34, 44%, P<0.014). Toxicity was often severe, leading to patient death in two cases (both women). The toxicity score (sum of WHO grading, theoritical range 0–20) was twice as high in patients with marked DD (below 100 pmol min−1 mg−1 protein, n = 11, mean score = 13.2) compared with patients with moderate DD (between 150 and 100 pmol min−1 mg−1 protein, n = 8, mean score = 6.8), P = 0.008. In the DD group, there was a high frequency of neurotoxic syndromes (7 out of 19, 37%). The two deceased patients both had severe neurotoxicity. The occurrence of cardiac toxicity was relatively rare (1 out of 19, 5%). These data suggest that women are particularly prone to DPD deficiency and allow a more precise definition of the DD toxicity profile. © 1999 Cancer Research Campaign

Keywords: 5-fluorouracil, dihydropyrimidine dehydrogenase, anti-cancer drug-related toxicity

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Selected References

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  1. Diasio R. B., Harris B. E. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet. 1989 Apr;16(4):215–237. doi: 10.2165/00003088-198916040-00002. [DOI] [PubMed] [Google Scholar]
  2. Etienne M. C., Lagrange J. L., Dassonville O., Fleming R., Thyss A., Renée N., Schneider M., Demard F., Milano G. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol. 1994 Nov;12(11):2248–2253. doi: 10.1200/JCO.1994.12.11.2248. [DOI] [PubMed] [Google Scholar]
  3. Fleming R. A., Milano G. A., Gaspard M. H., Bargnoux P. J., Thyss A., Plagne R., Renée N., Schneider M., Demard F. Dihydropyrimidine dehydrogenase activity in cancer patients. Eur J Cancer. 1993;29A(5):740–744. doi: 10.1016/s0959-8049(05)80358-2. [DOI] [PubMed] [Google Scholar]
  4. Fleming R. A., Milano G., Thyss A., Etienne M. C., Renée N., Schneider M., Demard F. Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res. 1992 May 15;52(10):2899–2902. [PubMed] [Google Scholar]
  5. Floyd R. A., Hornbeck C. L., Byfield J. E., Griffiths J. C., Frankel S. S. Clearance of continuously infused 5-fluorouracil in adults having lung or gastrointestinal carcinoma with or without hepatic metastases. Drug Intell Clin Pharm. 1982 Sep;16(9):665–667. doi: 10.1177/106002808201600904. [DOI] [PubMed] [Google Scholar]
  6. Harris B. E., Song R., Soong S. J., Diasio R. B. 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. 1990 Jan 1;50(1):197–201. [PubMed] [Google Scholar]
  7. Houyau P., Gay C., Chatelut E., Canal P., Roché H., Milano G. Severe fluorouracil toxicity in a patient with dihydropyrimidine dehydrogenase deficiency. J Natl Cancer Inst. 1993 Oct 6;85(19):1602–1603. doi: 10.1093/jnci/85.19.1602. [DOI] [PubMed] [Google Scholar]
  8. Johnson M. R., Wang K., Tillmanns S., Albin N., Diasio R. B. Structural organization of the human dihydropyrimidine dehydrogenase gene. Cancer Res. 1997 May 1;57(9):1660–1663. [PubMed] [Google Scholar]
  9. Langer C. J., Hageboutros A., Kloth D. D., Roby D., Shaer A. H. Acute encephalopathy attributed to 5-FU. Pharmacotherapy. 1996 Mar-Apr;16(2):311–313. [PubMed] [Google Scholar]
  10. Lu Z., Zhang R., Diasio R. B. 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. 1993 Nov 15;53(22):5433–5438. [PubMed] [Google Scholar]
  11. Milano G., Etienne M. C., Cassuto-Viguier E., Thyss A., Santini J., Frenay M., Renee N., Schneider M., Demard F. Influence of sex and age on fluorouracil clearance. J Clin Oncol. 1992 Jul;10(7):1171–1175. doi: 10.1200/JCO.1992.10.7.1171. [DOI] [PubMed] [Google Scholar]
  12. Milano G., Etienne M. C. Potential importance of dihydropyrimidine dehydrogenase (DPD) in cancer chemotherapy. Pharmacogenetics. 1994 Dec;4(6):301–306. doi: 10.1097/00008571-199412000-00002. [DOI] [PubMed] [Google Scholar]
  13. Stenram U. 5-FU toxicity and nutritional deficiencies. Br J Cancer. 1993 May;67(5):1157–1157. doi: 10.1038/bjc.1993.214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Takimoto C. H., Lu Z. H., Zhang R., Liang M. D., Larson L. V., Cantilena L. R., Jr, Grem J. L., Allegra C. J., Diasio R. B., Chu E. Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency. Clin Cancer Res. 1996 Mar;2(3):477–481. [PubMed] [Google Scholar]
  15. Thyss A., Milano G., Schneider M., Demard F. Circulating drug levels in patients presenting cardiotoxicity to 5-FU. Eur J Cancer Clin Oncol. 1988 Oct;24(10):1675–1676. doi: 10.1016/0277-5379(88)90062-4. [DOI] [PubMed] [Google Scholar]
  16. Tuchman M., Stoeckeler J. S., Kiang D. T., O'Dea R. F., Ramnaraine M. L., Mirkin B. L. Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. N Engl J Med. 1985 Jul 25;313(4):245–249. doi: 10.1056/NEJM198507253130407. [DOI] [PubMed] [Google Scholar]
  17. Wei X., McLeod H. L., McMurrough J., Gonzalez F. J., Fernandez-Salguero P. Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest. 1996 Aug 1;98(3):610–615. doi: 10.1172/JCI118830. [DOI] [PMC free article] [PubMed] [Google Scholar]

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