Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity

Abstract

More than 80% of an administered dose of fluorouracil (FU) is eliminated by catabolism through dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of pyrimidines (Diasio and Harris, 1989). Tuchman and colleagues (1985) were the first to describe a patient with severe FU toxicity associated with a pyrimidine metabolism disorder. On the basis of another case report, Diasio et al (1988) conducted a familial study, the conclusions of which suggested an autosomal recessive pattern of inheritance for DPD deficiency. Since then, similar pharmacogenetic syndromes have been reported by the same group (Harris et al, 1991;Lu et al, 1993), others (Houyau et al, 1993) and ourselves (Fleming et al, 1993). We recently performed a review analysis on previously published cases of DPD deficiency associated with FU toxicity. It appeared that a complete absence of DPD activity is extremely rare and even partial enzyme activity might result in more or less severe FU toxicity . In addition, the fact that among 15 cumulated cases (most with digestive cancer) 13 (87%) were women was very striking and suggestive of a sex-linked deficiency in DPD activity. We report on the clinical and pharmacological results from 19 cancer patients with more or less intense FU-related toxicity, who were phenotyped in our centre as carrying a DPD deficiency diagnosed in peripheral blood mononuclear cells. Different features were analysed including sex ratio, the toxicity profile, and a possible link between the intensity of DPD deficiency and the severity of FU toxicity. MATERIAL AND METHODS PatientsThis study represents a 3-year collection of blood lymphocytes taken from 53 consecutive patients treated by FU-based chemotherapy in different French institutions (general hospitals, cancer centres, private hospitals). These patients had experienced unpredicted more or less severe FU-related toxicity. Blood lymphocytes were collected in the respective hospitals within a period of 1 month after the FU toxicity episode. All lymphocyte samples were shipped in dry-ice to our laboratory. Among this group of 53 patients (23 men, 30 women, mean age 58, range 36Ð73), 19 exhibited a moderate or marked DPD deficiency (less than 70% of the mean population value, i.e. less than 150 fmol min Ð1 mg Ð1 protein; Etienne et al, 1994). A complete description of these 19 case reports is given in Table 1. We defined a toxicity score which was the sum of the toxicity grades (WHO classification) for mucositis, neutropenia, thrombocytopenia and digestive toxicity. The presence of neurotoxicity was graded 4. The maximal toxicity score was 20. Determination of DPD activityLymphocyte preparation was carried out in the hospital where the patient received the FU-based treatment. Because of a known circadian pattern of DPD activity (Harris et al, 1990), blood samples were drawn between 8 a.m. and 10 a.m. to minimize the influence of circadian variability. When patients developed severe haematological toxicity, a normalization of blood cell count (white blood cells) was awai...

Analysis of the time course and prognostic factors determining toxicity due to infused fluorouracil

“…More than 80% of an administered dose of 5FU is eliminated by catabolism by the enzyme dihydropyrimidine dehydrogenase (DPD). Severe 5FU toxicity may occur in patients with partial or complete DPD deficiency and these individuals show marked impairment of 5FU clearance (Diasio et al, 1988;Lu et al, 1993;Milano et al, 1999). Fluorouracil clearance has been shown to be impaired in females although it does not appear to be affected by age .…”

“…Unfortunately, assessment of peripheral blood DPD levels correlates only weakly with 5FU clearance and is a poor predictor of 5FU toxicity (Fleming et al, 1992;Etienne et al, 1994). Even among patients who had developed severe 5FU toxicities, who might have been expected to be relatively DPD deficient, only a proportion of patients had reduced peripheral blood DPD levels (Milano et al, 1999;van Kuilenburg et al, 2000). Therefore, measurement of DPD levels before 5FU treatment has limited utility for the prediction of patients destined to develop severe 5FU-related toxicities.…”

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

“…DPD catabolizes >80% of 5-FU into fluorinated b-alanine (Heggie et al, 1987). A causative link between DPD deficiency and severe toxicity in response to 5-FU treatment has been repeatedly shown (Milano et al, 1999;van Kuilenburg et al, 2000;Johnson et al, 1999). While clinical assays of enzymatic DPD activity are available, they are not always easy to obtain, and there has been a substantial effort to characterize causative genetic variants within the DPYD gene relating to the DPD deficient phenotype (Yen and McLeod, 2007;Van Kuilenburg et al, 1999).…”

Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity

“…The postulated causative mechanisms involved in 5-FU cardiotoxicity are the following: an autoimmune response to damaged cells; an increased oxygen demand in patients receiving 5-FU; a coronary spasm caused by protein kinase C-mediated vasoconstriction; dihydropyrimidine dehydrogenase deficiency (Milano et al, 1999) and the 5-FU contaminant fluoroacetate. Inhibition of DNA synthesis, due to 5-FU incorporation into myocardial cells, was suggested to be the first step of cardiotoxicity and myocardial depression has been explained by inhibition of mitochondrial DNA synthesis due to 5-FU (Kohne et al, 1998).…”