Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome

ArticleinCancer 68(3):499-501 · September 1991with 58 Reads
Abstract
This study describes the inheritance of a defect in pyrimidine catabolism and its association with drug-induced toxicity in a patient receiving 5-fluorouracil (FUra) as adjuvant chemotherapy for breast carcinoma. The study population included the affected patient (proband), nine of her blood relatives, and seven healthy volunteers. The activity of dihydropyrimidine dehydrogenase (DPD), the initial enzyme of pyrimidine (and FUra) catabolism, in peripheral blood mononuclear cells was measured in each subject by a specific radiometric assay using FUra as the substrate. The proband had no detectable DPD activity. When enzyme levels in the proband and relatives were compared with that in controls, an autosomal recessive pattern of inheritance was demonstrated. This is the third patient with severe FUra toxicity secondary to an alteration in pyrimidine catabolism and the second from our clinic population suggesting that the frequency of this genetic defect may be greater than previously thought. Monitoring DPD activity may be important in the management of patients experiencing severe toxicity secondary to FUra chemotherapy.

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  • ... Dihydropyrimidine dehydro- genase (DPD) breaks down 5-FU (Wasternack, 1980;Diasio and Harris, 1989;Longley et al., 2003). DPD plays a crucial role in toxicity associated with 5-FU chemotherapy (Harris et al., 1991). The activity of DPD was decreased in female and the difference in DPD activity between males and females is 15% (Etienne et al., 1994). ...
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    The incidence and mortality of various cancers are associated with sex-specific disparities. Sex differences in cancer epidemiology are one of the most significant findings. Men are more prone to die from cancer, particularly hematological malignancies. Sex difference in cancer incidence is attributed to regulation at the genetic/molecular level and sex hormones such as estrogen. At the genetic/molecular level, gene polymorphism and altered enzymes involving drug metabolism generate differences in cancer incidence between men and women. Sex hormones modulate gene expression in various cancers. Genetic or hormonal differences between men and women determine the effect of chemotherapy. Until today, animal studies and clinical trials investigating chemotherapy showed sex imbalance. Chemotherapy has been used without consideration of sex differences, resulting in disparity of efficacy and toxicity between sexes. Based on accumulating evidence supporting sex differences in chemotherapy, all clinical trials in cancer must incorporate sex differences for a better understanding of biological differences between men and women. In the present review, we summarized the sex differences in (1) incidence and mortality of cancer, (2) genetic and molecular basis of cancer, (3) sex hormones in cancer incidence, and (4) efficacy and toxicity of chemotherapy. This review provides useful information for sex-based chemotherapy and development of personalized therapeutic strategies against cancer.
  • ... DPD (dihydropyrimidine dehydrogenase), encoded by DPYD gene, is the initial and rate-limiting enzyme of the metabolic pathway of fluoropyrimidines, such as 5-Fu, capecitabine and tegafur [6][7][8]. The clinical importance of DPD was initially identified due to severe or lethal toxicity in patients given fluoropyrimidines who are deficient in or have low levels of DPD activity [9][10][11]. Since then, more than 50 DPYD polymorphisms have been reported to cause fluoropyrimidine-associated toxicity in the treatment of malignancies such as colorectal carcinoma, gastroesophageal cancer and lymphoblastic leukemia [12][13][14]. ...
  • ... DPYD has been the top candidate for pharmacogenetic studies on 5-FU toxicity, as a reduced DPD activity results in an increased halflife of the drug, and thus an increased risk of toxicity. [5,[8][9][10][11][12][13][14]The splice site variant IVS14+1G>A polymorphism in the DPYD gene (rs3918290; allele A also known as *2A allele) is the most consistent genetic marker for toxicity. Unfortunately the low minor allele frequency and the fact that just about a 50% of the *2A allele carriers actually develop severe toxicity limit its prediction power. ...
    Article
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    Background: 5-fluorouracil (5-FU) based chemotherapy is the most common first line regimen used in gastric and gastroesophageal junction cancer, but development of severe toxicity is a main concern in the treatment. The present study is aimed to evaluate a novel pre-treatment assay, known as the 5-FU degradation rate (5-FUDR), as a predictive factor for 5-FU toxicity. Methods: Pre-treatment 5-FUDR and gene polymorphisms related to 5-FU metabolism (DPYDIVS14+1G>A, MTHFRA1298T or C677T, TMYS TSER) were characterized in gastro-esophageal cancer patients. Association with toxicities was retrospectively evaluated, using multivariate logistic regression analysis. Results: 107 gastro-esophageal cancer patients were retrospectively analyzed. No relation between gene polymorphisms and toxicity were detected, while low (< 5th centile) and high (> 95th centile) 5-FUDRs were associated with development of grade 3-4 toxicity (OR 11.14, 95% CI 1.09-113.77 and OR 9.63, 95% CI 1.70-54.55, p = 0.002). Conclusions: Compared to currently used genetic tests, the pre-treatment 5-FUDR seems useful in identifying patients at risk of developing toxicity.
  • ... One of the main reasons for the short half-life time of 5-FU is the presence of dihydropyrimidine dehydrogenase (DPD) in humans which breaks down 80 % of the 5-FU to dihy- drofluorouracil in the liver (Diasio & Harris, 1989). Patients with decreased DPD activity are more sensitive to 5-FU and are more likely to develop side effects, like mucositis, neu- rotoxicity and myelosuppression (Diasio et al., 1988;Harris et al., 1991;Takimoto et al., 1996). Interestingly, some microbial species also possess DPD activity (Hidese et al., 2011), which might play a role in their sensitivity to 5-FU. ...
    Article
    5-Fluorouracil (5-FU), a commonly used chemotherapeutic agent, often causes oral mucositis, an inflammation and ulceration of the oral mucosa. Microorganisms in the oral cavity are thought to play an important role in the aggravation and severity of mucositis, but the mechanisms behind this remain unclear. Although 5-FU has been shown to elicit antibacterial effects at high concentrations (>100 µM), its antibacterial effect at physiologically relevant concentrations in the oral cavity is unknown. This study reports the effect of different concentrations of 5-FU (range 0.1-50 µM) on the growth and viability of bacterial monocultures that are present in the oral cavity and the possible role in the activity of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU resistance. Our data showed a differential sensitivity among the tested oral species towards physiological concentrations of 5-FU. Klebsiella oxytoca, Streptococcus salivarius, Streptococcus mitis, Streptococcus oralis, Pseudomonas aeruginosa and Lactobacillus salivarius appeared to be highly resistant to all tested concentrations. In contrast, Lactobacillus oris, Lactobacillus plantarum, Streptococcus pyogenes, Fusobacterium nucleatum and Neisseria mucosa already showed a significant reduction in growth and viability already starting from very low concentrations (0.2 - 3.1 µM). We could also provide evidence that DPD is not involved in the 5-FU resistance of the selected species. The observed variability in response to physiological 5-FU concentrations may explain why certain microbiota lead to a community dysbiosis and/or an overgrowth of certain resistant microorganisms in the oral cavity following cancer treatment.
  • ... Previous studies have investigated the relationship between DPD activity and 5-FU toxicity [7][8][9][10][11]. Clinically severe 5-FU toxicity was reported in a family with DPD deficiency [12]. Moreover, relatively low DPD activity was reported to be a risk factor for severe cytotoxic adverse effects [7]. ...
    Article
    Full-text available
    Over the past decades, 5-Fluorouracil (5-FU) has been widely used to treat several types of carcinoma, including esophageal squamous cell carcinoma. In addition to its common side effects, including diarrhea, mucositis, neutropenia, and anemia, 5-FU treatment has also been reported to cause hyperammonemia. However, the exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown. We encountered an esophageal carcinoma patient who developed hyperammonemia when receiving 5-FU-containing chemotherapy but did not exhibit any of the other common adverse effects of 5-FU treatment. At the onset of hyperammonemia, laboratory tests revealed high dihydropyrimidine dehydrogenase (DPD) activity and rapid 5-FU clearance. Our findings suggested that 5-FU hypermetabolism may be one of the key mechanisms responsible for hyperammonemia during 5-FU treatment.
  • Article
    Purpose 5-Fluorouracil (5FU) drug exposure correlates with treatment response and toxicity in cancer patients. Dosing is based upon body surface area which does not correlate with 5FU pharmacokinetics (PK)/pharmacodynamics. Therapeutic drug monitoring has enabled real-time 5FU dose adjustments: reducing toxicity with increased efficacy. The aim of this study was to assess feasibility of a 5FU monitoring service utilising a commercial kit in a quaternary cancer centre and to compare PK parameters to previously published studies. Methods Cancer patients receiving continuous infusional (CI) 5FU with ECOG PS 0–2, and adequate organ function, were eligible. Patients had blood samples taken at t = 0, mid infusion (if feasible) then 2 h pre infusion end. 5FU levels were measured using a commercial kit (My-5FU PCM™). A feasibility questionnaire was completed by trial nurses and toxicity data were recorded at baseline and at the commencement of the next cycle. 5FU pharmacokinetic exposure parameters were calculated. Results Twenty patients (12 male; 8 female), median age 62, (range 37–71) had samples taken. Twenty (100%) feasibility forms were available for assessment. Blood samples were taken at 51/69 (74%) specified time points. Ease of sample processing was recorded as easy in all 20 patients. Patient compliance with scheduled visits was 18/20 (90%). One form noted other difficulties with predicting end of infusion time. 19/20 patients had blood samples analysed. Mean measured 5FU AUC (0-Tlast) for 5FU 1 g/m² with platinum: 35.8 h mg/L (range 28.56–44.26), mean Css 372.2 µg/L (range 297.5–461.0); 5FU 600 mg/m² with platinum: 12.42 h mg/L (range 6.91–18.29), mean Css 111.0 µg/L (72.0–190.5) and 5FU 2400 mg/m² as part of FOLFOX ± bevacizumab: 14.75 h mg/L (range 6.74–22.93), mean Css 320.70 µg/L (range 146.5–498.5). One patient had grade 4 neutropenia and one patient without PK parameters experienced febrile neutropenia (grade 4 neutropenia). Mucositis was observed in two patients: [5FU/platinum (1), grade 1, FOXFOX ± bevacizumab (1) grade 1]. Diarrhoea was reported in three patients [5FU/platinum (2) grade 1–2, FOXFOX ± bevacizumab (1) grade 1]. Conclusion Therapeutic 5FU drug monitoring was feasible using commercial kits and analysers and hence warrants development as a routine standard of care in cancer patients. The variability in the 5FU exposure parameters is consistent with other studies using the My 5FU PCM kit.
  • Chapter
    The number of known inherited defects of pyrimidine metabolism is limited. Only four enzyme defects of pyrimidine metabolism have been described in association with inborn errors of metabolism: UMP-synthetase deficiency, generally ascribed as hereditary orotic aciduria Pyrimidine-5′-nucleotidase deficiency Dihydropyrimidine dehydrogenase deficiency Dihydropyrimidine amidohydrolase deficiency (a patient with this deficiency has been reported recently at the meeting of the Society of Inherited Metabolic Disease (SIMD) in Santa Fé [1])
  • Chapter
    Over the past decade, there has been increasing evidence of the importance of the pyrimidine catabolic pathway in regulating the metabolism of 5-fluorouracil (5-FU) and thus critically influencing the pharmacology of 5-FU and other fluoropyrimidine drugs (1). Dihydropyrimidine dehydrogenase or DPD (also known as, dihydrouracil dehydrogenase, dihydrothymine dehydrogenase, uracil reductase, E.C. 1.3.1.2) is the initial rate-limiting enzymatic step in the catabolism of not only the widely used antimetabolite cancer chemotherapy drug 5-FU but also the naturally occurring pyrimidines uracil and thymine (2–3). As shown in Fig. 1, DPD occupies an important position in the regulation of the metabolism of 5-FU, converting over 85% of a standard intravenous dose of administered 5-FU to dihydrofluorouracil (5-FUH2), an inactive metabolite, in an enzymatic step that physiologically is essentially irreversible (4,5). Although DPD is critical in regulating 5-FU metabolism, 5-FU cytotoxic action is dependent on the anabolism of 5-FU to the “active” nucleotides 5-fluorodeoxyuridine monophosphate (FdUMP), 5-fluorouridine triphosphate (FUTP), and 5-fluorodeoxyuridine triphosphate (FdUTP). These important “active” metabolites are, in turn, responsible for inhibition of cell replication through primarily inhibition of thymidylate synthase and secondarily through incorporation into RNA or DNA.
  • Chapter
    It is well known that, with respect to cytostatic drug, there is a small therapeutic range between the dose with the desired antitumor activity and the dose which can cause severe side effects. Side effects occur usually in rapidly proliferating self-regenerating tissues such as bone marrow and mucosae.
  • Chapter
    Pyrimidine und Purine sind Grundbausteine der Nukleinsäuren und daher essentiell für die Speicherung und Weitergabe der genetischen Information. Zusätzlich wirken sie auch als Koenzyme und aktive Intermediate im Kohlenhydrat- und Phospholipidstoffwechsel. Purine und Pyrimidine werden im menschlichen Stoffwechsel auf 2 Wegen für die Nukleotidsynthese bereitgestellt. Ein Weg führt über die De-novo-Synthese, die mit Ribosephosphat, Aminosäuren, C02 und Ammoniumionen beginnt, und der andere über den Salvage-Stoffwechsel, der freie Stickstoffbasen und Nukleoside zu den entsprechenden Nukleotiden zusammenführt. Durch Interkonversion können Nukleotide ineinander überführt werden. Die De-novo-Synthese, die Interkonversion und der Salvage-Stoffwechsel werden balanciert und sind durch Enzyme, die überschüssige Nukleotide zu β-Aminosäuren, C02 und Harnsäure degradieren, miteinander verbunden. In diesem Kapitel sollen hereditäre Defekte der De-novo-Synthese, des Salvage-Stoffwechsels, der Interkonversion und des Katabolismus von Purinen und Pyrimidinen vorgestellt, die molekularen Grundlagen der klinischen Erscheinungen her geleitet und therapeutische Ansätze aufgezeigt werden. Aufgrund der biochemischen Besonderheiten der Stoffwechselwege sollen die hereditären Purinund Pyrimidinstoffwechselstörungen getrennt voneinander behandelt werden.
  • Article
    Normal and leukemic leukocytes catabolize thymine to dihydrothymine in the presence of TPNH. There is presumptive evidence that dihydrothymine may be furthe converted to β-ureido-isobutyric acid by normal leukocytes and, to a lesser extent, by leukemic leukocytes. There was no evidence in these studies of β-aminoisobutyric acid formation by either type of cell.
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    5-Fluorouracil, first introduced as a rationally synthesized anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metabolic pathways as uracil. Although several potential sites of antitumour activity have been identified, the precise mechanism of action and the extent to which each of these sites contributes to tumour or host cell toxicity remains unclear. Several assay methods are available to quantify 5-fluorouracil in serum, plasma and other biological fluids. Unfortunately, there is no evidence that plasma drug concentrations can predict antitumour effect or host cell toxicity. The recent development of clinically useful pharmacodynamic assays provides an attractive alternative to plasma drug concentrations, since these assays allow the detection of active metabolites of 5-fluorouracil in biopsied tumour or normal tissue. 5-Fluorouracil is poorly absorbed after oral administration, with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). Recently, studies have demonstrated the pharmacokinetic rationale and clinical feasibility of hepatic arterial infusion and intraperitoneal administration of 5-fluorouracil. In addition, 5-fluorouracil continues to be used in topical preparations for the treatment of malignant skin cancers. Following parenteral administration of 5-fluorouracil, there is rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes. The rapid elimination is primarily due to swift catabolism of the liver. As with all drugs, caution should be used in administering 5-fluorouracil in various pathophysiological states. In general, however, there are no set recommendations for dose adjustment in the presence of renal or hepatic dysfunction. Drug interactions continue to be described with other antineoplastic drugs, as well as with other classes of agents.
  • Article
    Phase I observations of combined therapy with thymidine (TdR) and 5-fluorouracil (FU) have demonstrated that when TdR is administered by rapid infusion at a dose of 7.5 or 15g and FU is given by bolus injection 60 minutes after the start of the TdR dose, the biologic activity of FU is increased five- to eight-fold. The observed toxicity is primarily hematopoietic: 15g TdR and 7.5 or 10mg/kg FU produced median white blood count nadirs of 2,600 on day 16 and platelet count nadirs of 150,000 on day 14. The combined therapy produced two partial remissions in 18 patients with colon cancer, 17 of which had experienced progression of disease on FU containing regimens. Partial remissions were also obtained in two heavily pretreated patients with ovarian cancer and diffuse, poorly differentiated lymphocytic lymphoma. Plasma analyses for TdR and FU and their metabolic products by high pressure liquid chromatography have demonstrated a marked elevation and prolongation of FU levels. The β phase T1/2 for 7.5mg/kg FU were: FU alone 6 minutes, 7.5g TdR + FU 135 minutes, 15g TdR + FU 188 minutes, and TdR 45g + FU 190 minutes. The addition of TdR all but eliminated oxidative metabolism of FU; renal clearance became the primary detoxification route. Thymidine levels exceeded 10−3M; the β phase T1/2 of TdR varied with the administered dose: 3g TdR, 7 minutes; 7.5g TdR, 24 minutes; 15g TdR, 52 minutes; and 45g TdR, 98 minutes.
  • Article
    This report describes the severe adverse effects produced in a female patient after treatment with a limited dosage of fluorouracil given on a weekly schedule. Subsequent studies identified a disorder of pyrimidine metabolism, manifested by pyrimidinemia or pyrimidinuria in the propositus and her brother. A genetic defect of pyrimidine-base degradation has been proposed as the cause of the severe fluorouracil toxicity manifested in this patient. Such a defect may not be clinically apparent unless the affected patient is treated with a pyrimidine-base analogue.
  • Article
    Full-text available
    Severe neurotoxicity due to 5-fluorouracil (FUra) has previously been described in a patient with familial pyrimidinemia. We now report the biochemical basis for both the pyrimidinemia and neurotoxicity in a patient we have recently studied. After administration of a "test" dose of FUra (25 mg/m2, 600 microCi[6-3H]FUra by intravenous bolus) to a patient who had previously developed neurotoxicity after FUra, a markedly prolonged elimination half-life (159 min) was observed with no evidence of FUra catabolites in plasma or cerebrospinal fluid and with 89.7% of the administered dose being excreted into the urine as unchanged FUra. Using a sensitive assay for dihydropyrimidine dehydrogenase in peripheral blood mononuclear cells, we demonstrated complete deficiency of enzyme activity in the patient and partial deficiency of enzyme activity in her father and children consistent with an autosomal recessive pattern of inheritance. Patients who are deficient in this enzyme are likely to develop severe toxicity after FUra administration.
  • Article
    Phase I observations of combined therapy with thymidine (TdR) and 5-fluorouracil (FU) have demonstrated that when TdR is administered by rapid infusion at a dose of 7.5 or 15g and FU is given by bolus injection 60 minutes after the start of the TdR dose, the biologic activity of Fu is increased five- to eight-fold. The observed toxicity is primarily hematopoietic: 15g TdR and 7.5 or 10mg/kg FU produced median white blood count nadirs of 2,600 on day 16 and platelet count nadirs of 150,000 on day 14. The combined therapy produced two partial remissions in 18 patients with colon cancer, 17 of which had experienced progression of disease on FU containing regimens. Partial remissions were also obtained in two heavily pretreated patients with ovarian cancer and diffuse, poorly differentiated lymphocytic lymphoma. Plasma analyses for TdR and FU and their metabolic products by high pressure liquid chromatography have demonstrated a marked elevation and prolongation of FU levels. The beta phase T 1/2 for 7.5mg/kg FU were: FU alone 6 minutes, 7.5g TdR + FU 135 minutes, 15g TdR + FU 188 minutes, and TdR 45g + FU 190 minutes. The addition of TdR all but eliminated oxidative metabolism of FU; renal clearance became the primary detoxification route. Thymidine levels exceeded 10(-3)M; the beta phase T 1/2 of TdR varied with the administered dose: 3gTdR, 7 minutes; 7.5g TdR, 24 minutes; 15g TdR, 52 minutes; and 45g TdR, 98 minutes.