Lethal Toxicity After 5-Fluorouracil Chemotherapy and Its Possible Relationship to Dihydropyrimidine Dehydrogenase Deficiency: A Case Report and Review

Díaz, Roberto; Segura, Ángel; Aparicio, Jorge; Calderero, V.; Guerrero, Angélica I. Hernández; Pellín, Lorena

doi:10.1179/joc.2004.16.6.599

Cited by 7 publications

(2 citation statements)

References 16 publications

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“…5-Fluorouracil is a pyrimidine analog that inhibits nucleoside metabolism. However, the response threatening toxic reaction when treated with 5-fluorouracil because it doesn't break down efficiently and build up toxic molecules (fluoropyrimidine) which lead to severe inflammation, hemorrhage, neutropenia, and hand-foot syndrome (Diaz et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Study of the Dihydropyridine Dehydrogenase Gene in Jordanian Patients with Colorectal Cancer

Almashagbah

Mahasneh

Bodoor

2022

Asian Pac J Cancer Prev

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Introduction: Several studies have shown an association between 5-fluorouracil toxicity and variations in the dihydropyrimidine dehydrogenase (DPYD) gene. Objectives: This cross-sectional study aims to elucidate the association between genetic variations in the DPYD gene and 5-fluorouracil toxicity among Jordanians with colorectal cancer (CRC). Methods: 80 CRC Patients were recruited to screen for mutations in the DPYD gene using the Sanger sequencing technique. Sequencing results were analyzed using Mutation Surveyor software, and mutational effects were predicted by the Mutation Tester bioinformatics tool. Results: Three reported variants (c.85T>C, c.1740+40A>G, c.1740+39C>T) and one novel (g.97515583_97515584insA) variant were identified in this study. Results showed a significant association between these variants and toxicity to 5-Fluorouracil with P-values 0.002, 0.005, 0.019, 0.017, respectively. However, there was no significant association between variants and cancer free survival. Conclusion:The present study identified several variants in the DPYD gene among Jordanians with colorectal cancer, which are associated with toxicity to 5-Fluorouracil treatment.

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Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Study of the Dihydropyridine Dehydrogenase Gene in Jordanian Patients with Colorectal Cancer

Almashagbah

Mahasneh

Bodoor

2022

Asian Pac J Cancer Prev

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“…The importance of this enzyme in 5-FU metabolism is underlined by the fact that individuals with inherited DPD deficiency develop severe side effects following 5-FU therapy (3,4). The activity of DPD is highly variable in various normal and tumor tissues, and the highest activity of DPD was observed in the liver (5).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors

Krugluger

Brandstaetter²,

Kállay³

et al. 2007

Cancer Research

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Expression of dihydropyrimidine dehydrogenase (DPD) displays a regular daily oscillation in nonmalignant cells. In colorectal cancer cells, the expression of this 5-fluorouracilmetabolizing enzyme is decreased, but the reason remains unclear. In this study, we analyzed by real-time reverse transcription-PCR (RT-PCR) the expression of DPD and of members of the cellular oscillation machinery, period 1 (Per1), period 2 (Per2), and CLOCK, in primary colorectal tumors and normal colon mucosa derived from the same patients. Analysis of tumors according to differentiation grade revealed a 0.46-fold (P = 0.005) decrease for DPD mRNA and a 0.49-fold (P = 0.004) decrease for Per1 mRNA in undifferentiated (G3) tumors compared with paired normal mucosa. In this tumor cohort, the correlation between DPD and Per1 levels was r = 0.64, P < 0.01. In moderately differentiated (G2) colon carcinomas, reduction of DPD and Per1 mRNA levels did not reach significance, but a significant correlation between the respective mRNA levels was detectable (r = 0.54; P < 0.05). The decrease and correlation of DPD and Per1 mRNA levels were even more pronounced in female (G3) patients (DPD: female, 0.35-fold, P < 0.001 versus male, 0.58-fold, P < 0.05; and Per1: female, 0.47-fold, P < 0.01 versus male, 0.52-fold, P < 0.01). The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. Our results also revealed a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma cells. [Cancer Res 2007;67(16):7917-22]

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Pretherapeutic uracil and dihydrouracil levels of colorectal cancer patients are associated with sex and toxic side effects during adjuvant 5‐fluorouracil–based chemotherapy

Wettergren

Carlsson

Odin

et al. 2011

Cancer

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BACKGROUND:In Nordic countries, the standard treatment of colorectal cancer (CRC) in the adjuvant setting is bolus 5-fluorouracil (5-FU) plus leucovorin alone or in combination with oxaliplatin. 5-FU competes with the natural occurring pyrimidine uracil (Ura) as a substrate for dihydropyrimidine dehydrogenase (DPD; enzyme commission number 1.3.1.2). Low DPD activity is associated with toxicity during treatment. Pretherapeutic detection of DPD deficiency could prevent severe toxicity otherwise limiting drug administration. Assays showing that DPD deficiency impairs breakdown of Ura to dihydrouracil (UH 2 ) seem promising for clinical use. METHODS: Urine was collected from 56 untreated volunteers and 143 patients with CRC before adjuvant treatment. Ura and UH 2 were analyzed using a column-switching high-performance liquid chromatography method that incorporates reversed-phase and cationexchange columns. Ura, UH 2 , and UH 2 /Ura levels were related to toxicity. RESULTS: Ura and UH 2 in patients were not different from controls. UH 2 was significantly higher in women compared with men. The UH 2 /Ura ratio, however, did not differ according to sex. Low UH 2 and UH 2 /Ura levels were associated with diarrhea in men. Women experiencing thrombocytopenia had significantly higher Ura compared with women with no thrombocytopenia. The UH 2 /Ura ratio correlated negatively with total toxicity score in men (r ¼ À0.39, P ¼ .020). CONCLUSION: Pretherapeutic Ura and UH 2 levels per se may be related to risk of side effects during adjuvant 5-FU-based treatment, whereas the UH 2 /Ura ratio may not always reveal such a risk. Sex is a strong risk factor for toxicity, showing the importance of evaluating male and female patients separately.

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Lethal Toxicity After 5-Fluorouracil Chemotherapy and Its Possible Relationship to Dihydropyrimidine Dehydrogenase Deficiency: A Case Report and Review

Cited by 7 publications

References 16 publications

Pharmacogenetic Study of the Dihydropyridine Dehydrogenase Gene in Jordanian Patients with Colorectal Cancer

Pharmacogenetic Study of the Dihydropyridine Dehydrogenase Gene in Jordanian Patients with Colorectal Cancer

Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors

Pretherapeutic uracil and dihydrouracil levels of colorectal cancer patients are associated with sex and toxic side effects during adjuvant 5‐fluorouracil–based chemotherapy

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