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The article discusses lethal capecitabine toxicity in patients with complete dihydropyrimidine dehydrogenase deficiency due to ultra-rare DPYD variants. It emphasizes the importance of preemptive genetic analysis of DPYD to reduce fluoropyrimidine-related adverse events and highlights the need for comprehensive genotyping and phenotyping strategies for identifying patients at risk of severe toxicity. The study presents two cases of patients with complete DPYD deficiency due to ultra-rare DPYD variants and lethal capecitabine toxicity, underscoring the challenges in predicting severe toxicity in patients with rare DPYD variants. The research advocates for a combined genotyping/phenotyping approach to enhance the safety of fluoropyrimidine-based therapy, even in patients with complete DPYD deficiency. [Extracted from the article]

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene ( DPYD ) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense mutations, 2 splice-site mutations, 1 intronic mutation, a deletion of 21 nucleotides and a genomic amplification of exons 9–12. Two novel/rare variants (c.2843T > C, c.321 + 1G > A) were present in multiple, unrelated patients. Functional analysis of recombinantly-expressed DPD mutants carrying the p.I948T and p.G284V mutation showed residual DPD activities of 30% and 0.5%, respectively. Analysis of a DPD homology model indicated that the p.I948T and p.G284V mutations may affect electron transfer and the binding of FAD, respectively. cDNA analysis showed that the c.321 + 1G > A mutation in DPYD leads to skipping of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD pre-mRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates a more comprehensive genotyping approach combined with phenotyping strategies for upfront screening for DPD deficiency to ensure the safe administration of fluoropyrimidines. [ABSTRACT FROM AUTHOR]

Abstract: Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in the metabolism of 5FU. The prognostic significance of DPD activity in peripheral blood mononuclear (PBM) cells and buccal mucosa cells with respect to toxicity was investigated in 44 patients treated with 5FU-leucovorin. Grade III/IV haematological and grade III/IV gastrointestinal toxicity were observed in 25% and 21% of the patients, respectively. No association was observed between the DPD activity in buccal mucosa cells and toxicity. In contrast, the mean DPD activity in PBM cells proved to be increased in patients experiencing grade I/II neutropenia when compared to patients without neutropenia and those suffering from grade III/IV neutropenia (P =0.002). Patients with a high-normal DPD activity proved to be at risk of developing mild toxicity upon treatment with 5FU-leucovorin, suggesting an important role of DPD in the aetiology of toxicity associated with catabolites of 5FU. [Copyright &y& Elsevier]

The identification of genetic factors associated with either responsiveness or resistance to 5-fluorouracil (5-FU) chemotherapy, as well as genetic factors predisposing patients to the development of severe 5-FU-associated toxicity, is increasingly being recognised as an important field of study. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Although the role of tumoral levels as a prognostic factor for clinical responsiviness has not been firmly established, there is ample evidence that a deficiency of DPD is associated with severe toxicity after the administration of 5-FU. Patients with a partial DPD deficiency have an increased risk of developing grade IV neutropenia. In addition, the onset of toxicity occurred twice as fast compared with patients with a normal DPD activity. To date, 39 different mutations and polymorphisms have been identified in DPYD. The IVS14+1G>A mutation proved to be the most common one and was detected in 24–28% of all patients suffering from severe 5-FU toxicity. Thus, a deficiency of DPD appears to be an important pharmacogenetic syndrome. [Copyright &y& Elsevier]

The treatment of cancer patients with 5-fluorouracil (5FU)-based chemotherapy can be accompanied by severe and sometimes lethal toxicity. Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in the metabolism of 5FU and as such, a deficiency of DPD has been recognized as an important risk factor, predisposing patients to the development of severe 5FU-associated toxicity. To date, screening of patients for the presence of a DPD deficiency prior to the treatment is not yet routinely performed. Taking into account the relatively small impact of adjuvant 5FU-based chemotherapy on survival, patients should be informed about the risks of the therapy and should be offered the possibility of testing for the presence of a DPD deficiency in advance of receiving such treatment. [ABSTRACT FROM AUTHOR]

A rapid yet reliable chemical diagnosis for dihydropyrimidine dehydrogenase (DHPD) deficiency, and possibly dihydropyrimidinase (DHP) deficiency in cancer patients, prior to therapy with pyrimidine analogues such as 5-fluorouracil, is desired for prevention of severe side-effects by these drugs. We have reported the basic separation and quantitation technology for pyrimidine metabolites using gas chromatography–mass spectrometry. A proposal to use the number (n) of standard deviations (SD) above the normal mean, as the index of the excessive urinary excretion of the metabolites appears not to be commonly used. When used, the values were too small, such as two or three, even in genetic disorders. Here, we applied the method to 11 urine specimens from proven cases including two DHP carriers and proved how specific the method is, because “n”-values were markedly large for thymine (T), uracil (U) and/or dihydrothymine (DHT) and dihydrouracil (DHU). In three cases with DHPD deficiency, two were siblings, one with symptoms and the other without, n was 12 for T and 5.9 for U, and 5-hydroxymethyluracil was distinctly detected. These values indicate that the nature of genetic mutation relates closely to the degree of metabolite accumulation in pyrimidine disorders. In six patients with DHP deficiency, n was 8.4–12 for DHT and 7.2–11 for DHU. Many mutations are known for both genes and the assay of residual enzyme activity may be time-consuming or invasive especially for those with DHP deficiency. Thus, this noninvasive yet comprehensive urinalysis has great value for those without a family history, as the first trial, before DNA or the enzyme assay. Our findings again raise the question whether the metabolic block really causes the symptoms found in pyrimidine disorders. [Copyright &y& Elsevier]