5-Fluorouracil-related severe toxicity: A comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency

Boisdron‐Celle, Michèle; Remaud, Gaëlle; Traore, Sory Ibrahima; Poirier, A; Gamelin, Laurence; Morel, Alain; Gamelin, Érick

doi:10.1016/j.canlet.2006.09.006

Cited by 193 publications

(182 citation statements)

References 26 publications

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“…Recently, the common fragile site FRA1E was localized in DPYD gene, however the large deletions in DPYD were not studied so far [43]. Combinatory approaches implementing functional and expression analyses alongside to genotyping introduced by Morel et al (2006) could enhance specificity and sensitivity of 5-FU toxicity detection, however it seems to be less suitable for routine clinical settings [44]. Therefore, despite substantial effort, there is currently unavailable a simple and reliable test predicting serious toxicity following 5-FU treatment [45,46].…”

Section: Discussionmentioning

confidence: 99%

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Kleibl

Fidlerová²,

Kleiblová³

et al. 2009

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Alterations in dihydropyrimidine dehydrogenase gene (DPYD) coding for the key enzyme (DPD) of fluoropyrimidines (FPs) catabolism contribute to the development of serious FPs-related toxicity. We performed mutation analysis of DPYD based on cDNA sequencing in 76 predominantly colorectal cancer patients treated by FPs with early development of high (grade 3-4) hematological and/or gastrointestinal toxicity. Six previously described [85T>C (C29R), 496A>G (M166V), 775A>G (K259E), 1601G>A (S534N), 1627A>G (I543V), IVS14+1G>A, 2194G>A (V732I)] and two novel [187A>G (K63E) and 1050 G>A (R357H)] non-synonymous DPYD variants were found in 56/76 (73.7%) high-toxicity patients. Subsequently, these alterations were analyzed in 48 patients with excellent long-term tolerance of FPs and in 243 controls and were detected in 37/48 (77.1%) and 166/243 (68.3%) cases, respectively. Analysis of these alterations as risk factors for development of toxicity in pooled FPs-treated population demonstrated that C29R negatively correlated with overall gastrointestinal toxicity (OR = 0.48; 95%CI 0.23-1.0) and M166V in women protected against overall hematological toxicity and neutropenia (both OR = 0.26; 95%CI 0.07-0.89), whereas IVS14+1G>A (found in five high-toxicity patients only) increased risk of mucositis in overall population (OR = 7.0; 95%CI 1.1-44.53), and thrombocytopenia in women (OR = 10.8; 95%CI 1.24-93.98). Moreover, we identified a strong association of V732I with leucopenia (OR = 8.17; 95%CI 2.44 -27.31) and neutropenia (OR=2.78; 95% CI 1.03-7.51). Our data enabled characterization of "high risk" haplotypes (carriers of IVS14+1G>A or V732 lacking M166V) representing small (22% female and 11% male patients), population in high risk of serious hematological toxicity development, and in patients with "lower risk" that unlikely develop serious hematological toxicity [carriers of M166V without IVS14+1G>A and V732I in females (32% women), and non-carriers of C29R, M166V, IVS14+1G>A, and V732I in males (46% men)]. Our results indicate that genotyping of several DPYD variants may lead to stratification of patients with respect to the risk of serious hematological toxicity development during FPs treatment. Key words: dihydropyrimidine dehydrogenase gene [DPYD], fluoropyrimidines, 5-fluorouracil toxicity, mutation analysis, haplotypes, association study* Corresponding author † These authors contributed equally to this work.Fluoropyrimidines -5-fluorouracil (5-FU) and its derivates (e.g. capecitabine) -belong to the most frequently used anticancer drugs in treatment of solid cancers. Mechanism of action of 5-FU involves its anabolic conversions to 5-fluoropyrimidine nucleotides that exert profound inhibitory effect on thymidylate synthetase activity and interfere with RNA and DNA metabolism [1]. The development of severe toxicity is the critical complication of 5-FU-based therapy. It occurs in nearly one third of cases with progression to life-threatening complications in approximately 0.5% patients [2].About 80% of 5-FU is quickly ina...

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Section: Discussionmentioning

confidence: 99%

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Kleibl

Fidlerová²,

Kleiblová³

et al. 2009

neo

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“…The presence of DPD deficiency results in a reduced ability to metabolize and clear 5-FU, and the half-life of the drug, which is normally in the range of 10–15 minutes, can be markedly prolonged [63–71]. A pharmacogenetic autosomal recessive syndrome has been identified in which partial and/or compete deficiency in the DPD enzyme has been observed in 3–5% and 0.1% of the general population, respectively [67, 68, 72–75]. In this setting, patients experience excessive, severe toxicity in the form of myelosuppression, diarrhea and mucositis, and neurotoxicity.…”

Section: Dihydropyrimidine Dehydrogenase (Dpd)mentioning

confidence: 99%

“…These findings suggest that there must be factors other than DPD status that contribute to 5-FU metabolism and eventual 5-FU toxicity. It has been suggested that fewer than 50% of individuals who experience grade 3–4 toxicity have mutations in the DPD gene and/or have diminished DPD activity that would identify individuals with low 5-FU clearance [68, 72, 74]. It is now known that 5-FU clearance is a function of several factors in addition to DPD.…”

Section: Dihydropyrimidine Dehydrogenase (Dpd)mentioning

confidence: 99%

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

179

147

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Purpose For over 50 years, 5-FU has played a critical role in the systemic chemotherapy of cancer patients. 5-FU serves as the main backbone of combination chemotherapy for patients with colorectal cancer (CRC) in both the adjuvant and metastatic disease settings. Herein, we review the current status of 5-FU therapeutic drug monitoring (TDM) and discuss its potential role in the clinical practice setting. Method PubMed and abstracts from the American Society of Clinical Oncology (ASCO) were searched up through September 2015 for clinical data relating to 5-FU TDM. Results 5-FU dosing has been typically determined by using body surface area (BSA). However, it is now well-established that BSA-based 5-FU dosing is correlated with a wide variation of 5-FU systemic exposure. Pharmacokinetic (PK) studies of 5-FU systemic exposure have shown a wide range of interpatient variation of 5-FU plasma drug levels. Over the past 30 years, increasing efforts have been placed on optimizing 5-FU dosing with the main goals of increasing antitumor efficacy while reducing drug-associated toxicity. There is growing evidence to show that 5-FU dosing based on plasma 5-FU drug level is feasible and that 5-FU TDM can improve clinical outcomes by improving efficacy of 5-FU-based combination regimens and reducing toxicities. Conclusion Dose adjustment of 5-FU is feasible and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy.

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“…Results showed that, the inhibition rate of SGC-7901 tumor in high-dose DDPA group was basically equivalent to that in 5-Fu group. Generally, the drug over a certain concentration will produce toxic side effects to the body, which are mainly manifested in the blood system and liver and kidney function (Boisdron-Celle et al, 2007). In this study, compared with model group, the spleen and thymus indexes of nude mice in 5-Fu group were significantly decreased (P < 0.05).…”

Section: Discussionmentioning

confidence: 63%

Inhibitory effect of Dendrobium officinale polysaccharide on human gastric cancer cell xenografts in nude mice

2017

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5-Fluorouracil-related severe toxicity: A comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency

Cited by 193 publications

References 26 publications

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Therapeutic drug monitoring of 5-fluorouracil

Inhibitory effect of Dendrobium officinale polysaccharide on human gastric cancer cell xenografts in nude mice

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