A narrative review of genetic factors affecting fluoropyrimidine toxicity

Gmeiner, William H.

doi:10.21037/pcm-21-17

Cited by 15 publications

(17 citation statements)

References 76 publications

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“…Of the remaining percentage, about 10% is excreted by the kidneys, and 80% of the administered drug is converted to an inactive metabolite (5,6-dihydro-5-fluorouracil, FUH2) by DPD [ 7 ]. Approximately 20–30% of cancer patients treated with fluoropyrimidines develop severe and potentially life-threatening toxicity early on during treatment [ 8 ]. According to the FDA, the toxicity caused by these drugs is distinguished by the development of mucositis, stomatitis or esophagopharyngitis, diarrhea (grade 3 or 4), palmar-plantar erythrodysesthesia (hand-foot syndrome), myelosuppression, hyperammonemic encephalopathy, and systemic toxicity.…”

Section: Introductionmentioning

confidence: 99%

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations

Farinango

Gallardo-Cóndor

Freire‐Paspuel

et al. 2022

JPM

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Dihydropyrimidine dehydrogenase is one of the main pharmacological metabolizers of fluoropyrimidines, a group of drugs widely used in clinical oncology. Around 20 to 30% of patients treated with fluoropyrimidines experience severe toxicity caused by a partial or total decrease in enzymatic activity. This decrease is due to molecular variants in the DPYD gene. Their prevalence and allelic frequencies vary considerably worldwide, so their description in heterogeneous groups such as the Ecuadorian population will allow for the description of pharmacogenetic variants and proper characterization of this population. Thus, we genotyped all the molecular variants with a predictive value for DPYD in a total of 410 Ecuadorian individuals belonging to Mestizo, Afro-Ecuadorian, and Indigenous ethnic groups. Moreover, we developed a genetic ancestry analysis using 46 autosomal ancestry informative markers. We determined 20 genetic variations in 5 amplified regions, including 3 novel single nucleotide variants. The allele frequencies for DPYD variants c.1627G>A (*5, rs1801159), c.1129-15T>C (rs56293913), c.1218G>A (rs61622928), rs1337752, rs141050810, rs2786783, rs2811178, and g.97450142G>A (chr1, GRCh38.p13) are significantly related to Native American and African ancestry proportions. In addition, the FST calculated from these variants demonstrates the closeness between Indigenous and Mestizo populations, and evidences genetic divergence between Afro-Ecuadorian groups when compared with Mestizo and Indigenous ethnic groups. In conclusion, the genetic variability in the DPYD gene is related to the genetic component of ancestral populations in different Ecuadorian ethnic groups. The absence and low frequency of variants with predictive value for fluoropyrimidine toxicity such as DPYD *2A, HapB3, and c.2846A>T (prevalent in populations with European ancestry) is consistent with the genetic background found.

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Section: Introductionmentioning

confidence: 99%

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations

Farinango

Gallardo-Cóndor

Freire‐Paspuel

et al. 2022

JPM

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“…We detected a frequency of 0.06% of patients carrying multiple DPYD variants, which is lower in comparison of what it is described in the literature from data provided from publicly available databases (approximately 0.2%), but not from well-performed studies. 7 , 12 Therefore, to our knowledge, this is the first study to analyze the frequency of patients carrying multiple DPYD variants. Patients carrying multiple DPYD variants could be at higher risk of developing severe toxicity; however, standard dose reductions from DPWG and CPIC guidelines cannot be accurately applied, as the phasing of them is generally unknown.…”

Section: Discussionmentioning

confidence: 99%

Allelic Frequency of DPYD Genetic Variants in Patients With Cancer in Spain: The PhotoDPYD Study

et al. 2023

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Introduction Identifying polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene is gaining importance to be able to predict fluoropyrimidine-associated toxicity. The aim of this project was to describe the frequency of the DPYD variants DPYD*2A (rs3918290); c.1679T>G (rs55886062); c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in the Spanish oncological patients. Material and methods Cross-sectional and multicentric study (PhotoDPYD study) conducted in hospitals located in Spain designed to register the frequency of the most relevant DPYD genetic variants in oncological patients. All oncological patients with DPYD genotype were recruited in the participant hospitals. The measures determined where the presence or not of the 4 DPYD previously described variants. Results Blood samples from 8054 patients with cancer from 40 different hospitals were used to determine the prevalence of the 4 variants located in the DPYD gene. The frequency of carriers of one defective DPYD variant was 4.9%. The most frequently identified variant was c.1129-5923C>G (rs75017182) (HapB3), in 2.9%, followed by c.2846A>T (rs67376798) in 1.4%, c.1905 + 1G>A (rs3918290, DPYD*2A) in 0.7% and c.1679T>G (rs55886062) in 0.2% of the patients. Only 7 patients (0.08%) were carrying the c.1129-5923C>G (rs75017182) (HapB3) variant, 3 (0.04%) the c.1905 + 1G>A (rs3918290, DPYD*2A) and one (0.01%) the DPYD c.2846A>T (rs67376798, p.D949V) variant in homozygosis. Moreover, 0.07% were compound heterozygous patients, 3 carrying the DPYD variants DPYD*2A + c.2846A>T, 2 the DPYD c.1129-5923C>G + c.2846A>T and one the DPYD*2A + c.1129-5923C>G variants. Conclusions Our results demonstrate the relatively high frequency of DPYD genetic variants in the Spanish patient with cancer population, which highlights the relevance of their determination before initiating a fluoropirimidine-containing regimen.

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“…However, the drug has a great toxic effect on bone marrow and digestive tract, so it is important to improve the therapeutic effect of the drug and reduce the toxic side effects. William (2021) ( 19 ) found that 5-FU was beneficial to improve the survival rate of colorectal cancer patients, but severe systemic toxicity (including neutropenia) occurred in 30% of patients, and 0.5-1% of patients were fatal.…”

Section: Discussionmentioning

confidence: 99%

Effects of Biofilm Nano-Composite Drugs OMVs-MSN-5-FU on Cervical Lymph Node Metastases From Oral Squamous Cell Carcinoma

Huang

2022

Front. Oncol.

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This work was developed to the effects of biofilm composite nano-drug delivery system (OMVs-MSN-5-FU) on lymph node metastasis from oral squamous cell carcinoma. Mesoporous silica nanoparticles loaded with 5-FU (MSN-5-FU) were prepared first. Subsequently, the outer membrane vesicles (OMV) of Escherichia coli were collected to wrap MSN-5-FU, and then OMVs-MSN-5-FU was prepared. It was then immersed in artificial gastric juice and artificial intestinal juice to explore the drug release rate. Next, the effects of different concentrations of the nano-drug delivery systems on the proliferation activity of oral squamous carcinoma cell line KOSC-2 cl3-43 were analyzed. Tumor-bearing nude mice models were prepared by injecting human tongue squamous cell carcinoma cells Tca8113 into BALB/c-nu nude mice. They were injected with the OMVs-MSN-5-FU nano drug carrier system, and peri-carcinoma tissue and cervical lymph node tissue were harvested to observe morphological changes by Hematoxylin – eosin (HE) staining. The scanning electron microscope (SEM) results showed that all MSN, MSN-5-FU, OMV, and OMV-MSN-5-FU were spherical and uniformly distributed, with particle sizes of about 60nm, 80nm, 90nm, and 140nm, respectively. Among them, OMV had a directional core-shell structure. The cumulative drug release rates of artificial gastric juice in 48 hours were 61.2 ± 2.3% and 26.5 ± 3.1%, respectively. The 48 hours cumulative drug release rates of artificial intestinal juice were 70.5 ± 6.3% and 32.1 ± 3.8%, respectively. The cumulative release of MSN-5-FU was always higher than OMV-MSN-5-FU. The cumulative release of MSN-5-FU was always higher than OMV-MSN-5-FU. After injection of OMVS-MSN-5-FU, the number of cancer cells was significantly reduced and cervical lymph node metastasis was significantly controlled. HE staining results showed that OMVS-MSN-5-FU injection reduced the number of stained cells. Dense lymphocytes were clearly observed in the cortex of neck lymphocytes. The OMVs-MSN-5-FU drug delivery system can slow down the drug release rate, significantly inhibit the proliferation activity of oral squamous cancer cells, and control the metastasis of cancer cells to cervical lymph nodes.

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A narrative review of genetic factors affecting fluoropyrimidine toxicity

Cited by 15 publications

References 76 publications

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations

Allelic Frequency of DPYD Genetic Variants in Patients With Cancer in Spain: The PhotoDPYD Study

Effects of Biofilm Nano-Composite Drugs OMVs-MSN-5-FU on Cervical Lymph Node Metastases From Oral Squamous Cell Carcinoma

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