Evaluation of adverse effects of chemotherapy regimens of 5-fluoropyrimidines derivatives and their association with DPYD polymorphisms in colorectal cancer patients

Negarandeh, Reza; Salehifar, Ebrahim; Saghafi, Fatemeh; Jalali, Hossein; Janbabaei, Ghasem; Abdhaghighi, Mohammad Javad; Nosrati, Anahita

doi:10.1186/s12885-020-06904-3

Cited by 31 publications

(15 citation statements)

References 21 publications

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“…The importance of this is illustrated by Negarandeh et al who conducted a prospective observational study of 73 Iranian colorectal cancer patients undergoing FP chemotherapies. 38 They found 4/73 (5.5%) patients were heterozygous for c.1905+1G>A, tested via RFLP PCR. Both c.2846A>T and c.2194G>A were also investigated, and both were absent in the study population.…”

Section: Genotype/phenotype Correlation Of Dpyd Variantsmentioning

confidence: 99%

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

White¹,

Scott²,

Paul³

et al. 2021

PGPM

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Pharmacogenomic screening can identify patients with gene variants that predispose them to the development of severe toxicity from fluoropyrimidine (FP) chemotherapy. Deficiency of the critical metabolic enzyme dihydropyrimidine dehydrogenase (DPD) leads to excessive toxicity on exposure to fluoropyrimidine chemotherapy. This can result in hospitalisation, intensive care admissions and even death. Upfront screening of the gene that encodes for DPD ( DPYD ) has recently been implemented in regions throughout Europe and the United Kingdom. Current screening evaluates DPYD variants that are well described within Caucasian patient populations and provides genotyped-guided dose adjustment recommendations based upon the presence of these variants. This article reviews the differences in DPYD gene variants within non-Caucasian populations compared to Caucasian populations, with regard to the implications for clinical tolerance of fluoropyrimidine chemotherapies and genotype guided dose adjustment guidelines.

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Section: Genotype/phenotype Correlation Of Dpyd Variantsmentioning

confidence: 99%

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

White¹,

Scott²,

Paul³

et al. 2021

PGPM

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“…Of the potential 112 articles assessed for eligibility, after considering the inclusion and exclusion criteria, 22 studies were included in the analysis [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Table 3 shows such studies subdivided with respect to the analysed DPYD polymorphisms ( DPYD -PGx), the used phenotyping methods and the presence of clinical monitoring.…”

Section: Resultsmentioning

confidence: 99%

“…However, a high allelic frequency for DPYD*2A (5.5%) was reported. Surprisingly, Negarandeh et al did not find any significant association between DPYD*2A and severe toxicity [40].…”

Section: Systematic Reviewmentioning

confidence: 90%

“…Moreover, as shown in Table 3, three studies have performed a combined DPYD-PGx/phenotyping [27,37,41] approach, and eleven carried out the DPYD-PGx together with clinical monitoring. However, among these, only 2/11 genotyped all the four DPYD SNPs recommended in the CPIC and DPWG guidelines [29,39]; the other studies performed at least one of such SNPs, together with other DPYD genetic variants [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

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A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

Conti

Bellis

Manzo

et al. 2020

JPM

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Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.

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“…The only source of thymine in cells is the de novo synthesis pathway, and the high expression of thymidylate synthetase (TYMS) is often associated with poor prognosis of tumors(Donner et al, 2019). 5-FU blocks DNA synthesis to induce cell death by inhibiting TYMS, while dihydropyrimidine dehydrogenase (DPYD) could decompose and deactivate 5-FU before it was converted into active metabolites(Negarandeh et al, 2020). Compared with the 2D cultures, the transcription level of TYMS were 2.15 and 3.48 times higher up-regulated, meanwhile the transcript level of DPYD were 3.66 and 1.26 times higher up-regulated in 3D MTSs before and after the 5-FU treatment conditions, respectively (Figure.…”

mentioning

confidence: 99%

Multi-Omics Analysis Defines 5-Fluorouracil Drug Resistance in 3D Hela Carcinoma Cell Model

Wang

et al. 2021

Preprint

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Cervical cancer is a serious health problem in women around the globe, with 600 thousand new cases each year. However, the use of clinical drug is seriously dampened by the development of drug resistance, which has been evidenced to be associated with metabolic reprogramming and heterogeneity in tumor cells. Efficient in vitro tumor model is essential to improve the efficiency of drug screening and the accuracy of clinical application. Multicellular tumor spheroids (MTSs) can in a way recapitulates tumor traits in vivo, thereby representing a powerful transitional model between 2D monolayer culture and xenograft. In this study, based on the liquid overlay method, a protocol for rapid generation of the MTSs with uniform size and high reproducibility in a high-throughput manner was established. As expected, the cytotoxicity results showed that there was enhanced 5-FU resistance of HeLa carcinoma cells in 3D MTSs than 2D monolayer culture with a resistance index of 5.72. In the presence of both glucose and glutamine, HeLa carcinoma cells preferentially used glutamine as the bioenergetic substrate to support cell proliferation and maintenance under all conditions, while the ubiquitous by-product ammonium might be only recycled in the 3D MTSs. Furthermore, in order to obtain a holistic view of the molecular mechanisms that drive 5-FU resistance in 3D HeLa carcinoma cells, a multi-omics study was applied to discover hidden biological regularities. It was observed that in the 3D MTSs mitochondrial function-related proteins and the metabolites of the tricarboxylic acid cycle (TCA cycle) were significantly decreased, and the cellular metabolism was shifted towards glycolysis. The differences in the protein synthesis, processing, and transportation between 2D monolayer cultures and 3D MTSs was significant, mainly in the heat shock protein family, with the upregulation of protein folding function in endoplasmic reticulum (ER), which promoted the maintenance of ER homeostasis in the 3D MTSs. In addition, at the transcript and protein level, the expression of extracellular matrix (ECM) proteins (e.g., laminin and collagen) were up-regulated in the 3D MTSs, which enhanced the physical barrier of drug penetration. Summarizing, this study formulates a rapid, scalable and reproducible in vitro model of 3D MTS for drug screening purposes, and the findings establish a critical role of glycolytic metabolism, ER hemostasis and ECM proteins expression profiling in tumor chemoresistance of HeLa carcinoma cells towards 5-FU.

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Evaluation of adverse effects of chemotherapy regimens of 5-fluoropyrimidines derivatives and their association with DPYD polymorphisms in colorectal cancer patients

Cited by 31 publications

References 21 publications

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

Multi-Omics Analysis Defines 5-Fluorouracil Drug Resistance in 3D Hela Carcinoma Cell Model

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