Genetics and Adverse Events with Irinotecan Treatment: What do we Know?

Páez, David

doi:10.2217/pgs-2019-0012

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…There are concerns that reduced dose will not be equally effective, and an open question whether patients with UGT1A1 *28/*28 genotype should be treated with other chemotherapeutic regimens which would be more suitable and effective for them (5).…”

Section: Clinical Significance Of Ugt1a1 Gene Polymorphismsmentioning

confidence: 99%

“…The patient safety and clinical outcomes could be substantially improved by upfront UG-T1A1 screening and UGT1A1-guided dose individualization to predict, diminish and even avoid toxicity to improve the therapeutic effect of irinotecan (5).…”

Section: Current Status Of Ugt1a1 Gene Polymorphism Screeningmentioning

confidence: 99%

“…Irinotecan is usually co-administered with infusional 5-fluorouracil/leucovorin (FOLFIRI regimen), with the addition of targeted therapies, as a front line for patients with metastatic colorectal cancer. Irinotecan treatment has an acceptable safety profile in most patients, but up to 35% of patients treated with combination regimens of 5-FU and irinotecan experience clinically relevant treatmentrelated toxicities, mainly diarrhea, stomatitis and myelosuppression (4,5). The number of clinically relevant treatment-related toxicities increases sig-nificantly, up to 35-50%, with the intensification of the treatment using triplet regimen (FOLFOXIRI; 5-FU, oxaliplatin and irinotecan) (6,7).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

UGT1A1 polymorphisms as a pharmacogenetic markers for prediction of irinotecan-induced toxicities in metastatic colorectal cancer

Vuković

Žigman

Vučetić³

et al. 2019

lib oncol

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This paper aimed to review the current status of UGT1A1 polymorphisms as a pharmacogenetic marker for prediction of irinotecan-induced toxicities in metastatic colorectal cancer. Deficiencies in the activity uridine diphosphate glucuronosyltransferases (UGT) are mostly due to gene polymorphisms and can lead to increased exposure to irinotecan and its active metabolite causing severe, sometimes life-threatening treatment-related toxicities. Although data suggest that UGT1A1 polymorphisms, especially homozygous (UGT1A1*28/*28, UGT1A1*6/*6) are related to severe irinotecan toxicity and some guidelines highlighted the importance of upfront UGT1A1 genotyping in order to give safer irinotecan dose, UGT1A1 genotyping is currently not being routinely performed in the daily clinical practice. It is important to note that genetic polymorphisms of UGT1A1 show ethnic differences and it is suggested that Caucasian patients should be upfront screened for UGT1A1*28 and Asian patients for UGT1A1*6 as these polymorphisms are common genetic variation in these populations. Data regarding the association of UGT1A1 polymorphisms and treatment response and survival are conflicting. Nevertheless, it is important to think about other genetic variations in the context of chemotherapy-induced toxicities, especially dihydropyrimidine dehydrogenase deficiency (DYPD). In conclusion, UGT1A1 polymorphisms are pharmacogenetic markers which can be used for stratification of patients who are at higher risk of irinotecan-induced toxicities to allow preventive dose reduction to reduce potential toxicities.

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Section: Clinical Significance Of Ugt1a1 Gene Polymorphismsmentioning

confidence: 99%

Section: Current Status Of Ugt1a1 Gene Polymorphism Screeningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

UGT1A1 polymorphisms as a pharmacogenetic markers for prediction of irinotecan-induced toxicities in metastatic colorectal cancer

Vuković

Žigman

Vučetić³

et al. 2019

lib oncol

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Role of MRPs transporters in pharmacokinetics and intestinal toxicity of irinotecan

Du,

Luo,

Wang

et al. 2023

Food and Chemical Toxicology

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PharmFrag: An Easy and Fast Multiplex Pharmacogenetics Assay to Simultaneously Analyze 9 Genetic Polymorphisms Involved in Response Variability of Anticancer Drugs

Bouvet

Verdier

Baroudi

et al. 2020

IJMS

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Regarding several cytotoxic agents, it was evidenced that genetic polymorphisms in genes encoding enzymes involved in their metabolism are associated with higher risk of toxicity. Genotyping these genes before treatment is a valuable strategy to prevent side effects and to predict individual response to drug therapy. This pharmacogenetic approach is recommended for chemotherapies such as thiopurines (azathioprine, 6-mercaptopurine, thioguanine), irinotecan, and fluoropyrimidines (capecitabine and 5-fluorouracil). In this study, we aimed at developing and validating a fast, cost-effective, and easily implementable multiplex genotyping method suitable for analyzing a panel of nine variants involved in the pharmacogenetics of widely prescribed anticancer drugs. We designed a multiplex-specific PCR assay where fragments were labeled by two different fluorescent dye markers (HEX/FAM) identifiable by fragment analysis. These two labels were used to discriminate bi-allelic variants, while the size of the fragment allowed the identification of a particular polymorphism location. Variants of interest were TPMT (rs1800462, rs1142345, rs1800460), NUDT15 (rs116855232), DPYD (rs55886062, rs3918290, rs67376798, rs75017182), and UGT1A1 (rs8175347). The assay was repeatable, and genotypes could be determined when DNA sample amounts ranged from 25 to 100 ng. Primers and dye remained stable in a ready-to-use mixture solution after five freeze–thaw cycles. Accuracy was evidenced by the consistency of 187 genotyping results obtained with our multiplex assay and a reference method. The developed method is fast and cost-effective in simultaneously identifying nine variants involved in the pharmacological response of anticancer drugs. This assay can be easily implemented in laboratories for widespread access to pharmacogenetics in clinical practice.

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Genetics and Adverse Events with Irinotecan Treatment: What do we Know?

Abstract: the clinical utility of routine UGT1A1 genotyping to pre-emptively adjust irinotecan dosage reduces toxicity while maintaining drug efficacy "

Cited by 3 publications

References 20 publications

UGT1A1 polymorphisms as a pharmacogenetic markers for prediction of irinotecan-induced toxicities in metastatic colorectal cancer

UGT1A1 polymorphisms as a pharmacogenetic markers for prediction of irinotecan-induced toxicities in metastatic colorectal cancer

Role of MRPs transporters in pharmacokinetics and intestinal toxicity of irinotecan

PharmFrag: An Easy and Fast Multiplex Pharmacogenetics Assay to Simultaneously Analyze 9 Genetic Polymorphisms Involved in Response Variability of Anticancer Drugs

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