Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5006-5006
Author(s):  
N. van Erp ◽  
R. H. Mathijssen ◽  
A. A. van der Veldt ◽  
J. B. Haanen ◽  
A. K. Reyners ◽  
...  
Keyword(s):  
Drug Targets ◽  
Single Agent ◽  
Mucosal Inflammation ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Metabolizing Enzymes ◽  
Genes Encoding ◽  
Hand Foot Syndrome ◽  
T Haplotype

5006 Background: To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities; thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome and ‘any toxicity according to Common Terminology Criteria > grade 2.’ Methods: A multicenter pharmacogenetic association study was performed in 219 patients treated with single agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several non-genetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. Results: The risk for leukopenia was increased when the G-allele in CYP1A1 2455A/G (OR = 6.24; p = 0.029) or the T-allele in FLT3 738T/C (OR = 2.8; p = 0.008) were present or CAG in the NR1I3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR = 1.74; p = 0.041) was absent. ‘Any toxicity > grade 2’ prevalence was increased when the T-allele of VEGFR-2 1191C/T (OR = 2.39; p = 0.046) or a copy of TT in the ABCG2 (-15622C/T, 1143C/T) haplotype (OR = 2.63; p = 0.016) were present. The risk for mucosal inflammation was increased in the presence of the G-allele in CYP1A1 2455A/G (OR = 4.03; p = 0.021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR = 2.56; p = 0.035) was present. Conclusions: This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters and drug targets are associated with sunitinib related toxicities. A better understanding of genetic and non-genetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients. [Table: see text]

Pharmacogenetic Pathway Analysis for Determination of Sunitinib-Induced Toxicity

2009 ◽  
Vol 27 (26) ◽  
pp. 4406-4412 ◽  
Author(s):  
Nielka P. van Erp ◽  
Karel Eechoute ◽  
Astrid A. van der Veldt ◽  
John B. Haanen ◽  
An K.L. Reyners ◽  
...  
Keyword(s):  
Drug Targets ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Mucosal Inflammation ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Genes Encoding ◽  
Hand Foot Syndrome ◽  
Endothelial Growth Factor ◽  
T Haplotype

Purpose To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities: thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome, and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2. Patients and Methods A multicenter pharmacogenetic association study was performed in 219 patients treated with single-agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several nongenetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. Results The risk for leukopenia was increased when the G allele in CYP1A1 2455A/G (odds ratio [OR], 6.24; P = .029) or the T allele in FLT3 738T/C (OR, 2.8; P = .008) were present or CAG in the NR1I3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR, 1.74; P = .041) was absent. Any toxicity higher than grade 2 prevalence was increased when the T allele of vascular endothelial growth factor receptor 2 1191C/T (OR, 2.39; P = .046) or a copy of TT in the ABCG2 (−15622C/T, 1143C/T) haplotype (OR, 2.63; P = .016) were present. The risk for mucosal inflammation was increased in the presence of the G allele in CYP1A1 2455A/G (OR, 4.03; P = .021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR, 2.56; P = .035) was present. Conclusion This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters, and drug targets are associated with sunitinib-related toxicities. A better understanding of genetic and nongenetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients.

ABCB1, CYP3A5*3, and CYP3A4*1B SNPs and risk of toxicity with sunitinib treatment for mRCC.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 485-485
Author(s):  
Maria Bassanelli ◽  
Alessandra Felici ◽  
Michele Milella ◽  
Diana Giannarelli ◽  
Silvana Giacinti ◽  
...  
Keyword(s):  
Nucleotide Polymorphisms ◽  
Test Results ◽  
Chi Square ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Genes Encoding ◽  
Hand Foot Syndrome ◽  
Chi Square Test ◽  
Grade 3 ◽  
The Individual

485 Background: Currently there are no biomarkers to predict either toxicity or activity of targeted therapy in mRCC. The aim of this study was to correlate single nucleotide polymorphisms (SNPs) of genes encoding for efflux transporters and metabolizing enzymes with sunitinib toxicity in metastatic renal cell carcinoma (mRCC) patients (pts). Methods: We conducted an observational, retrospective analysis of 60 Caucasian pts who received sunitinib for mRCC from 2 Italian institutions. Correlation between adverse events (AE, according to CTCAE v.4.0) and 4 polymorphisms in 3 genes (ABCB1 [1236C>T, 3435C>T], CYP3A5*3 6986A>G, CYP3A4*1B-392A>G) was analyzed. SNPs were detected in blood samples using pyrosequencing technique. Association between SNPs and toxicities was evaluated using the Chi Square test. Results: 60pts (median age: 61 years; male: 63.3%) with mRCC (clear cell: 85%, other histologies: 15%) were treated with sunitinib (83.3% as first-line). The most common AE (any-grade) reported were: hypertension (85%), asthenia (83.3%), hypothyroidism (65%), anemia (61.6%), nausea/vomiting (60%), stomatitis (58.3%), diarrhoea (48.3%), neutropenia (48.3%), thrombocytopenia (46.7%), leukopenia (46.7%), hypertriglyceridemia (45%), hyperglycaemia (38.4%), hypercholesterolemia (35%), and hand-foot syndrome (35%). Treatment was discontinued and sunitinib dose was reduced due to AE in 28.3% and 61.7% of pts, respectively. The G/A-variant in CYP3A5*3 was associated with thrombocytopenia (any grade, p=0.03); homozygous C/C alleles in ABCB1 1236C>T significantly correlated with leukopenia (any grade, p=0.01), while the C/C genotype in ABCB1 3435C>T was associated with hypertension (grade≥3, p=0.05); hypertriglyceridemia showed a trend towards increased prevalence in the presence of the C allele (grade≥3, p=0.08). Conclusions: Polymorphisms in ABCB1 and CYP3A5*3 are predictive of toxicity, as hypertension, leukopenia, and thrombocytopenia in pts with mRCC treated with sunitinib. This analysis could support the selection of the more appropriate drug to the individual patient.

Pharmacogenetics in oncology: Where we stand today?

2016 ◽  
Vol 1 (1) ◽  
pp. 2 ◽  
Author(s):  
Padmaj S. Kulkarni
Keyword(s):  
Drug Targets ◽  
Drug Response ◽  
Chemotherapeutic Drugs ◽  
Nucleotide Polymorphisms ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
A Genome ◽  
The Right ◽  
The Cost

<p>In a given population, there is considerable variation between individuals with regard to response to as well as toxicity of different drugs. The term “Pharmacogenetics” has largely been used in relation to genes determining drug metabolism, while “Pharmacogenomics” is a broader based term that encompasses all genes in a genome that may determine drug response. In oncology, efficacy and safety of many chemotherapeutic drugs show substantial individual and/or population variability. It can be explained, to a great extent, by gene polymorphism encoding drug-metabolizing enzymes, drug transporters, and drug targets which influence the pharmacokinetics and pharmacodynamics and affect clinical outcomes. Single nucleotide polymorphisms (SNPs) are the most studied genetic variants at present due to ease, accuracy, and reduced the cost of processing as well as due to public availability of online resources for SNPs. Candidate genes for a therapeutic and adverse response can be divided into three categories: Pharmacokinetic, receptor/target, and disease-modifying. Many anticancer drugs are evaluated for their variation in response according to germline variations. This information can be easily incorporated in day-to-day practice to improve efficacy and/or safety of these drugs. In the future, advances gained from pharmacogenetics research will provide information to guide doctors in advising just enough of the right medicine to a person – The practice of “personalized medicine.”</p>

scholarly journals Association of Polymorphisms in Inflammatory Cytokines Encoding Genes With Anti-N-methyl-D-Aspartate Receptor Encephalitis in the Southern Han Chinese

2020 ◽  
Vol 11 ◽  
Author(s):  
Xing Li ◽  
Jiajia Zhu ◽  
Yu Peng ◽  
Hongbing Guan ◽  
Jinyu Chen ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Protective Role ◽  
Han Chinese ◽  
Nucleotide Polymorphisms ◽  
Degree Relative ◽  
Aspartate Receptor ◽  
Nmdar Encephalitis ◽  
Genes Encoding ◽  
The Relationship

Background: Single nucleotide polymorphisms (SNPs) that occur within genes encoding inflammatory cytokines can result in quantitative or qualitative changes in their expression or functionality, potentially leading to the development of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. This study sought to evaluate the relationship between SNPs in inflammatory cytokines genes and the incidence of anti-NMDAR encephalitis in the Southern Han Chinese.Methods: In total, we enrolled 107 patients with anti-NMDAR encephalitis as well as 202 inpatient controls who had no first-degree relative with autoimmune diseases. Genotyping determination of all 309 patients was conducted for the IL-1β rs16944, IL-4 rs2243250, IL-4 rs2070874, IL-6 rs1800796, IL-10 rs1800872, and IL-17 rs2275913 gene SNPs.Results: We observed statistically significant differences in the frequencies of G allele in IL-1β rs16944 between anti-NMDAR encephalitis and controls (p = 0.017). Also, IL-1β, IL-4, IL-6, IL-10, and IL-17 SNPs were not associated with the disease (p &gt; 0.05).Conclusions: We found that patients with anti-NMDAR encephalitis exhibit a distinct immunological profile, and we found that the decreased frequency of G allele in IL-1β rs16944 showed a protective role for anti-NMDAR encephalitis in the Southern Han Chinese.

scholarly journals Dexketoprofen Pharmacokinetics is not Significantly Altered by Genetic Polymorphism

2021 ◽  
Vol 12 ◽  
Author(s):  
Gina Mejía-Abril ◽  
Pablo Zubiaur ◽  
Marcos Navares-Gómez ◽  
Gonzalo Villapalos-García ◽  
Manuel Román ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Genetic Polymorphism ◽  
Univariate Analysis ◽  
Current Evidence ◽  
Nucleotide Polymorphisms ◽  
Pharmacokinetic Variability ◽  
Metabolizing Enzymes ◽  
Genes Encoding ◽  
Metabolizing Enzyme ◽  
Individualization Of Therapy

Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p &lt; 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2*1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes (p &lt; 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (p &lt; 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW (p &lt; 0.05 in multivariate analysis). The remaining studied transporter genes (ABCC2, SLC22A1, and SLCO1B1) and metabolizing enzyme genes (CYP3A5, CYP2C19, CYP2C9, CYP2C8, CYP3A4, CYP2A6, and UGT1A1) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6, CYP2D6, CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.

scholarly journals Genotype Analysis of Fruit Color using a Molecular Marker in Watermelon [Citrul luslanatus (Thunb.) Matsum & Nakai]

HortScience ◽  
2005 ◽  
Vol 40 (4) ◽  
pp. 1114B-1114
Author(s):  
Haejeen Bang ◽  
Sunggil Kim ◽  
Daniel I. Leskovar ◽  
Stephen King
Keyword(s):  
Molecular Marker ◽  
Snp Markers ◽  
Fruit Color ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Color Determination ◽  
Genes Encoding ◽  
Differential Gene ◽  
Different Color

Fruit color and carotenoid composition are important traits in watermelon. Watermelon fruit color inheritance has revealed that several genes are involved in color determination. Carotenoids are known to have various functions in plants and animals, such as providing antioxidant activity and other health benefits for humans, and UV protection and pigmentation for plants. Differential gene activity in the carotenoid biosynthetic pathway may result in different color determination of mature fruit. Eight genes encoding enzymes involved in the pathway were isolated and their structures were characterized. While obtaining full-length cDNA of these enzymes, two single-nucleotide polymorphisms were detected in a coding region of lycopene β-cyclase (LCYB). These SNP markers showed cosegregation with red and canary yellow fruit color based on the genotyping of two segregating populations. This will lead to development of a codominant molecular marker for the selection of LCYB allele, which may allow breeders to distinguish between red and canary yellow watermelon fruit colors at the seedling stage.

scholarly journals Pharmacogenetic Markers of Treatment Response of Imatinib Mesylate in Chronic Myeloid Leukemia Brazilian Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5458-5458
Author(s):  
Natália M Vieira ◽  
Renata Leite ◽  
Fabíola Reginato ◽  
Marília Zandoná ◽  
Tito Vanelli Costa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Response To Treatment ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Genes Encoding ◽  
Polymerase Chain

Abstract The treatment of chronic myeloid leukemia (CML) was revolutionized by the introduction of imatinib mesylate (IM). However, approximately 20% of patients are non-responsive and interpatient variability in response to IM is still a phenomenon lacking explanation. Single nucleotide polymorphisms (SNPs) located in genes encoding proteins involved in IM pharmacokinetics are potentially involved in the causes of this variation. In this study, we investigated the association of SNPs in the genes encoding IM metabolizing enzymes CYP3A4 (rs35599367 and rs2740574) and CYP3A5 (rs776746) and efflux transporter proteins ABCB1 (rs3213619, rs1128503, rs2032582 and rs1045642), ABCG2 (rs2231142) and ABCC4 (rs9561765) with response to treatment and with IM plasma through levels and hair concentrations. The analyzed sample was constituted of 182 CML patients on IM treatment. DNA samples were genotyped for the nine SNPs using real-time polymerase chain reaction. Hair and plasma trough IM concentrations were measured through liquid chromatography coupled to mass spectrometry methods. Clinical response was defined according to the European Leukemia Net guidelines. The number of responders to standard IM therapy was 104. A trend to a higher frequency of CYP3A4 *22 (rs35599367) allele carriers was observed among responders to IM (12.5 vs. 3.4% of non-responders, P = 0.087), although no significant differences in plasma or hair concentrations between genotypes were found. Pharmacogenetics may become a valuable approach to optimize therapy with IM in CML, but many factors still need to be clarified to make possible its application in clinical practice. Disclosures No relevant conflicts of interest to declare.

scholarly journals The role of genetics and genomics in clinical psychiatry

2018 ◽  
Vol 20 (3) ◽  
pp. 169-177 ◽  
Keyword(s):  
Genetic Variants ◽  
Drug Targets ◽  
Drug Response ◽  
Disease Risk ◽  
Individual Response ◽  
Sources Of Information ◽  
Metabolizing Enzymes ◽  
Genes Encoding ◽  
Genetics And Genomics

The enormous successes in the genetics and genomics of many diseases have provided the basis for the advancement of precision medicine. Thus, the detection of genetic variants associated with neuropsychiatric disorders, as well as treatment outcome, has raised growing expectations that these findings could soon be translated into the clinic to improve diagnosis, the prediction of disease risk and individual response to drug therapy. In this article, we will provide an introduction to the search for genes involved in psychiatric illness and summarize the present findings in major psychiatric disorders. We will review the genetic variants in genes encoding drug metabolizing enzymes and specific drug targets which were found to be associated with variable drug response and severe side effects. We will evaluate the clinical translatability of these findings, whether there is currently any role for genetic testing and in this context, make valuable sources of information available to the clinician seeking guidance and advice in this rapidly developing field of psychiatric genetics.

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