scholarly journals Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5′-nucleotidase

2013 ◽  
Vol 88 (12) ◽  
pp. 1001-1006 ◽  
Author(s):  
Ingrid Jakobsen Falk ◽  
Anna Fyrberg ◽  
Esbjörn Paul ◽  
Hareth Nahi ◽  
Monica Hermanson ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Cytidine Deaminase ◽  
Normal Karyotype ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Genes Encoding

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.

Influence of Genetic Single Nucleotide Polymorphisms in CYP3A4, CYP3A5, GSTP1, GSTM1, GSTT1 and MDR1 Genes on Survival and Treatment Related Toxicity in Patients with Multiple Myeloma Treated in the HOVON 24 Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 505-505 ◽  
Author(s):  
Pieter Sonneveld ◽  
Celine Schilthuizen ◽  
Henk Lokhorst ◽  
Edo Vellenga ◽  
Reinier Raymakers ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Single Nucleotide Polymorphisms ◽  
Enzymatic Activity ◽  
Drug Metabolizing Enzymes ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Free Survival ◽  
Intensified Chemotherapy

Abstract Cytochromes P450 (CYP 450) and gluthatione-S-transferases (GSTs) are drug metabolizing enzymes involved in the detoxification of numerous chemotherapeutic agents.The Multidrug Resistance gene 1 (MDR1, ABCB1) is a transmembrane drug transporter present in tumor cells and mucosal epithelium. Genetic single nucleotide polymorphisms (SNP’s) in these genes are frequent and may alter the metabolism of certain anti-cancer drugs. The CYP3A4*1B (A-290G) polymorphism has not yet been proven to alter enzymatic activity. Polymorphisms in the CYP3A5*3 gene (A6986G) and the GSTP1 gene (Ile105Val) lead to decreased enzymatic activity. Homozygous deletions in the GSTM1 and GSTT1 genes lead to complete absence of the enzyme. Genetic polymorphism of MDR1 (C3435T) are frequent and associated with enhanced efflux function. We hypothesized that SNP haplotypes of these drug metabolizing enzymes may determine the interindividual differences of patients to treatment response and toxicity. We have investigated the presence of SNP’s of 211/345 previously untreated patients with multiple myeloma from whom diagnostic material was available and who were treated according to the HOVON-24 protocol, a clinical trial comparing myeloablative therapy with stem cell rescue added to intensified chemotherapy to intensified chemotherapy alone. Peripheral blood or bone marrow samples were analyzed by PCR or multiplex PCR. Patients with different haplotypes of CYP3A4, GSTP1, GSTM1, GSTT1 genes did not have significant differences of overall survival (OS), time to progression (TTP), progression free survival (PFS), event free survival (EFS), partial remission (PR), complete remission (CR) as determined by multivariate analysis with all clinical variables. Patients with mutant GSTP1(Ile/Val) had significantly more toxicity following high-dose melphalan (p=0.003). Patients with MDR1 C3435T mutation or absence of GSTP1 Ile105Val mutations had a lower probability to achieve at least a partial response(p=0.01). Patients genotyped homozygously for the mutant allele CYP3A5 gene had increased toxicity (p=0.040), improved OS (p=0.01) and PFS (p=0.04) and a decrease in TTP (p=0.03). This study is part of an ongoing analysis and the results will be validated in the next HOVON trial. We conclude that in patients with multiple myeloma who are treated with intensive chemotherapy and stem cell transplantation, analysis of genetic polymorphisms of metabolic enzymes may improve our understanding of treatment associated toxicity and treatment outcome.

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