In conclusion, PlncRNA-1 and TUG1 genes may play a critical role in GC progression and may serve as potential diagnostic biomarkers in GC patients.
Introduction: The polymorphic enzyme cytochrome P450 2D6 (CYP2D6) catalyzes a major step in the bioactivation of tamoxifen. Genotyping of clinically relevant CYP2D6 alleles and subsequent dose adjustment is a promising approach to individualize breast cancer therapy. The aim of this study was to investigate the relationship between the plasma levels of tamoxifen and its metabolites and different CYP2D6 genotypes under standard (20 mg/day) and dose-adjusted therapy (Registration ID in Iranian Registry of Clinical Trials: IRCT2015082323734N1). Materials and Methods: Using TaqMan ® assays common alleles of CYP2D6 ( ∗ 1, ∗ 2, ∗ 4, ∗ 5, ∗ 6, ∗ 10, ∗ 17, and ∗ 41) and gene duplication were identified in 134 breast cancer patients. Based on CYP2D6 genotypes patients with an activity score 1 ( n = 15) and 0–0.5 ( n = 2) were treated with tamoxifen adjusted dosage of 30 and 40 mg/day, respectively. The concentration of tamoxifen and its metabolites before and after 4 and 8 months of dose adjustment were measured using LC-MS/MS technology. Results: At baseline, (Z)-endoxifen plasma concentrations (33 ± 15.5, 28.1 ± 14, 26.6 ± 23.4, 14.3 ± 8.6, and 10.7 ± 5.5 nmol/l for EM/EM, EM/IM, EM/PM, IM/IM and PM/PM, respectively) and the metabolic ratio (Z)-Endoxifen/N-desmethyltamoxifen (0.0558 ± 0.02, 0.0396 ± 0.0111, 0.0332 ± 0.0222, 0.0149 ± 0.0026, and 0.0169 ± 0.0177 for EM/EM, EM/IM, EM/PM, IM/IM, and PM/PM, respectively) correlated with CYP2D6 genotype (Kruskal–Wallis p = 0.013 and p < 0.0001, respectively). Dose escalation to 30 and 40 mg/day in patients with a CYP2D6 activity score of 1 ( n = 15) and 0–0.5 ( n = 2) resulted in a significant increase in (Z)-endoxifen plasma levels (22.17 ± 24.42, 34.43 ± 26.54, and 35.77 ± 28.89 nmol/l at baseline, after 4 and 8 months, respectively, Friedman p = 0.0388) along with the plasma concentrations of tamoxifen and its other metabolites. No severe side effects were recorded during dose escalation. Conclusion: For the first time, we show the feasibility of dose escalation of tamoxifen in breast cancer patients with compromised CYP2D6 activity and Iranian ethnic background to increase the plasma concentrations of (Z)-endoxifen.
Cytochrome P450 2D6 (CYP2D6) is an important drug-metabolizing enzyme involved in the pharmacokinetic metabolism of drugs. CYP2D6 gene is highly polymorphic, and the combination of its different alleles yields different phenotypes including extensive metabolizer (EM), intermediate metabolizer (IM), poor metabolizer (PM), and ultrarapid metabolizer (UM). Genotyping of the important alleles for this gene in different ethnicities is of particular importance for assessing the efficacy of various drugs. In this study, we reviewed the CYP2D6 allele and phenotype frequencies predicted from the genotypes of CYP2D6 in the Middle East area. Regardless of different ethnicities, the CYP2D6 *41 allele frequency was shown to be higher than that of other reduced functional alleles. In addition, CYP2D6 *4 was the most frequent nonfunctional allele in all studied populations in the Middle East. Taken together, our findings illustrated that the frequencies of PM or IM alleles and different genotypes harboring these alleles are relatively high in the Middle Eastern countries. Therefore, the study of CYP2D6 alleles for each patient to detect those that are at risk is of great importance to prevent adverse drug reactions through individualization therapy.
Introduction: Pharmacogenetics is the study of inherited genetic variations in pathways responsible for metabolism of drugs and their effects on the individual responses. Cytochrome P450 2D6 (CYP2D6) is an important drug metabolizing enzyme involved in the metabolism of many drugs. The CYP2D6 gene is highly polymorphic and currently more than 100 allelic variants have been reported for it. The combination of different alleles yields different phenotypes such as: extensive metabolizer (EM), intermediate metabolizer (IM) and poor metabolizer (PM). The most important IM allele with reduced activity of the enzyme is CYP2D6*10. Variant CYP2D6*4 is the most important null allelic variant responsible for eliminating enzymatic activity and a poor metabolism (PM). Genotyping of these two alleles in the population for assessing the efficacy of drug is of particular importance. TaqMan® assays are widely utilized for genotyping CYP2D6 alleles, but due to the existence of two pseudogenes, CYP2D7 and CYP2D8, and highly polymorphic nature of the gene, assay design can be challenging. Materials and Methods:Here we compared TaqMan® allelic discrimination assay and PCR-sequencing method for genotyping CYP2D6*10 and CYP2D6*4 in 134 breast cancer patients in Isfahan province of Iran. Results: According to our study, the results of both methods for CYP2D6*4 allele were concordant with the reported allele frequency of 10.4 %. However, as the results of the two methods for genotyping CYP2D6*10 allele were contradictory, we conducted more experiments to examine the reasons behind these conflicting results. Conclusions: Taken together, our findings illustrate that TaqMan® assay may be not precise enough to genotype all CYP2D6 alleles; therefor other alternative genotyping methods should be considered.
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