Pharmacokinetics of Gemcitabine in Japanese Cancer Patients: The Impact of a Cytidine Deaminase Polymorphism

2007 ◽  
Vol 26 (1) ◽  
pp. 32-42 ◽  
Author(s):  
Emiko Sugiyama ◽  
Nahoko Kaniwa ◽  
Su-Ryang Kim ◽  
Ruri Kikura-Hanajiri ◽  
Ryuichi Hasegawa ◽  
...  
Keyword(s):  
Cancer Patients ◽  
High Performance ◽  
Cytidine Deaminase ◽  
Direct Sequencing ◽  
Pharmacokinetic Parameters ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inactive Metabolite ◽  
Grade 3 ◽  
The Impact

PurposeGemcitabine is rapidly metabolized to its inactive metabolite, 2′,2′-difluorodeoxyuridine (dFdU), by cytidine deaminase (CDA). We previously reported that a patient with homozygous 208A alleles of CDA showed severe adverse reactions with an increase in gemcitabine plasma level. This study extended the investigation of the effects of CDA genetic polymorphisms on gemcitabine pharmacokinetics and toxicities.Patients and MethodsGenotyping of CDA was performed by a direct sequencing of DNA obtained from the peripheral blood of Japanese gemcitabine-naïve cancer patients (n = 256). The patients recruited to the association study received a 30-minute intravenous infusion of gemcitabine at a dose of either 800 or 1,000 mg/m2, and eight blood samples were periodically collected (n = 250). Plasma levels of gemcitabine and dFdU were measured by high-performance liquid chromatography. Plasma CDA activities toward cytidine and gemcitabine were also measured (n = 121).ResultsTwenty-six genetic variations, including 14 novel ones and two known nonsynonymous single nucleotide polymorphisms (SNPs), were detected. Haplotypes harboring the nonsynonymous SNPs 79A>C (Lys27Gln) and 208G>A (Ala70Thr) were designated *2 and *3, respectively. The allelic frequencies of the two SNPs were 0.207 and 0.037, respectively. Pharmacokinetic parameters of gemcitabine and plasma CDA activities significantly depended on the number of haplotype *3. Haplotype *3 was also associated with increased incidences of grade 3 or higher neutropenia in the patients who were coadministered fluorouracil, cisplatin, or carboplatin. Haplotype *2 showed no significant effect on gemcitabine pharmacokinetics.ConclusionHaplotype *3 harboring a nonsynonymous SNP, 208G>A (Ala70Thr), decreased clearance of gemcitabine, and increased incidences of neutropenia when patients were coadministered platinum-containing drugs or fluorouracil.

scholarly journals Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes

2018 ◽  
Vol 47 (4) ◽  
pp. 1604-1616 ◽  
Author(s):  
Yan Fang ◽  
Na Gao ◽  
Xin Tian ◽  
Jun Zhou ◽  
Hai-Feng Zhang ◽  
...  
Keyword(s):  
Gene Polymorphisms ◽  
High Performance ◽  
Liver Microsomes ◽  
Nucleotide Polymorphisms ◽  
Liquid Chromatograph ◽  
Single Nucleotide ◽  
P450 Oxidoreductase ◽  
Human Livers ◽  
Metabolic Activities ◽  
The Impact

Background/ Aims: Little is known about the effect of P450 oxidoreductase (POR) gene polymorphisms on the activities of CYPs with multiple genotypes. Methods: We genotyped 102 human livers for 18 known POR single nucleotide polymorphisms (SNPs) with allelic frequencies greater than 1% as well as for 27 known SNPs in 10 CYPs. CYP enzyme activities in microsomes prepared from these livers were determined by measuring probe substrate metabolism by high performance liquid chromatograph. Results: We found that the effects of the 18 POR SNPs on 10 CYP activities were CYP genotype-dependent. The POR mutations were significantly associated with decreased overall Km for CYP2B6 and 2E1, and specific genotypes within CYP1A2, 2A6, 2B6, 2C8, 2D6 and 2E1 were identified as being affected by these POR SNPs. Notably, the effect of a specific POR mutation on the activity of a CYP genotype could not be predicted from other CYP genotypes of even the same CYP. When combining one POR SNP with other POR SNPs, a hitherto unrecognized effect of multiple-site POR gene polymorphisms (MSGP) on CYP activity was uncovered, which was not necessarily consistent with the effect of either single POR SNP. Conclusions: The effects of POR SNPs on CYP activities were not only CYP-dependent, but more importantly, CYP genotype-dependent. Moreover, the effect of a POR SNP alone and in combination with other POR SNPs (MSGP) was not always consistent, nor predictable. Understanding the impact of POR gene polymorphisms on drug metabolism necessitates knowing the complete SNP complement of POR and the genotype of the relevant CYPs.

Dihydropyrimidine dehydrogenases (DPYD), and cytidine-deaminase (CDA) gene polymorphisms as genomic predictors of clinical outcome in resected gastric cancer patients (GCP) treated with fluoropyrimidine-based adjuvant chemotherapy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4052-4052
Author(s):  
J. J. Grau ◽  
M. Monzo ◽  
C. Muñoz ◽  
J. A. Bombi ◽  
J. Domingo-Domenech ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Cancer Patients ◽  
Cytidine Deaminase ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
The Status ◽  
Gastric Cancer Patients ◽  
Colorectal Cancer Patients

4052 Background: Single nucleotide polymorphisms (SNPs) of DPYD gene induces DPD deficiency resulting in decreased activity of 5-fluorouracil derivatives in treatment of colorectal cancer patients (pts). In GCP has not been previously analysed. Methods: We analysed paraffin-embedded biopsies from 50 consecutive resected GCP who received adjuvant chemotherapy with four cycles of Mitomycin C (MMC), 20 mg/m2 iv day 1 plus oral Tegafur (TG), 500 mg/m2 day 1 to day 45 every six weeks, for SNPs of genes DPYD1 (A/G; Ile/Val), DPYD2 (C/T; Arg/Cys) and CDA (A/C; Lys/Gin). The status of alleles (wild type or at least 1 polymorphism) was correlated with outcome, overall survival (OS) and toxicity. Results: The status of SNPs frequencies according to the classification between wild type/non-wild type, were 36/14 in DPYD1; 26/24 in DPYD2; and 17/23 in CDA or between homozygous/heterozygous were 39/11 in DPYD1; 33/17 in DPYD2 and 26/24 in CDA respectively. After 77 months of median follow-up, 18 pts died of tumor relapse, (7 in peritoneum and 11 in distant organs). Difference in survival was observed in DPYD1 pts only, for non wild-type over wild-type (p = 0.0283) and in any of the 3 genes tested heterozygous over homozygous pts (p = 0.0463). In 10 pts (20%) total dose was reduced by toxicity (5 diarrhea, 2 neutropenia, 2 hepatotoxicity, 1 vomiting), only 3 of them were homozygous. Conclusions: SNPs of DPYD1, DPYD2 and CDA predict outcome, survival and toxicity of GCP treated with 5-FU-based adjuvant chemotherapy. No significant financial relationships to disclose.

scholarly journals Polymorphisms in the cytotoxic T lymphocyte-associated protein-4 immune regulatory gene and their impact on inhibitor development in patients with hemophilia A

2019 ◽  
Vol 47 (10) ◽  
pp. 4981-4992
Author(s):  
Aveen M. Raouf Abdulqader ◽  
Ali Ibrahim Mohammed ◽  
Shwan Rachid
Keyword(s):  
T Lymphocyte ◽  
Hemophilia A ◽  
Fragment Length Polymorphism ◽  
Cytotoxic T Lymphocyte ◽  
Direct Sequencing ◽  
Regulatory Gene ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inhibitor Development ◽  
The Impact

Objective The development of inhibitors against infused factor VIII represents the most severe complication of substitution therapy in hemophilia A (HA) patients. Data on risk factors for inhibitor formation in Iraqi Kurdish patients with HA are unavailable. This study aimed to evaluate the impact of two single nucleotide polymorphisms (SNPs) in an immune regulatory gene in the emergence of inhibitors. Methods We focused on 126 patients with either severe or mild/moderate HA presenting with and without inhibitors. We analyzed the frequency of two polymorphisms in the cytotoxic T lymphocyte-associated protein-4 gene ( CTLA-4; CTLA-4-318C > T and CTLA-4 + 49A > G). Genotyping was performed using restriction fragment length polymorphism–PCR and direct sequencing. Results We found no significant correlation between the CTLA-4-318 C > T T allele and inhibitor development among patients with severe or mild/moderate HA. However, a significantly high inhibitor risk was detected for the CTLA-4 + 49 A > G G allele (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 1.383–7.024) and (OR = 4, 95% CI = 1.719–9.437) among patients with severe and mild/moderate HA, respectively. Conclusion We conclude that the CTLA-4 +49 A > G SNP plays a substantial role as a potential risk determinant for inhibitor formation in Iraqi Kurdish patients with HA.

Mutational Screening of FGFR1, CER1, and CDON in a Large Cohort of Trigonocephalic Patients

2006 ◽  
Vol 43 (2) ◽  
pp. 148-151 ◽  
Author(s):  
Fernanda Sarquis Jehee ◽  
Luis G. Alonso ◽  
Denise P. Cavalcanti ◽  
Chong Kim ◽  
Steven A. Wall ◽  
...  
Keyword(s):  
High Performance ◽  
Direct Sequencing ◽  
Nucleotide Polymorphisms ◽  
Related Gene ◽  
Inclusion Criteria ◽  
Coding Region ◽  
Single Nucleotide ◽  
Metopic Synostosis ◽  
Mutational Screening ◽  
Johns Hopkins University

Objective Screen the known craniosynostotic related gene, FGFR1 (exon 7), and two new identified potential candidates, CER1 and CDON, in patients with syndromic and nonsyndromic metopic craniosynostosis to determine if they might be causative genes. Design Using single-strand conformational polymorphisms (SSCPs), denaturing high-performance liquid chromatography, and/or direct sequencing, we analyzed a total of 81 patients for FGFR1 (exon 7), 70 for CER1, and 44 for CDON. Patients Patients were ascertained in the Centro de Estudos do Genoma Humano in São Paulo, Brazil (n = 39), the Craniofacial Unit, Oxford, U.K. (n = 23), and the Johns Hopkins University, Baltimore, Maryland (n = 31). Clinical inclusion criteria included a triangular head and/or forehead, with or without a metopic ridge, and a radiographic documentation of metopic synostosis. Both syndromic and nonsyndromic patients were studied. Results No sequence alterations were found for FGFR1 (exon 7). Different patterns of SSCP migration for CER1 compatible with the segregation of single nucleotide polymorphisms reported in the region were identified. Seventeen sequence alterations were detected in the coding region of CDON, seven of which are new, but segregation analysis in parents and homology studies did not indicate a pathological role. Conclusions: FGFR1 (exon 7), CER1, and CDON are not related to trigonocephaly in our sample and should not be considered as causative genes for metopic synostosis. Screening of FGFR1 (exon 7) for diagnostic purposes should not be performed in trigonocephalic patients.

scholarly journals The Interplay between miRNA-Related Variants and Age-Related Macular Degeneration: EVIDENCE of Association of MIR146A and MIR27A

2019 ◽  
Vol 20 (7) ◽  
pp. 1578 ◽  
Author(s):  
Claudia Strafella ◽  
Valeria Errichiello ◽  
Valerio Caputo ◽  
Gianluca Aloe ◽  
Federico Ricci ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Direct Sequencing ◽  
Bioinformatic Analysis ◽  
Age Related Macular Degeneration ◽  
Italian Population ◽  
Nucleotide Polymorphisms ◽  
Complex Interplay ◽  
Single Nucleotide ◽  
Age Related ◽  
The Impact

The complex interplay among genetic, epigenetic, and environmental variables is the basis for the multifactorial origin of age-related macular degeneration (AMD). Previous results highlighted that single nucleotide polymorphisms (SNPs) of CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA, and COL8A1 were significantly associated with the risk of AMD in the Italian population. Given these data, this study aimed to investigate the impact of SNPs in genes coding for MIR146A, MIR31, MIR23A, MIR27A, MIR20A, and MIR150 on their susceptibility to AMD. Nine-hundred and seventy-six patients with exudative AMD and 1000 controls were subjected to an epigenotyping analysis through real-time PCR and direct sequencing. Biostatistical and bioinformatic analysis was performed to evaluate the association with susceptibility to AMD. These analyses reported that the SNPs rs11671784 (MIR27A, G/A) and rs2910164 (MIR146A, C/G) were significantly associated with AMD risk. Interestingly, the bioinformatic analysis showed that MIR27A and MIR146A take part in the angiogenic and inflammatory pathways underlying AMD etiopathogenesis. Thus, polymorphisms within the pre-miRNA sequences are likely to affect their functional activity, especially the interaction with specific targets. Therefore, our study represents a step forward in the comprehension of the mechanisms leading to AMD onset and progression, which certainly include the involvement of epigenetic modifications.

scholarly journals Impact of PD-1 gene polymorphism and its interaction with tea drinking on susceptibility to tuberculosis

2021 ◽  
Vol 149 ◽  
Author(s):  
Jing Wang ◽  
Mian Wang ◽  
Zihao Li ◽  
Xinyin Wu ◽  
Xian Zhang ◽  
...  
Keyword(s):  
Case Control Study ◽  
Preventive Measures ◽  
Nucleotide Polymorphisms ◽  
Unconditional Logistic Regression ◽  
Negative Interaction ◽  
Single Nucleotide ◽  
High Risk Populations ◽  
Tea Drinking ◽  
The Impact ◽  
Control Study

Abstract The aim of this study was to explore the impact of polymorphism of PD-1 gene and its interaction with tea drinking on susceptibility to tuberculosis (TB). A total of 503 patients with TB and 494 controls were enrolled in this case–control study. Three single-nucleotide polymorphisms of PD-1 (rs7568402, rs2227982 and rs36084323) were genotyped and unconditional logistic regression analysis was used to identify the association between PD-1 polymorphism and TB, while marginal structural linear odds models were used to estimate the interactions. Genotypes GA (OR 1.434), AA (OR 1.891) and GA + AA (OR 1.493) at rs7568402 were more prevalent in the TB patients than in the controls (P < 0.05). The relative excess risk of interaction (RERI) between rs7568402 of PD-1 genes and tea drinking was −0.3856 (95% confidence interval −0.7920 to −0.0209, P < 0.05), which showed a negative interaction. However, the RERIs between tea drinking and both rs2227982 and rs36084323 of PD-1 genes were not statistically significant. Our data demonstrate that rs7568402 of PD-1 genes was associated with susceptibility to TB, and there was a significant negative interaction between rs7568402 and tea drinking. Therefore, preventive measures through promoting the consumption of tea should be emphasised in the high-risk populations.

miR-146a and miR-196a-2 genes polymorphisms and its circulating levels in lung cancer patients

2019 ◽  
Vol 166 (4) ◽  
pp. 323-329 ◽  
Author(s):  
Randa H Mohamed ◽  
Heba F Pasha ◽  
Doaa M Gad ◽  
Mostafa M Toam
Keyword(s):  
Lung Cancer ◽  
Cancer Risk ◽  
Cancer Patients ◽  
Lung Cancer Risk ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Lung Cancer Patients ◽  
Increased Risk ◽  
Increase Risk ◽  
Circulating Levels

AbstractRecently, MicroRNAs polymorphisms and their serum expression have been linked to increase risk of various cancers. The aim of this study was to elucidate the association between single nucleotide polymorphisms of miR-146a and miR-196a-2 and their serum expression and lung cancer risk. One hundred and twenty lung cancer patients and 120 health controls were included in this study. Genotyping and expression for miR-146a and miR-196a-2 were performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and quantitative real-time PCR. Individuals carrying miR-146a CG and CC genotypes had significantly increased risk for lung cancer than those carrying miR-146a GG genotype. MiR-146a expression significantly decreased in miR-146a CG and CC genotypes carriers as compared with GG genotype carriers. MiR-196a-2 CT and TT genotypes were significantly associated with increased lung cancer while the highest expression of MiR-196a-2 was detected in miR-196a-2 CC genotype carriers. Serum miR-146a was significantly decreased in lung cancer patients while serum miR-196a-2 expression was significantly increased in lung cancer patients. In conclusion, miR-146a and miR-196a-2 genes polymorphisms and their circulating levels were associated with lung cancer risk in Egyptians and may be helpful in early detection of lung cancer.

Single nucleotide polymorphisms to predict taxanes toxicities and effectiveness in cancer patients

2021 ◽  
Author(s):  
Sara Demurtas ◽  
Nicla La Verde ◽  
Selene Rota ◽  
Giovanni Casazza ◽  
Cristina Montrasio ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Cancer Patients ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide
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