A study of pharmacokinetic analysis of capecitabine and cytidine deaminase activity
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ABSTRACT:
DISEASE(S): Breast And Colorectal Cancer
PROVIDER: 2634538 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Objective: To assess the role of aldoketoreductases and other doxorubicin pharmacokinetic or pharmacogenomic genes in doxorubicin cytotoxicity, resistance, DNA binding activity, and subcellular localization, Methods: We conducted a whole genome microarray study to identify differences in between doxorubicin-sensitive MCF-7cc cells and doxorubicin-resistant MCF-7Dox2-12 cells in terms of their expression of genes related to doxorubicin pharmacokinetics or pharmacodynamics. Targets were then validated by pharmacologic inhibition in conjunction with drug metabolite profiling, drug localization, drug cytotoxicity, and drug DNA binding studies. Results: 2063 differentially expressed transcripts were identified, including 17% and 43% of genes or gene families associated with doxorubicin pharmacokinetics or pharmacodynamics (p values of significance of 0.05 and <0.0001, respectively). The largest changes in the expression of genes associated with doxorubicin pharmacokinetics and pharmacodynamics were chiefly among the aldo-keto reductases (AKRs) Akr1c2, Akr1c3 and Akr1b10 which convert doxorubicin to doxorubicinol. We observed that doxorubicinol exhibits dramatically reduced drug toxicity, reduced drug DNA-binding activity, and altered drug subcellular localization to lysosomes. Pharmacologic inhibition of these AKRs in MCF-7Dox2-12 cells restored drug cytotoxicity, and drug localization to the nucleus. Conclusion: These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledgebases to identify highly relevant genes associated with doxorubicin resistance. The products of one or more of these genes could effectively be shown to alter the drug’s properties, while inhibiting them restored drug DNA binding, cytotoxicity, and subcellular localization. Doxorubicin resistant cell lines of breast MCF-7 cells were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with four labelling replicates of both forward and reverse labellings plus another set of 8 arrays with forward labelling. Sixteen arrays were used for this experiments. The co-cultured control cells MCF-7cc12 was generated by parallel selection process in the absence of drug.
2012-11-22 | E-GEOD-27254 | biostudies-arrayexpress
Project description:Objective: To assess the role of aldoketoreductases and other doxorubicin pharmacokinetic or pharmacogenomic genes in doxorubicin cytotoxicity, resistance, DNA binding activity, and subcellular localization, Methods: We conducted a whole genome microarray study to identify differences in between doxorubicin-sensitive MCF-7cc cells and doxorubicin-resistant MCF-7Dox2-12 cells in terms of their expression of genes related to doxorubicin pharmacokinetics or pharmacodynamics. Targets were then validated by pharmacologic inhibition in conjunction with drug metabolite profiling, drug localization, drug cytotoxicity, and drug DNA binding studies. Results: 2063 differentially expressed transcripts were identified, including 17% and 43% of genes or gene families associated with doxorubicin pharmacokinetics or pharmacodynamics (p values of significance of 0.05 and <0.0001, respectively). The largest changes in the expression of genes associated with doxorubicin pharmacokinetics and pharmacodynamics were chiefly among the aldo-keto reductases (AKRs) Akr1c2, Akr1c3 and Akr1b10 which convert doxorubicin to doxorubicinol. We observed that doxorubicinol exhibits dramatically reduced drug toxicity, reduced drug DNA-binding activity, and altered drug subcellular localization to lysosomes. Pharmacologic inhibition of these AKRs in MCF-7Dox2-12 cells restored drug cytotoxicity, and drug localization to the nucleus. Conclusion: These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledgebases to identify highly relevant genes associated with doxorubicin resistance. The products of one or more of these genes could effectively be shown to alter the drug’s properties, while inhibiting them restored drug DNA binding, cytotoxicity, and subcellular localization.
2012-11-22 | GSE27254 | GEO
Project description:MCF7 cells were treated during 90 minuts with 5'DFUR 250uM in presence or absence of NBTI 100nM. RNA from two independent experiments was isolated and hybridization was performed in duplicate in all cases, using reciprocal labelling Keywords: 5'DFUR effect. Time 24h
2006-07-13 | GSE2931 | GEO
Project description:Background Testosterone (T) is the main androgen playing a crucial role in regulating the function of both reproductive and non-reproductive organs. Current methods for assessing T levels in humans do not reflect the biological androgenic activity (BAA), which may be important for example in the diagnosis of hypogonadism and clarifying pathogenetic mechanisms linking androgen deficiency to various comorbidities. In this study, we aimed to identify new protein markers of BAA in humans and test their predictive value in relation to some androgen deficiency linked pathologies. Methods and Findings Plasma samples (n=90) from 30 healthy chemically castrated young volunteer males (19-32 years) were collected at three different time points: baseline – prior to treatment with GnRH antagonist), three weeks after GnRH antagonist treatment, and at the end of the study, two weeks thereafter. Following the second blood sampling, all men were supplemented with 1000 mg T undecanoate. The samples were analysed by mass spectrometry-based proteomics. A total of 676 proteins were identified among which expression of 46 was statistically significantly associated with T concentration (p<0.05, ANOVA paired). Based on ROC-analysis, 3 candidate proteins were selected, 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6) and fructose-bisphosphate aldolase (ALDOB). Together with a mathematically calculated variable (MMA: Multi-Marker Algorithm), based on the combination of 4HPPD and IGFBP6 values, their predictive value in relation to low T levels and cardio-metabolic risk factors was tested in 75 males suffering from infertility, 32-43 years of age. Of these males, four were diagnosed with type 2-diabetes and 14 with the metabolic syndrome. Clinical chemistry data regarding cardio-metabolic parameters, bone mineral density and androgen receptor CAG repeat lengths were assessed. The three proteins significantly distinguished between low (< 8 nmol/L) and normal (> 12 nmol/L) morning fasting T (AUC: 0.70-0.77). The MMA had an even higher accuracy (AUC=0.80) in identifying subjects with low T. 4HPPD, ALDOB and MMA showed higher accuracy than T (AUC=0.85-0.92 vs. AUC=0.55; p<.001) in identifying infertile patients with type 2 diabetes mellitus and metabolic syndrome (AUC=0.74-0.78 vs. AUC=0.56; p<0.05). These markers also showed higher AUC than T in predicting adverse cardiovascular risk lipid profile and insulin resistance patients but the differences were not statistically significant. 4HPPD and MMA distinguished patients with low bone density (z-score in DEXA scan < -1), but no difference was observed when comparing with AUC for T,. The androgenic dependence of 4HPPD and ALDOB were confirmed by finding statistically significant lower levels of these markers in men with androgen CAG repeat lengths < 21 (p=0.002) and >22 (p=0.038) as compared to those with CAG of 21-22. No statistical significances were found for IGFBP6. Conclusions 4HPPD and ALDOB were identified as potential biomarkers for diagnosis of male hypogonadism and in identifying subjects at high risk of some of its clinical sequelae. More extensive testing should be carried out in order to elucidate their usefulness in clinical assessment of androgenic activity, not only in adult males but also in women and in pre-pubertal boys.
2022-04-07 | PXD024448 | Pride
Project description:MCF7 cells were treated during 90 min with 5'DFUR 250 uM in presence or absence of NBTI 100nM. The effect was analyzed 4 hours after the beginning of treatment. RNA from two independent experiments was isolated and hybridization was performed in duplicate in all cases, using reciprocal labelling. Keywords: 5'DFUR effect. Time 4h
2006-07-13 | GSE2930 | GEO
Project description:Pharmacokinetic, antihypertension and deep sequencing MiRNomes analysis of aorta from SHR fed with EGCG
| PRJNA430821 | ENA
Project description:<p><strong>OBJECTIVES:</strong> High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.</p><p><strong>MATERIALS AND METHODS:</strong> Systemic IDO1 activity was calculated by Kyn:Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. Dynamic change of IDO1 activity was followed in 24 patients by measuring Kyn:Trp ratio before, during and after RT administration.</p><p><strong>RESULTS:</strong> In 24 patients with dynamic tracking of plasma IDO1 activity, there was no significant alterations observed among the 3 time points (Friedman test, p=0.13). The changing pattern of Kyn:Trp ratio was divided into 4 groups: decreased consistently during RT, first increased then decreased, increased consistently, first decreased then increased. Patients whose Kyn:Trp ratio kept decreasing or first increased then decreased were defined as good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p=0.04; p=0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than bad-change group (p=0.01, HR=0.22). In 113 stage III NSCLC patients with pre-radiation Kyn:Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p=0.079).</p><p><strong>CONCLUSION: </strong>Favorable change of IDO1 activity during RT was associated with superior OS, PFS and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.</p>
2022-08-05 | MTBLS5267 | MetaboLights
Project description:Global transcriptome analyses provide an excellent basis for the identification and definition of biomarkers with high relevance in infection processes, therapeutic intervention and protective immunity. The measurement applies three different state of the art transcriptomic technologies for global expression profiling to vaccine development. Different microarray platforms in conjunct to next generation sequencing (NGS) will build the basis for comparative approaches, such as up-down classification and correlation coefficients. This measurement is based on Agilent microarrays and a clinical trial phase Ib study with M. bovis BCG vaccination. • Surrogate measurement using whole human blood • 4 time points: d0 (naïve, pre-immunization) and d14, d28,d56, d168 post m. bovis BCG immunization • Responses of PPD positive study groups • Group size of approximately 6 individuals European network of vaccine research and development (TRANSVAC)
2013-10-31 | GSE51060 | GEO
Project description:Rosuvastatin is a quite known lipid-lowering agent generally used for hypercholesterolemia treatment and coronary artery diseases prevention. There is substantial inter-individual variability in the absorption of statins usually caused by genetic polymorphisms leading to variation in the corresponding pharmacokinetic parameters, which may affect drug therapy safety and efficacy. Therefore, the investigation of metabolic markers associated with rosuvastatin inter-individual variability is exceedingly relevant for drug therapy optimization and minimizing side effects. This work describes the application of pharmacometabolomics strategies using liquid chromatography coupled to mass spectrometry to investigate endogenous plasma metabolites capable of predicting pharmacokinetic parameters in predose samples. First, a targeted method for the determination of plasma concentration levels of rosuvastatin was validated and applied to obtain the pharmacokinetic parameters from the 40 enrolled individuals, then predose samples were analyzed using the metabolomics approach to search for associations between endogenous metabolites and the corresponding pharmacokinetic parameters. Data processing using machine learning revealed some candidates including sterols and bile acids, carboxylated metabolites as well as lipids suggesting the approach herein described as promising for personalized drug therapy.
2021-10-29 | MTBLS3128 | MetaboLights
Project description:Global transcriptome analyses provide an excellent basis for the identification and definition of biomarkers with high relevance in infection processes, therapeutic intervention and protective immunity. The measurement applies three different state of the art transcriptomic technologies for global expression profiling to vaccine development. Different microarray platforms in conjunct to next generation sequencing (NGS) will build the basis for comparative approaches, such as up-down classification and correlation coefficients. This measurement is based on Agilent microarrays and a pre-clinical study with M. bovis BCG vaccination, using two different non-human primate Chinese and Indian rhesus macaque spectrotypes. • Surrogate measurement using whole blood RNA • 7 time points: d-14 and d0 (naïve, pre-immunization) and d1, d3, d7, d21, d42 post M. bovis BCG immunization • Responses of two macaque spectrotypes • Group size of 6 animals European network of vaccine research and development (TRANSVAC)
2016-05-01 | GSE51061 | GEO