Research of pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of 5-Fluorouracil in colorectal cancer patients
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ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2619548 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:PURPOSE:To assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib. PATIENTS AND METHODS:A prospective clinical study of 80 patients with non-small-cell lung cancer, head and neck cancer, and ovarian cancer was performed. Detailed pharmacokinetics and toxicity of erlotinib were assessed. Polymorphic loci in EGFR, ABCG2, CYP3A4, and CYP3A5 were genotyped, and their effects on pharmacokinetics and toxicities were evaluated. RESULTS:A novel diplotype of two polymorphic loci in the ABCG2 promoter involving -15622C/T and 1143C/T was identified, with alleles conferring lower ABCG2 levels associated with higher erlotinib pharmacokinetic parameters, including area under the curve (P = .019) and maximum concentration (P = .006). Variability in skin rash was best explained by a multivariate logistic regression model incorporating the trough erlotinib plasma concentration (P = .034) and the EGFR intron 1 polymorphism (P = .044). Variability in diarrhea was associated with the two linked polymorphisms in the EGFR promoter (P < .01), but not with erlotinib concentration. CONCLUSION:Although exploratory in nature, this combined pharmacogenomic and pharmacokinetic model helps to define and differentiate the primary determinants of skin and gastrointestinal toxicity of erlotinib. The findings may be of use both in designing trials targeting a particular severity of rash and in considering dose and schedule modifications in patients experiencing dose-limiting toxicities of erlotinib or similarly targeted agents. Further studies of the relationship between germline polymorphisms in EGFR and the toxicity and efficacy of EGFR inhibitors are warranted.
| S-EPMC5846189 | biostudies-literature
Project description:This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6beta-hydroxylation determination could help to determine the optimal dose of irinotecan.
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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:5-Fluorouracil (5-FU) is a standard chemotherapeutic agent to treat solid cancers such as breast, colon, head, and neck. Computational modeling plays an essential role in predicting the outcome of chemotherapy and developing optimal dosing strategies. We developed an integrated mechanistic pharmacokinetics/pharmacodynamics (PK/PD) model examining the influence of 5-FU, as an S-phase specific double-strand break (DSB)-inducing agent, on tumor proliferation. The proposed mechanistic PK/PD model simulates the dynamics of critical intermediate components and provides the accurate tumor response prediction. The integrated model is composed of PK, cellular, and tumor growth inhibition (TGI) sub-models, quantitatively capturing the essential drug-related physiological processes. In the cellular model, thymidylate synthase (TS) inhibition, resultant deoxynucleoside triphosphate (dNTP) pool imbalance, and DSB induction are considered, as well as 5-FU incorporation into RNA and DNA. The amount of 5-FU anabolites and DSBs were modeled to drive the kinetics of the pharmacological tumor response. Model parameters were estimated by fitting to literature data. Our simulation results successfully describe the kinetics of the intermediates regulating the 5-FU cytotoxic events and the pattern of tumor suppression. The comprehensive model simulated the tumor volume change under various dose regimens, and its generalizability was attested by comparing it with literature data. The potential causes of the tumor resistance to 5-FU are also investigated through Monte Carlo analysis. The simulation of various dosage regimens helps quantify the relationship between treatment protocols and chemotherapy potency, which will lead to the development of efficacy optimization.
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Project description:Primary outcome(s): To determine the correlation between the baseline endogenous DPD substrate plasma ratios of DHU/U and DHT/T with the pharmacokinetics of 5-FU in patients with pancreas or colorectal cancer treated with intravenous 5-FU-based chemotherapy.
Study Design: N/A: single arm study, Open (masking not used), N/A , unknown, Other
| 2442076 | ecrin-mdr-crc
Project description:In the present study, goal was to scan the potential biomarker for acute kidney injury induced by aristolochic acid I (AAI).We utilized the microarry analysis to investigate the microRNA (miRNA) expression profile in kidneys from rat treated by 40mg/kg AA I for 2-6 days. miRNAs with significantly different expression of global miRNA expression profile were validated by qRT-PCR. For miRNAs still significantly disregulation, we further examined the expression in plasma of rats treated with AAI dosed at 10, 20 and 40mg/kg AAI for 2-6 days by qRT-PCR. miRNAs with significantly dysregulation in plasma, their expression in brain, liver and heart was examined for kicking out the non-specific disregulation in AAI induced acute kidney injury, so that the significant dysregulation miRNAs with specificity in kidney and plasma was found as potential biomarkers for AAI induced acute kidney injury. Five control and 15 kidneys treated with 40mg/kg AAI on day 2, 4 and 6 was examined by microarray.
2016-03-10 | E-GEOD-79063 | biostudies-arrayexpress
Project description:The extensive drug resistance of hepatocellular carcinoma (HCC) has become the main cause of chemotherapy failure. The mechanisms leading to drug resistance in tumor cells are not well understood. Previous studies demonstrated that plasma membrane proteins play important roles in mediating drug disposal or pharmacokinetics. Therefore, we performed proteomic studies on the composition of 5-fluorouracil (5-Fu) resistant Bel/5Fu cell line and its parent Bel7402 cell line by using an ionic liquid-assisted proteins extraction method with the advantage of extracting plasma membrane proteins to a greater extent. In total, 4,532 unique proteins were quantified and 103 proteins (>2-fold change, p-value <0.05) including 25 plasma membrane proteins showed to be differentially expressed in Bel/5Fu compared with Bel7402. Western blot analysis results were further confirmed that the plasma membrane proteins EPHX1 PLIN2 RAB27B SLC4A2 were up-regulated in Bel/5Fu cells in accordance with the proteomics data. Moreover, cell viability assay and clonogenic survival assay results demonstrated that EPHX1 are closely related to the chemoresistance of Bel/5Fu to 5Fu.
2019-10-19 | PXD015917 |
Project description:Development depression-associated biomarkers research
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Project description:Mechanism (s) of the epigallocatechin-3-gallate (EGCG) as major effective components in green tea regarding the reduction of hypertensive risk might associate with microRNAs (miRNAs). The plasma distribution of EGCG and epigallocatechin (EGC) in Sprague-Dawley rats were analyzed pharmacokinetically and found that they did not distribute well in plasma but widely in tissues, and their plasma deposition best fitted a mono-compartmental model with Cmax (6.65 vs 4.45 μg/mL) and Tmax (15 vs 10 min). Blood pressure monitoring of spontaneously hypertensive rats (SHR) intragastrically administrated with 300 mg/kg BW showed that systolic blood pressure (SBP) decreased to the lowest point by 34.04 mmHg and recovered by 23.39 mmHg after 15 and 30 min of administration, respectively, and it decreased again at 60 min and recovered at time 2 h. Total 150 upregulated and 18 downregulated miRNAs were identified via the deep sequencing and were 1.0 or 0.5 fold to the control group (P<0.01) after EGCG administration. And, hypertension-associated miRNA-126-3p and miRNA-150 were further validated by qRT-PCR. It might help explore novel pathways involving antihypertensive effect of EGCG.
2018-01-20 | GSE109412 | GEO