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Ma B, Shi J, Zhang Y, Li Z, Yong H, Zhou YN, Liu S, A S, Zhou D. Enzymatically Activatable Polymers for Disease Diagnosis and Treatment. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2306358. [PMID: 37992728 DOI: 10.1002/adma.202306358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 11/03/2023] [Indexed: 11/24/2023]
Abstract
The irregular expression or activity of enzymes in the human body leads to various pathological disorders and can therefore be used as an intrinsic trigger for more precise identification of disease foci and controlled release of diagnostics and therapeutics, leading to improved diagnostic accuracy, sensitivity, and therapeutic efficacy while reducing systemic toxicity. Advanced synthesis strategies enable the preparation of polymers with enzymatically activatable skeletons or side chains, while understanding enzymatically responsive mechanisms promotes rational incorporation of activatable units and predictions of the release profile of diagnostics and therapeutics, ultimately leading to promising applications in disease diagnosis and treatment with superior biocompatibility and efficiency. By overcoming the challenges, new opportunities will emerge to inspire researchers to develop more efficient, safer, and clinically reliable enzymatically activatable polymeric carriers as well as prodrugs.
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Affiliation(s)
- Bin Ma
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Jiahao Shi
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Yuhe Zhang
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Zhili Li
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Haiyang Yong
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Ya-Nan Zhou
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Shuai Liu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Sigen A
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
- School of Medicine, Anhui University of Science and Technology, Huainan, 232001, China
| | - Dezhong Zhou
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
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Beierlein F, Horn AHC, Sticht H, Mokhir A, Imhof P. In Silico Study of Camptothecin-Based Pro-Drugs Binding to Human Carboxylesterase 2. Biomolecules 2024; 14:153. [PMID: 38397391 PMCID: PMC10886758 DOI: 10.3390/biom14020153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/22/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Pro-drugs, which ideally release their active compound only at the site of action, i.e., in a cancer cell, are a promising approach towards an increased specificity and hence reduced side effects in chemotherapy. A popular form of pro-drugs is esters, which are activated upon their hydrolysis. Since carboxylesterases that catalyse such a hydrolysis reaction are also abundant in normal tissue, it is of great interest whether a putative pro-drug is a probable substrate of such an enzyme and hence bears the danger of being activated not just in the target environment, i.e., in cancer cells. In this work, we study the binding mode of carboxylesters of the drug molecule camptothecin, which is an inhibitor of topoisomerase I, of varying size to human carboxylesterase 2 (HCE2) by molecular docking and molecular dynamics simulations. A comparison to irinotecan, known to be a substrate of HCE2, shows that all three pro-drugs analysed in this work can bind to the HCE2 protein, but not in a pose that is well suited for subsequent hydrolysis. Our data suggest, moreover, that for the irinotecan substrate, a reactant-competent pose is stabilised once the initial proton transfer from the putative nucleophile Ser202 to the His431 of the catalytic triad has already occurred. Our simulation work also shows that it is important to go beyond the static models obtained from molecular docking and include the flexibility of enzyme-ligand complexes in solvents and at a finite temperature. Under such conditions, the pro-drugs studied in this work are unlikely to be hydrolysed by the HCE2 enzyme, indicating a low risk of undesired drug release in normal tissue.
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Affiliation(s)
- Frank Beierlein
- Department for Chemistry and Pharmacy, Computer Chemistry Center, Friedrich-Alexander University Erlangen Nürnberg (FAU), Nägelsbachstraße 25, 91052 Erlangen, Germany;
- Erlangen National High Performance Computing Center (NHR@FAU), Friedrich-Alexander University Erlangen Nürnberg (FAU), Martensstraße 1, 91058 Erlangen, Germany;
| | - Anselm H. C. Horn
- Erlangen National High Performance Computing Center (NHR@FAU), Friedrich-Alexander University Erlangen Nürnberg (FAU), Martensstraße 1, 91058 Erlangen, Germany;
- Institute of Biochemistry, Friedrich-Alexander University Erlangen Nürnberg (FAU), Fahrstraße 17, 91054 Erlangen, Germany;
| | - Heinrich Sticht
- Institute of Biochemistry, Friedrich-Alexander University Erlangen Nürnberg (FAU), Fahrstraße 17, 91054 Erlangen, Germany;
| | - Andriy Mokhir
- Department for Chemistry and Pharmacy, Institute for Organic Chemistry, Friedrich-Alexander University Erlangen Nürnberg (FAU), Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany;
| | - Petra Imhof
- Department for Chemistry and Pharmacy, Computer Chemistry Center, Friedrich-Alexander University Erlangen Nürnberg (FAU), Nägelsbachstraße 25, 91052 Erlangen, Germany;
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Carboxylesterase-2 plays a critical role in dabigatran etexilate active metabolite formation. Drug Metab Pharmacokinet 2022; 47:100479. [DOI: 10.1016/j.dmpk.2022.100479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/13/2022] [Accepted: 10/11/2022] [Indexed: 11/22/2022]
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Liu J, Yao B, Gao L, Zhang Y, Huang S, Wang X. Emerging role of carboxylesterases in nonalcoholic fatty liver disease. Biochem Pharmacol 2022; 205:115250. [PMID: 36130649 DOI: 10.1016/j.bcp.2022.115250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/11/2022] [Accepted: 09/12/2022] [Indexed: 11/02/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a global public health problem. Carboxylesterases (CESs), as potential influencing factors of NAFLD, are very important to improve clinical outcomes. This review aims to deeply understand the role of CESs in the progression of NAFLD and proposes that CESs can be used as potential targets for NAFLD treatment. We first introduced CESs and analyzed the relationship between CESs and hepatic lipid metabolism and inflammation. Then, we further reviewed the regulation of nuclear receptors on CESs, including PXR, CAR, PPARα, HNF4α and FXR, which may influence the progression of NAFLD. Finally, we evaluated the advantages and disadvantages of existing NAFLD animal models and summarized the application of CES-related animal models in NAFLD research. In general, this review provides an overview of the relationship between CESs and NAFLD and discusses the role and potential value of CESs in the treatment and prevention of NAFLD.
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Affiliation(s)
- Jie Liu
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Bingyi Yao
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Liangcai Gao
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Yuanjin Zhang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Shengbo Huang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Xin Wang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China.
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Milano G, Innocenti F, Minami H. Liposomal irinotecan (Onivyde): Exemplifying the benefits of nanotherapeutic drugs. Cancer Sci 2022; 113:2224-2231. [PMID: 35445479 PMCID: PMC9277406 DOI: 10.1111/cas.15377] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 04/05/2022] [Accepted: 04/13/2022] [Indexed: 11/30/2022] Open
Abstract
Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first-line treatment in several countries. However, irinotecan has not been successfully introduced as a second-line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal-IRI) combined with 5-fluorouracil and leucovorin (5-FU/LV) was reported in the phase III NAPOLI-1 trial in metastatic PDAC following failure of gemcitabine-based therapy. Several features of nal-IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN-38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN-38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half-life and higher area under the concentration-time curve (0-∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal-IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small-cell lung cancer.
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Affiliation(s)
- Gérard Milano
- UPR 7497Scientific Valorisation UnitCentre Antoine Lacassagne and Côte d’Azur UniversityNiceFrance
| | | | - Hironobu Minami
- Medical Oncology and HematologyKobe University Graduate School of Medicine and HospitalKobeJapan
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6
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Popov AB, Melle F, Linnane E, González-López C, Ahmed I, Parshad B, Franck CO, Rahmoune H, Richards FM, Muñoz-Espín D, Jodrell DI, Fairen-Jimenez D, Fruk L. Size-tuneable and immunocompatible polymer nanocarriers for drug delivery in pancreatic cancer. NANOSCALE 2022; 14:6656-6669. [PMID: 35438701 PMCID: PMC9070568 DOI: 10.1039/d2nr00864e] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/28/2022] [Indexed: 06/14/2023]
Abstract
Nanocarriers have emerged as one of the most promising approaches for drug delivery. Although several nanomaterials have been approved for clinical use, the translation from lab to clinic remains challenging. However, by implementing rational design strategies and using relevant models for their validation, these challenges are being addressed. This work describes the design of novel immunocompatible polymer nanocarriers made of melanin-mimetic polydopamine and Pluronic F127 units. The nanocarrier preparation was conducted under mild conditions, using a highly reproducible method that was tuned to provide a range of particle sizes (<100 nm) without changing the composition of the carrier. A set of in vitro studies were conducted to provide a comprehensive assessment of the effect of carrier size (40, 60 and 100 nm) on immunocompatibility, viability and uptake into different pancreatic cancer cells varying in morphological and phenotypic characteristics. Pancreatic cancer is characterised by poor treatment efficacy and no improvement in patient survival in the last 40 years due to the complex biology of the solid tumour. High intra- and inter-tumoral heterogeneity and a dense tumour microenvironment limit diffusion and therapeutic response. The Pluronic-polydopamine nanocarriers were employed for the delivery of irinotecan active metabolite SN38, which is used in the treatment of pancreatic cancer. Increased antiproliferative effect was observed in all tested cell lines after administration of the drug encapsulated within the carrier, indicating the system's potential as a therapeutic agent for this hard-to-treat cancer.
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Affiliation(s)
- Andrea Bistrović Popov
- BioNano Engineering Lab, Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK.
| | - Francesca Melle
- The Adsorption & Advanced Materials Laboratory (A2ML), Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK
| | - Emily Linnane
- The Adsorption & Advanced Materials Laboratory (A2ML), Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK
| | - Cristina González-López
- BioNano Engineering Lab, Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK.
- CRUK Cambridge Centre Early Detection Program, Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge CB2 0RE, UK
| | - Ishtiaq Ahmed
- BioNano Engineering Lab, Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK.
| | - Badri Parshad
- BioNano Engineering Lab, Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK.
| | - Christoph O Franck
- BioNano Engineering Lab, Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK.
| | - Hassan Rahmoune
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK
| | - Frances M Richards
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK
- Translational Medicine, Oncology R&D, Astra Zeneca, Cambridge CB4 0WG, UK
| | - Daniel Muñoz-Espín
- CRUK Cambridge Centre Early Detection Program, Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge CB2 0RE, UK
| | - Duncan I Jodrell
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK
- Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
| | - David Fairen-Jimenez
- The Adsorption & Advanced Materials Laboratory (A2ML), Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK
| | - Ljiljana Fruk
- BioNano Engineering Lab, Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK.
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7
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Elkhanoufi S, Stefania R, Alberti D, Baroni S, Aime S, Geninatti Crich S. Highly Sensitive "Off/On" EPR Probes to Monitor Enzymatic Activity. Chemistry 2022; 28:e202104563. [PMID: 35175676 PMCID: PMC9314618 DOI: 10.1002/chem.202104563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Indexed: 11/16/2022]
Abstract
The assessment of unregulated level of enzyme activity is a crucial parameter for early diagnoses in a wide range of pathologies. In this study, we propose the use of electron paramagnetic resonance (EPR) as an easy method to probe carboxylesterase (CE) enzymatic activity in vitro. For this application, were synthesized two amphiphilic, nitroxide containing esters, namely Tempo-C12 (T-C12) and Tempo-2-C12 (T-2-C12). They exhibit low solubility in water and form stable micelles in which the radicals are EPR almost silent, but the hydrolysis of the ester bond yields narrows and intense EPR signals. The intensity of the EPR signals is proportional to the enzymatic activity. CEs1, CEs2 and esterase from porcine liver (PLE) were investigated. The obtained results show that T-C12 and T-2-C12-containing systems display a much higher selectivity toward the CEs2, with a Limit of Detection of the same order of those ones obtained with optical methods.
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Affiliation(s)
- Sabrina Elkhanoufi
- University of TorinoDepartment of Molecular Biotechnology and Health Sciencesvia Nizza 5210126TorinoItaly
| | - Rachele Stefania
- University of TorinoDepartment of Molecular Biotechnology and Health Sciencesvia Nizza 5210126TorinoItaly
| | - Diego Alberti
- University of TorinoDepartment of Molecular Biotechnology and Health Sciencesvia Nizza 5210126TorinoItaly
| | - Simona Baroni
- University of TorinoDepartment of Molecular Biotechnology and Health Sciencesvia Nizza 5210126TorinoItaly
| | - Silvio Aime
- University of TorinoDepartment of Molecular Biotechnology and Health Sciencesvia Nizza 5210126TorinoItaly
| | - Simonetta Geninatti Crich
- University of TorinoDepartment of Molecular Biotechnology and Health Sciencesvia Nizza 5210126TorinoItaly
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8
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Song YQ, He RJ, Pu D, Guan XQ, Shi JH, Li YG, Hou J, Jia SN, Qin WW, Fang SQ, Ge GB. Discovery and Characterization of the Biflavones From Ginkgo biloba as Highly Specific and Potent Inhibitors Against Human Carboxylesterase 2. Front Pharmacol 2021; 12:655659. [PMID: 34084136 PMCID: PMC8167799 DOI: 10.3389/fphar.2021.655659] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/08/2021] [Indexed: 11/13/2022] Open
Abstract
Human carboxylesterase 2 (CES2), one of the most abundant hydrolases distributed in the small intestine, has been validated as a key therapeutic target to ameliorate the intestinal toxicity caused by irinotecan. This study aims to discover efficacious CES2 inhibitors from natural products and to characterize the inhibition potentials and inhibitory mechanisms of the newly identified CES2 inhibitors. Following high-throughput screening and evaluation of the inhibition potency of more than 100 natural products against CES2, it was found that the biflavones isolated from Ginkgo biloba displayed extremely potent CES2 inhibition activities and high specificity over CES1 (>1000-fold). Further investigation showed that ginkgetin, bilobetin, sciadopitysin and isoginkgetin potently inhibited CES2-catalyzed hydrolysis of various substrates, including the CES2 substrate-drug irinotecan. Notably, the inhibition potentials of four biflavones against CES2 were more potent than that of loperamide, a marketed anti-diarrhea agent used for alleviating irinotecan-induced intestinal toxicity. Inhibition kinetic analyses demonstrated that ginkgetin, bilobetin, sciadopitysin and isoginkgetin potently inhibited CES2-catalyzed fluorescein diacetate hydrolysis via a reversible and mixed inhibition manner, with K i values of less than 100 nM. Ensemble docking and molecular dynamics revealed that these biflavones could tightly and stably bind on the catalytic cavity of CES2 via hydrogen bonding and π-π stacking interactions, while the interactions with CES1 were awfully poor. Collectively, this study reports that the biflavones isolated from Ginkgo biloba are potent and highly specific CES2 inhibitors, which offers several promising lead compounds for developing novel anti-diarrhea agent to alleviate irinotecan-induced diarrhea.
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Affiliation(s)
- Yun-Qing Song
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rong-Jing He
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dan Pu
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-Qing Guan
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jin-Hui Shi
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yao-Guang Li
- Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Jie Hou
- Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Shou-Ning Jia
- Qinghai Hospital of Traditional Chinese Medicine, Xining, China
| | - Wei-Wei Qin
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Pharmacy & Worldwide Medical Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Sheng-Quan Fang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang-Bo Ge
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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9
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Zhang XY, Liu TT, Liang JH, Tian XG, Zhang BJ, Huang HL, Ma XC, Feng L, Sun CP. A highly selective near infrared fluorescent probe for carboxylesterase 2 and its biological applications. J Mater Chem B 2021; 9:2457-2461. [PMID: 33630990 DOI: 10.1039/d0tb02673e] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Carboxylesterase 2 (CES 2) is a key enzyme in the activation of the prodrug irinotecan (CPT-11) in the treatment against colorectal cancer and also has some relationship with the side effect of CPT-11 in clinical applications. Herein, a near infrared (NIR) fluorescent probe (DSAB) has been designed for CES 2 which possesses the advantages of prominent selectivity and high sensitivity, and DSAB has been successfully applied for the imaging of endogenous CES 2 in living cells. Moreover, a high-throughput screening method for CES 2 inhibitors has been established using DSAB and discovered four novel CES 2 inhibitors from various herbal medicines. These results fully demonstrated that DSAB is a promising molecular tool for the investigation of the biological functions of CES 2 in living systems and the discovery of novel CES 2 inhibitors for the treatment of CES 2 related physiological diseases.
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Affiliation(s)
- Xin-Yue Zhang
- Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, People's Republic of China. and Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, College of Integrative Medicine, Dalian Medical University, Dalian, China.
| | - Tian-Tian Liu
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, College of Integrative Medicine, Dalian Medical University, Dalian, China.
| | - Jia-Hao Liang
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, College of Integrative Medicine, Dalian Medical University, Dalian, China.
| | - Xiang-Ge Tian
- Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, People's Republic of China. and Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, College of Integrative Medicine, Dalian Medical University, Dalian, China.
| | - Bao-Jing Zhang
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, College of Integrative Medicine, Dalian Medical University, Dalian, China.
| | - Hui-Lian Huang
- Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, People's Republic of China.
| | - Xiao-Chi Ma
- Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, People's Republic of China.
| | - Lei Feng
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, College of Integrative Medicine, Dalian Medical University, Dalian, China.
| | - Cheng-Peng Sun
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, College of Integrative Medicine, Dalian Medical University, Dalian, China.
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10
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Kailass K, Sadovski O, Capello M, Kang Y, Fleming JB, Hanash SM, Beharry AA. Measuring human carboxylesterase 2 activity in pancreatic cancer patient-derived xenografts using a ratiometric fluorescent chemosensor. Chem Sci 2019; 10:8428-8437. [PMID: 31803422 PMCID: PMC6844279 DOI: 10.1039/c9sc00283a] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 07/28/2019] [Indexed: 12/17/2022] Open
Abstract
Irinotecan-based therapy is a common treatment for pancreatic cancer. To elicit its anticancer activity, the drug requires first the hydrolysis action of the enzyme human carboxylesterase 2 (hCES2). It has been established that pancreatic cancer patients have various levels of hCES2, whereby patients having low levels respond poorer to Irinotecan than patients with higher levels, suggesting that hCES2 can be used to predict response. However, current methods that measure hCES2 activity are inaccurate, complex or lengthy, thus being incompatible for use in a clinical setting. Here, we developed a small molecule ratiometric fluorescent chemosensor that accurately measures hCES2 activity in a single-step within complex mixtures. Our chemosensor is highly selective for hCES2 over hCES1, cell permeable and can measure hCES2 activity in pancreatic cancer patient-derived xenografts. Given the simplicity, accuracy and tissue compatibility of our assay, we anticipate our chemosensor can be used to predict patient response to Irinotecan-based therapy.
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Affiliation(s)
- Karishma Kailass
- Department of Chemical and Physical Sciences , University of Toronto Mississauga , Mississauga , ON L5L 1C6 , Canada .
| | - Oleg Sadovski
- Department of Chemical and Physical Sciences , University of Toronto Mississauga , Mississauga , ON L5L 1C6 , Canada .
| | - Michela Capello
- Department of Clinical Cancer Prevention , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Ya'an Kang
- Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Jason B Fleming
- Department of Gastrointestinal Oncology , H. Lee Moffitt Cancer Center , Tampa , FL , USA
| | - Samir M Hanash
- Department of Clinical Cancer Prevention , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Andrew A Beharry
- Department of Chemical and Physical Sciences , University of Toronto Mississauga , Mississauga , ON L5L 1C6 , Canada .
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11
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Di L. The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics. Curr Drug Metab 2019; 20:91-102. [PMID: 30129408 PMCID: PMC6635651 DOI: 10.2174/1389200219666180821094502] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/03/2018] [Accepted: 08/08/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates and thioesters, as well as bioconverting prodrugs and soft drugs. The unique tissue distribution of CES enzymes provides great opportunities to design prodrugs or soft drugs for tissue targeting. Marked species differences in CES tissue distribution and catalytic activity are particularly challenging in human translation. METHODS Review and summarization of CES fundamentals and applications in drug discovery and development. RESULTS Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human intestine only expresses CES2. CES enzymes have moderate to high inter-individual variability and exhibit low to no expression in the fetus, but increase substantially during the first few months of life. The CES genes are highly polymorphic and some CES genetic variants show significant influence on metabolism and clinical outcome of certain drugs. Monkeys appear to be more predictive of human pharmacokinetics for CES substrates than other species. Low risk of clinical drug-drug interaction is anticipated for CES, although they should not be overlooked, particularly interaction with alcohols. CES enzymes are moderately inducible through a number of transcription factors and can be repressed by inflammatory cytokines. CONCLUSION Although significant advances have been made in our understanding of CESs, in vitro - in vivo extrapolation of clearance is still in its infancy and further exploration is needed. In vitro and in vivo tools are continuously being developed to characterize CES substrates and inhibitors.
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Affiliation(s)
- Li Di
- Pfizer Inc., Eastern Point Road, Groton, Connecticut, CT 06354, United States
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12
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Chen F, Zhang B, Parker RB, Laizure SC. Clinical implications of genetic variation in carboxylesterase drug metabolism. Expert Opin Drug Metab Toxicol 2018; 14:131-142. [DOI: 10.1080/17425255.2018.1420164] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Feng Chen
- Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Bo Zhang
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Robert B. Parker
- Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - S. Casey Laizure
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
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13
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Lee LSU, Seng KY, Wang LZ, Yong WP, Hee KH, Soh TI, Wong A, Cheong PF, Soong R, Sapari NS, Soo R, Fan L, Lee SC, Goh BC. Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI. PLoS One 2016; 11:e0147681. [PMID: 26808671 PMCID: PMC4726617 DOI: 10.1371/journal.pone.0147681] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 01/06/2016] [Indexed: 02/04/2023] Open
Abstract
Background Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods. Methods Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5. Results SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype. Conclusion Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy. Trial Registration Clinicaltrials.gov NCT00808184
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Affiliation(s)
- Lawrence Soon-U Lee
- Department of Medicine, National University Health System, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- * E-mail:
| | - Kok-Yong Seng
- Department of Pharmacology, National University of Singapore, Singapore, Singapore
| | - Ling-Zhi Wang
- Department of Pharmacology, National University of Singapore, Singapore, Singapore
- Cancer Science Institute, National University of Singapore, Singapore, Singapore
| | - Wei-Peng Yong
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
| | - Kim-Hor Hee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Thomas I. Soh
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
| | - Andrea Wong
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
| | - Pei F. Cheong
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
| | - Richie Soong
- Department of Pharmacology, National University of Singapore, Singapore, Singapore
| | - Nur S. Sapari
- Department of Pharmacology, National University of Singapore, Singapore, Singapore
| | - Ross Soo
- Department of Medicine, National University Health System, Singapore, Singapore
- Department of Pharmacology, National University of Singapore, Singapore, Singapore
| | - Lu Fan
- Cancer Science Institute, National University of Singapore, Singapore, Singapore
| | - Soo-Chin Lee
- Cancer Science Institute, National University of Singapore, Singapore, Singapore
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
| | - Boon C. Goh
- Department of Pharmacology, National University of Singapore, Singapore, Singapore
- Cancer Science Institute, National University of Singapore, Singapore, Singapore
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
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14
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Genetic polymorphisms in cytochrome P450 and clinical outcomes of FOLFIRI chemotherapy in patients with metastatic colorectal cancer. Tumour Biol 2015; 36:7691-8. [DOI: 10.1007/s13277-015-3492-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 04/23/2015] [Indexed: 12/18/2022] Open
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15
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Panczyk M. Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years. World J Gastroenterol 2014; 20:9775-827. [PMID: 25110414 PMCID: PMC4123365 DOI: 10.3748/wjg.v20.i29.9775] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 01/17/2014] [Accepted: 04/21/2014] [Indexed: 02/07/2023] Open
Abstract
During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation, as a result of large international research projects (Human Genome Project, the 1000 Genomes Project International HapMap Project, and Programs for Genomic Applications NHLBI-PGA). This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer. For clinical use in the treatment of patients with colorectal cancer (CRC), in addition to fluoropyrimidines, another two new cytostatic drugs were allowed: irinotecan and oxaliplatin. Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted. The last 20 years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance. One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells. Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine. Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics. Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential. This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy. The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.
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16
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Braun MS, Quirke P, Seymour MT. Molecular markers of chemotherapeutic response and toxicity in colorectal cancer. Expert Rev Anticancer Ther 2014; 7:489-501. [PMID: 17428170 DOI: 10.1586/14737140.7.4.489] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Outcomes in colorectal cancer have improved over the last 15 years; this is in part due to the optimization of 5-fluorouracil schedules and the introduction of new and effective chemotherapeutic agents, such as irinotecan and oxaliplatin. However, not all patients respond to these agents and a proportion may suffer severe side effects from particular chemotherapy drugs. These observations have resulted in a concerted research effort to identify markers of chemotherapy efficacy and toxicity. Here we review the evidence for using molecular markers to individualize chemotherapy treatment in colorectal cancer.
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17
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Iusuf D, Ludwig M, Elbatsh A, van Esch A, van de Steeg E, Wagenaar E, van der Valk M, Lin F, van Tellingen O, Schinkel AH. OATP1A/1B transporters affect irinotecan and SN-38 pharmacokinetics and carboxylesterase expression in knockout and humanized transgenic mice. Mol Cancer Ther 2013; 13:492-503. [PMID: 24194565 DOI: 10.1158/1535-7163.mct-13-0541] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Organic anion-transporting polypeptides (OATP) mediate the hepatic uptake of many drugs, thus codetermining their clearance. Impaired hepatic clearance due to low-activity polymorphisms in human OATP1B1 may increase systemic exposure to SN-38, the active and toxic metabolite of the anticancer prodrug irinotecan. We investigated the pharmacokinetics and toxicity of irinotecan and SN-38 in Oatp1a/1b-null mice: Plasma exposure of irinotecan and SN-38 was increased 2 to 3-fold after irinotecan dosing (10 mg/kg, i.v.) compared with wild-type mice. Also, liver-to-plasma ratios were significantly reduced, suggesting impaired hepatic uptake of both compounds. After 6 daily doses of irinotecan, Oatp1a/1b-null mice suffered from increased toxicity. However, Oatp1a/1b-null mice had increased levels of carboxylesterase (Ces) enzymes, which caused higher conversion of irinotecan to SN-38 in plasma, potentially complicating pharmacokinetic analyses. Ces inhibitors blocked this increased conversion. Interestingly, liver-specific humanized OATP1B1 and OATP1B3 transgenic mice had normalized hepatic expression of Ces1 genes. While irinotecan liver-to-plasma ratios in these humanized mice were similar to those in Oatp1a/1b-null mice, SN-38 liver-to-plasma ratios returned to wild-type levels, suggesting that human OATP1B proteins mediate SN-38, but not irinotecan uptake in vivo. Upon direct administration of SN-38 (1 mg/kg, i.v.), Oatp1a/1b-null mice had increased SN-38 plasma levels, lower liver concentrations, and decreased cumulative biliary excretion of SN-38. Mouse Oatp1a/1b transporters have a role in the plasma clearance of irinotecan and SN-38, whereas human OATP1B transporters may only affect SN-38 disposition. Oatp1a/1b-null mice have increased expression and activity of Ces1 enzymes, whereas humanized mice provide a rescue of this phenotype.
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Affiliation(s)
- Dilek Iusuf
- Corresponding Author: Alfred H. Schinkel, Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
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Paulík A, Grim J, Filip S. Predictors of irinotecan toxicity and efficacy in treatment of metastatic colorectal cancer. ACTA MEDICA (HRADEC KRÁLOVÉ) 2013; 55:153-9. [PMID: 23631285 DOI: 10.14712/18059694.2015.39] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The colorectal cancer ranks high among the malignant tumours in incidence and mortality and irinotecan is standardly used in palliative treatment of metastatic disease in every therapeutic line. Unfortunately, the treatment with irinotecan is often associated with severe toxicities, especially neutropenia and diarrhea. The majority of the toxic manifestation is caused by the insufficient deactivation (glucuronidation) of irinotecan active metabolite SN-38 by UGT1A enzyme. The elevated SN-38 plasma concentration is responsible for the hematological and gastrointestinal toxicity that can become life-threatening. The patients carrying the mutation of the gene encoding UGT1A enzyme lack the ability of bilirubin glucuronidation, and suffer from the inherited un-conjugated hyperbilirubinemia (Gilbert syndrome, Crigler-Najjar type 1 and 2 syndrome). The mutations in other enzyme systems also play role in the etiopathogenesis of the irinotecan toxicity: CYP3A (cytochrome P-450), ABC family of transmembrane transporters (adenosine-triphosphate binding cassette). The goal of the contemporary research is to determine the predictive factors that will enable the individual adjustment of the individual drug dosage while minimising the adverse effects and maintaining the treatment benefit.
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Affiliation(s)
- Adam Paulík
- Department of Oncology and Radiotherapy, Charles University in Prague, Faculty of Medicine and University Hospital Hradec Králové, Czech Republic.
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19
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Cai X, Cao W, Ding H, Liu T, Zhou X, Wang M, Zhong M, Zhao Z, Xu Q, Wang L. Analysis of UGT1A1*28 genotype and SN-38 pharmacokinetics for irinotecan-based chemotherapy in patients with advanced colorectal cancer: results from a multicenter, retrospective study in Shanghai. J Cancer Res Clin Oncol 2013; 139:1579-89. [PMID: 23892411 PMCID: PMC3742415 DOI: 10.1007/s00432-013-1480-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Accepted: 07/16/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai. METHODS One hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine-adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)6/(TA)6 and (TA)6/(TA)7 genotypes were analyzed statistically. RESULTS One hundred and fourteen patients (69.51 %) were identified with the (TA)6/(TA)6 genotype, forty-eight patients (29.27 %) with the (TA)6/(TA)7 genotype, and two patients (1.22 %) with the (TA)7/(TA)7 genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)6/(TA)7 genotype group were all higher than those in (TA)6/(TA)6 group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)6/(TA)6 genotype. In the (TA)6/(TA)7 group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)6/(TA)6 genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ (2) = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)6/(TA)7 genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ (2) = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)7/(TA)7 cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction. CONCLUSION The (TA)6/(TA)6 genotype and (TA)6/(TA)7 genotype accounted for the most, and (TA)7/(TA)7 genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)6/(TA)6 genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)6/(TA)7 genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)7/(TA)7 genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.
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Affiliation(s)
- Xun Cai
- Department of Oncology, Shanghai First People’s Hospital, Shanghai Jiaotong University, 100 Haining Road, Hongkou District, Shanghai, 200080 People’s Republic of China
| | - Weiguo Cao
- Department of Oncology, Ruijin Hospital, Medical School, Shanghai Jiaotong University, Shanghai, 200025 People’s Republic of China
| | - Honghua Ding
- Department of Oncology, Shanghai First People’s Hospital, Shanghai Jiaotong University, 100 Haining Road, Hongkou District, Shanghai, 200080 People’s Republic of China
| | - Tianshu Liu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032 People’s Republic of China
| | - Xinli Zhou
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai, 200040 People’s Republic of China
| | - Mei Wang
- Department of Oncology, Changhai Hospital, Second Military University, Shanghai, 200433 People’s Republic of China
| | - Ming Zhong
- Department of General Surgery, Renji Hospital, Medical School, Shanghai Jiaotong University, Shanghai, 200127 People’s Republic of China
| | - Ziyi Zhao
- Department of General Surgery, Central Hospital in Jing’an District, Shanghai, 200040 People’s Republic of China
| | - Qing Xu
- Department of Oncology, Shanghai Tenth People’s Hospital, Shanghai Tongji University, Shanghai, 200072 People’s Republic of China
| | - Liwei Wang
- Department of Oncology, Shanghai First People’s Hospital, Shanghai Jiaotong University, 100 Haining Road, Hongkou District, Shanghai, 200080 People’s Republic of China
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Silvestri A, Pin E, Huijbers A, Pellicani R, Parasido EM, Pierobon M, Petricoin E, Liotta L, Belluco C. Individualized therapy for metastatic colorectal cancer. J Intern Med 2013; 274:1-24. [PMID: 23527888 DOI: 10.1111/joim.12070] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Systemic therapeutic efficacy is central to determining the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive biomarkers to optimize efficacy whilst minimizing toxicity. The integration of a new generation of molecularly targeted drugs into the treatment of CRC, coupled with the development of sophisticated technologies for individual tumours as well as patient molecular profiling, underlines the potential for personalized medicine. In this review, we focus on the latest progress made within the genomic and proteomic fields, concerning predictive biomarkers for individualized therapy in metastatic CRC.
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Affiliation(s)
- A Silvestri
- Division of Experimental Oncology 2, CRO-IRCCS, National Cancer Institute, Aviano, Italy
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Schentag JJ, Hill G, Chu T, Rayner CR. Similarity in Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in Japanese and Caucasian Subjects. J Clin Pharmacol 2013; 47:689-96. [PMID: 17456583 DOI: 10.1177/0091270007299761] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The pharmacokinetics of oseltamivir and oseltamivir carboxylate in healthy Japanese (n = 14) and Caucasian (n = 14) males were compared. Subjects in each ethnic group were randomized to twice-daily oral oseltamivir 75 mg, 150 mg, or placebo for 13 doses. Oseltamivir was well tolerated across doses and ethnic groups. Oseltamivir was rapidly absorbed and hydrolyzed to oseltamivir carboxylate in all subjects. The mean plasma concentration-time profiles for oseltamivir and oseltamivir carboxylate were similar in Japanese and Caucasian subjects. At steady state, there was no evidence of any ethnic difference in the individual AUC(0-12) values for oseltamivir or oseltamivir carboxylate. Despite a significant difference in group mean body weight (approximately 20 kg) between the Japanese and Caucasian subjects, there was no evidence that dose-adjusted AUC(0-12) and C(max) for oseltamivir carboxylate were affected by body weight or ethnicity. Day 7 trough concentrations (C(min)) for oseltamivir carboxylate markedly exceeded the IC(50) (50% inhibitory concentration) against influenza A and B isolates. In conclusion, the results of this study support the use of the same dose regimens of oseltamivir in both Caucasian and Japanese subjects because of similarity in pharmacokinetics.
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Affiliation(s)
- Jerome J Schentag
- University at Buffalo School of Pharmacy, 517 Hochstetter Hall, Buffalo, NY 14260, USA.
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Solier S, Zhang YW, Ballestrero A, Pommier Y, Zoppoli G. DNA damage response pathways and cell cycle checkpoints in colorectal cancer: current concepts and future perspectives for targeted treatment. Curr Cancer Drug Targets 2012; 12:356-71. [PMID: 22385513 DOI: 10.2174/156800912800190901] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 07/05/2011] [Accepted: 12/22/2011] [Indexed: 01/28/2023]
Abstract
Although several drugs have been designed in the last few years to target specific key pathways and functions in colorectal cancer (CRC), the backbone of CRC treatment is still made up of compounds which rely on DNA damage to accomplish their role. DNA damage response (DDR) and checkpoint pathways are intertwined signaling networks that arrest cell cycle, recognize and repair genetic mistakes which arise during DNA replication and transcription, as well as through the exposure to chemical and physical agents that interact with nucleic acids. The good but highly variable activity of DNA damaging agents in the treatment of CRC suggests that intrinsic alterations in DDR pathways and cell cycle checkpoints may contribute differentially to the way cancer cells react to DNA damage. In the present review, our aim is to depict the recent advances in understanding the molecular basis of the activity of DNA damaging agents used for the treatment of CRC. We focus on the known and potential drug targets that are part of these complex and intertwined pathways. We describe the potential role of the checkpoints in CRC, and how their pharmacological manipulation could lead to chemopotentiation or synergism with currently used drugs. Novel therapeutic agents playing a role in DDR and checkpoint inhibition are assessed. We discuss the possible rationale for combining PARP inhibition with DNA damaging agents, and we address the link between DDR and EGFR pathways in CRC.
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Affiliation(s)
- S Solier
- Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda (MD), USA
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Bai JPF, Pacanowski M, Rahman A, Lesko LL. The Impact of Pharmacogenetics on the Clinical Outcomes of Prodrugs. PRODRUGS AND TARGETED DELIVERY 2011. [DOI: 10.1002/9783527633166.ch16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Bellanti F, Kågedal B, Della Pasqua O. Do pharmacokinetic polymorphisms explain treatment failure in high-risk patients with neuroblastoma? Eur J Clin Pharmacol 2011; 67 Suppl 1:87-107. [PMID: 21287160 PMCID: PMC3112027 DOI: 10.1007/s00228-010-0966-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2010] [Accepted: 11/27/2010] [Indexed: 12/30/2022]
Abstract
PURPOSE Neuroblastoma is the most common extracranial solid tumour in childhood. It accounts for 15% of all paediatric oncology deaths. In the last few decades, improvement in treatment outcome for high-risk patients has not occurred, with an overall survival rate <30-40%. Many reasons may account for such a low survival rate. The aim of this review is to evaluate whether pharmacogenetic factors can explain treatment failure in neuroblastoma. METHODS A literature search based on PubMed's database Medical Subject Headings (MeSH) was performed to retrieve all pertinent publications on current treatment options and new classes of drugs under investigation. One hundred and fifty-eight articles wer reviewed, and relevant data were extracted and summarised. RESULTS AND CONCLUSIONS Few of the large number of polymorphisms identified thus far showed an effect on pharmacokinetics that could be considered clinically relevant. Despite their clinical relevance, none of the single nucleotide polymorphisms (SNPs) investigated can explain treatment failure. These findings seem to reflect the clinical context in which anti-tumour drugs are used, i.e. in combination with multimodal therapy. In addition, many pharmacogenetic studies did not assess (differences in) drug exposure, which could contribute to explaining pharmacogenetic associations. Furthermore, it remains unclear whether the significant activity of new drugs on different neuroblastoma cell lines translates into clinical efficacy, irrespective of resistance or myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) amplification. Elucidation of the clinical role of pharmacogenetic factors in the treatment of neuroblastoma demands an integrated pharmacokinetic-pharmacodynamic approach to the analysis of treatment response data.
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Affiliation(s)
- Francesco Bellanti
- Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands
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Lipopolysaccharide down-regulates carbolesterases 1 and 2 and reduces hydrolysis activity in vitro and in vivo via p38MAPK-NF-κB pathway. Toxicol Lett 2011; 201:213-20. [PMID: 21237253 DOI: 10.1016/j.toxlet.2011.01.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Revised: 12/24/2010] [Accepted: 01/06/2011] [Indexed: 12/31/2022]
Abstract
Carboxylesterases constitute a class of enzymes that hydrolyze drugs containing such functional groups as carboxylic acid ester, amide, and thioester. Hydrolysis of many drugs is reduced in liver diseases such as hepatitis and cirrhosis. In this study, we have demonstrated, in vitro and in vivo, treatment with LPS decreased the expression of HCE1 and HCE2 and the capacity of hydrolytic activity. In HepG2 cells, the decreased expression by LPS occurred at both mRNA and protein levels. Both HCE1 and HCE2 promoters were significantly repressed by LPS, and the repression was comparable with the decrease in HCE1 and HCE2 mRNA, suggesting the transrepression is responsible for suppressed expression. Further study showed that both PDTC, a NF-κB inhibitor, and SB203580, a p38MAPK inhibitor, could abolish the repression of HCE1 and HCE2 mediated by LPS, but U0126, a selective ERK1/2 inhibitor, could not do so, suggesting the repression of HCE1 and HCE2 by LPS through the p38MAPK-NF-κB pathway. In addition, being pretreated with LPS, HepG2 cells altered the cellular responsiveness to ester therapeutic agents, including clopidogrel (hydrolyzed by HCE1) and irinotecan (hydrolyzed by HCE2). The altered cellular responsiveness occurred at low micromolar concentrations, suggesting that suppressed expression of carboxylesterases by LPS has profound pharmacological and toxicological consequences, particularly with those that are hydrolyzed in an isoform-specific manner. This study provides new insight into the understanding of the pharmacological and toxicological effects and the mechanisms for repressing drug metabolism enzymes in inflammation.
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Abstract
Irinotecan is a camptothecin analog used as an anticancer drug. Severe, potentially life-threatening toxicities can occur from irinotecan treatment. Although multiple genes may play a role in irinotecan activity, the majority of evidence to date suggests that variation in expression of UGT1A1 caused by a common promoter polymorphism (UGT1A1*28) is strongly associated with toxicity; however, this link is dose dependent. Variations in other pharmacokinetic genes, particularly the transporter ABCC2, also contribute to irinotecan toxicity. In addition, recent studies have shown that pharmacodynamic genes such as TDP1 and XRCC1 can also play a role in both toxicity and response.
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Affiliation(s)
- Sharon Marsh
- UNC Institute for Pharmacogenomics & Individualized Therapy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
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Sai K, Saito Y, Tatewaki N, Hosokawa M, Kaniwa N, Nishimaki-Mogami T, Naito M, Sawada JI, Shirao K, Hamaguchi T, Yamamoto N, Kunitoh H, Tamura T, Yamada Y, Ohe Y, Yoshida T, Minami H, Ohtsu A, Matsumura Y, Saijo N, Okuda H. Association of carboxylesterase 1A genotypes with irinotecan pharmacokinetics in Japanese cancer patients. Br J Clin Pharmacol 2011; 70:222-33. [PMID: 20653675 DOI: 10.1111/j.1365-2125.2010.03695.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Association of UDP-glucuronosyltransferase 1A1 (UGT1A1) genetic polymorphisms *6 and *28 with reduced clearance of SN-38 and severe neutropenia in irinotecan therapy was demonstrated in Japanese cancer patients. * The detailed gene structure of CES1 has been characterized. * Possible functional SNPs in the promoter region have been reported. WHAT THIS STUDY ADDS * Association of functional CES1 gene number with AUC ratio [(SN-38 + SN-38G)/irinotecan], an in vivo index of CES activity, was observed in patients with irinotecan monotherapy. * No significant effects of major CES1 SNPs on irinotecan PK were detected. AIMS Human carboxylesterase 1 (CES1) hydrolyzes irinotecan to produce an active metabolite SN-38 in the liver. The human CES1 gene family consists of two functional genes, CES1A1 (1A1) and CES1A2 (1A2), which are located tail-to-tail on chromosome 16q13-q22.1 (CES1A2-1A1). The pseudogene CES1A3 (1A3) and a chimeric CES1A1 variant (var1A1) are also found as polymorphic isoforms of 1A2 and 1A1, respectively. In this study, roles of CES1 genotypes and major SNPs in irinotecan pharmacokinetics were investigated in Japanese cancer patients. METHODS CES1A diplotypes [combinations of haplotypes A (1A3-1A1), B (1A2-1A1), C (1A3-var1A1) and D (1A2-var1A1)] and the major SNPs (-75T>G and -30G>A in 1A1, and -816A>C in 1A2 and 1A3) were determined in 177 Japanese cancer patients. Associations of CES1 genotypes, number of functional CES1 genes (1A1, 1A2 and var1A1) and major SNPs, with the AUC ratio of (SN-38 + SN-38G)/irinotecan, a parameter of in vivo CES activity, were analyzed for 58 patients treated with irinotecan monotherapy. RESULTS The median AUC ratio of patients having three or four functional CES1 genes (diplotypes A/B, A/D or B/C, C/D, B/B and B/D; n= 35) was 1.24-fold of that in patients with two functional CES1 genes (diplotypes A/A, A/C and C/C; n= 23) [median (25th-75th percentiles): 0.31 (0.25-0.38) vs. 0.25 (0.20-0.32), P= 0.0134]. No significant effects of var1A1 and the major SNPs examined were observed. CONCLUSION This study suggests a gene-dose effect of functional CES1A genes on SN-38 formation in irinotecan-treated Japanese cancer patients.
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Affiliation(s)
- Kimie Sai
- Division of Functional Biochemistry and Genomics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
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[Recent developments of pharmacogenomics in the treatment of colorectal cancers]. ANNALES PHARMACEUTIQUES FRANÇAISES 2010; 68:233-53. [PMID: 20637356 DOI: 10.1016/j.pharma.2010.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2010] [Revised: 04/16/2010] [Accepted: 04/16/2010] [Indexed: 12/27/2022]
Abstract
Colorectal cancer (CCR), which is one of the most common causes of cancer, has benefited from the major advances in the understanding of the intracellular signaling pathways implicated in the initiation, growing and local and metastasis dissemination of tumor, which have occurred during the 20 past years. The pharmacogenomics approach, especially the determination of the genetic polymorphisms, tries to find prognosis and predictive biomarkers permitting to identify patients who could benefit from a particular treatment or those exhibiting higher risks of toxicity. Among the numerous biomarkers, which have been studied, few are currently in use in clinical practice. The phenotyping of DPD and UGT1A1 activities, and to a lesser extent, its genotyping, appears as the most useful tool in terms of prediction of toxicities induced by two major drugs: 5-FU and irinotecan. For oxaliplatin, the determination of the polymorphisms of reparases and detoxification systems such as GSTpi seems interesting, but its exact place should be more defined. It is in the field of targeted therapies that the pharmacogenomics approach seems to be the more relevant. KRAS mutation is a dramatic example of single nucleotide polymorphism, which is able to identify a priori patients that could receive or not an anti-EGFR monoclonal antibody such as cetuximab or panitumumab. It is obvious that pre-clinical identification of molecular biomarkers predictive of the sensitivity of the drug targets, which subsequently implicate the selection of patients and the rational evaluation of responses, will be the cornerstone of any clinical trials concerning targeted therapies. Besides the determination of drug target polymorphisms, it is also important to consider those related to the distribution and metabolism. In this area, the determination of enzymatic activities should recover its place besides the genomic profiling.
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Ahowesso C, Piccolo E, Li XM, Dulong S, Hossard V, La Sorda R, Filipski E, Tinari N, Delaunay F, Iacobelli S, Lévi F. Relations between strain and gender dependencies of irinotecan toxicity and UGT1A1, CES2 and TOP1 expressions in mice. Toxicol Lett 2009; 192:395-401. [PMID: 19931604 DOI: 10.1016/j.toxlet.2009.11.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2009] [Revised: 10/31/2009] [Accepted: 11/15/2009] [Indexed: 10/20/2022]
Abstract
Irinotecan hydrochloride (CPT-11) can display severe toxicities in individual cancer patients. CPT-11 is bio-activated through CES, detoxified through UGT1A1 and inhibits TOP1. CPT-11 toxicity and UGT1A1, CES2 and TOP1 mRNAs and UGT1A1 protein were determined in male and female C57BL/6, B6D2F1 and B6CBAF1, as potential models for tailoring CPT-11 delivery. CPT-11 was administered intravenously (40-90 mg/kg/day for 4 days at 7h after light onset). The relations between dose and lethal toxicity or body weight loss were steep and similar in C57BL/6 (lethality, p=0.001; weight loss, p=0.002) and B6D2F1 (p=0.01; p=0.03, respectively), but weak in B6CBAF1. Females displayed less toxicity than males (p<0.001). Mean mRNA expression of UGT1A1 was highest in B6CBAF1 (p=0.039) and in females (p<0.001). Both CES2 and TOP1 varied according to strain and gender (p<0.001). The three gene expression data explained the most severe toxicity of CPT-11 in male B6D2F1, but displayed inconsistent relations with toxicity in the other groups. Mean UGT1A1 protein expression was highest in males as compared to females, and so by approximately 8-fold in C57BL/6 as compared to B6D2F1 (p<0.0001). Genetic background and gender significantly altered the molecular prediction of irinotecan toxicity by UGT1A1, CES2 and TOP1 mRNA expressions.
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Affiliation(s)
- C Ahowesso
- INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France
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Ellsworth P. Fesoterodine for the treatment of urinary incontinence and overactive bladder. Ther Clin Risk Manag 2009; 5:869-76. [PMID: 19956551 PMCID: PMC2781061 DOI: 10.2147/tcrm.s6483] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Indexed: 12/05/2022] Open
Abstract
Overactive bladder (OAB) is a highly prevalent condition, affecting males and females. The prevalence increases with age. Behavioral therapy and antimuscarinic therapy remain the first-line therapies for management of OAB. Despite improvements in symptoms, persistence with antimuscarinic therapy has remained low. Multiple factors including patient expectations, adverse effects and cost may affect persistence. Fesoterodine is one of the newest antimuscarinic agent approved for the management of OAB. It is unique in that it shares the same active metabolite as tolterodine, 5-hydoxymethyltolterodine (5-HMT); however, this conversion is established via ubiquitous esterases and not via the cytochrome P450 system, thus providing a faster and more efficient conversion to 5-HMT. Fesoterodine is available in 2 doses, 4 mg and 8 mg. Clinical trials have established a dose response relationship in efficacy parameters as well as improvements in quality of life. As with all antimuscarinics, dry mouth and constipation are the more common side effects. A combination of medical therapy and behavioral therapy improves the overall outcome in management of OAB. Dose flexibility may help improve efficacy outcomes and patient education on the management of common adverse effects may improve tolerability with these agents.
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Affiliation(s)
- Pamela Ellsworth
- The Alpert School of Medicine at Brown University Providence, RI, USA
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Nonclinical pharmacokinetics of oseltamivir and oseltamivir carboxylate in the central nervous system. Antimicrob Agents Chemother 2009; 53:4753-61. [PMID: 19721074 DOI: 10.1128/aac.01541-08] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking oseltamivir, and as part of a full assessment to determine whether oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of oseltamivir and oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of oseltamivir and oseltamivir carboxylate and oral doses of oseltamivir, (ii) the active transport of oseltamivir and oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of oseltamivir to oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of oseltamivir and especially oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for oseltamivir and 0.01 for oseltamivir carboxylate. Apart from oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for oseltamivir and oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.
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UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients. Int J Clin Oncol 2009; 14:136-42. [PMID: 19390945 DOI: 10.1007/s10147-008-0821-z] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2008] [Accepted: 07/08/2008] [Indexed: 12/25/2022]
Abstract
BACKGROUND Gene polymorphisms of the UDP-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) contribute to individual variations in adverse events among patients administered irinotecan, and the distribution of the polymorphisms shows large interethnic differences. Variation in the solute carrier organic anion-transporter family, member 1B1 (SLCO1B1) gene also has a significant effect on the disposition of irinotecan in Asian cancer patients. In the present study, we evaluated the association of genetic polymorphisms of UGT1A1 and SLCO1B1 with irinotecanrelated neutropenia in Japanese cancer patients. METHODS One hundred and thirty-five consecutive patients treated with irinotecan were enrolled. Genotypes of UGT1A1 (*60, *28, *6, and *27) and SLCO1B1 (*1b, *5, and haplotype *15) were determined by direct sequencing. Severe neutropenia refers to events observed during the first cycle of irinotecan treatment. RESULTS Severe neutropenia was observed in 29 patients (22%). Six patients were homozygous and 48 heterozygous for UGT1A1*6. Only 1 patient was homozygous for UGT1A1*28. Homozygosity for UGT1A1*6 was associated with a high risk of severe neutropenia (odds ratio [OR], 7.78; 95% confidence interval [CI], 1.36 to 44.51). No significant association was found between severe neutropenia and other UGT1A1 polymorphisms or SLCO1B1 polymorphisms. CONCLUSION These findings suggest that the UGT1A1*6 polymorphism is a potential predictor of severe neutropenia caused by irinotecan in Japanese cancer patients.
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Evaluation of drug–drug interactions with fesoterodine. Eur J Clin Pharmacol 2009; 65:551-60. [DOI: 10.1007/s00228-009-0648-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2008] [Accepted: 03/18/2009] [Indexed: 01/26/2023]
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Smith JR, Sacks S. Incidence of neuropsychiatric adverse events in influenza patients treated with oseltamivir or no antiviral treatment. Int J Clin Pract 2009; 63:596-605. [PMID: 19335705 DOI: 10.1111/j.1742-1241.2009.02010.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
AIMS The association between neuropsychiatric events and antiviral treatments for influenza has been under scrutiny. In this study, the incidence of neuropsychiatric events in influenza patients dispensed oseltamivir or no antiviral was assessed using a large US medical claims database. METHODS Propensity score balanced cohorts from a prior study of influenza patients with and without oseltamivir exposure were expanded and reanalysed in this retrospective study. Patients > or = 1 year with an influenza diagnosis [International Classification of Disease, 9th revision (ICD-9) 487.XX] during the study period (1 November 1999 to 30 April 2005) were identified and grouped into two cohorts: those dispensed oseltamivir [n = 60,267, 60,834 incident cases (ICs)] and those dispensed no-antiviral (n = 175,933, 183,786 ICs). Cohorts were stratified by age: < or = 17 years (oseltamivir, n = 20,501 ICs; no-antiviral, n = 84,871 ICs) and > or = 18 years (oseltamivir, n = 40,333 ICs; no-antiviral, n = 98,915 ICs). Medical claims in the 30 days (overall analysis) or 14 days (stratified analysis) after diagnosis were searched for indications of neuropsychiatric events. Claims-based outcome measures included three hierarchical neuropsychiatric categories: one broad, one restrictive (excluding particular disorders/conditions) and one limited to central nervous system (CNS)-specific disorders. RESULTS In the overall analysis, no increase in the incidence of claims-based neuropsychiatric events was detected in the patients dispensed oseltamivir vs. those dispensed no antiviral. Claims-based neuropsychiatric events were also reported with a similar frequency in patients < or = 17 years and > or = 18 years who did and did not receive antivirals. CONCLUSION In this retrospective cohort study, no increase in claims-based neuropsychiatric events was detected in influenza patients who were and were not exposed to oseltamivir.
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Affiliation(s)
- J R Smith
- F. Hoffmann-La Roche Ltd, Basel, Switzerland.
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35
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Fujiyama N, Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Habuchi T, Suzuki T. Influence of carboxylesterase 2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Xenobiotica 2009; 39:407-14. [DOI: 10.1080/00498250902807338] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Toovey S, Rayner C, Prinssen E, Chu T, Donner B, Thakrar B, Dutkowski R, Hoffmann G, Breidenbach A, Lindemann L, Carey E, Boak L, Gieschke R, Sacks S, Solsky J, Small I, Reddy D. Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf 2009; 31:1097-114. [PMID: 19026027 DOI: 10.2165/0002018-200831120-00006] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking oseltamivir phosphate (hereafter referred to as oseltamivir [Tamiflu; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004--5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company's own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received oseltamivir compared with those who have not; (ii) what levels of oseltamivir and its active metabolite, oseltamivir carboxylate are achieved in the CNS; (iii) whether oseltamivir and oseltamivir carboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of oseltamivir and/or oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS. In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1,000,000 prescriptions) in children (aged < or =16 years) and adults, respectively, were 99 and 28 events in Japan and 19 and 8 in the US. NPAEs were more commonly reported in children (2218 events in 1808 children aged < or =16 years vs 833 in 658 adults) and generally occurred within 48 hours of the onset of influenza illness and initiation of treatment. After categorizing the reported events according to International Classification of Diseases (9th edition) codes, abnormal behaviour (1160 events, 38.0%) and delusions/perceptual disturbances (661 events, 21.7%) were the largest categories of events, and delirium or delirium-like events (as defined by the American Psychiatric Association) were very common in most categories. No difference in NPAE reporting rates between oseltamivir and placebo was found in phase III treatment studies (0.5% vs 0.6%). Analyses of US healthcare claims databases showed the risk of NPAEs in oseltamivir-treated patients (n = 159,386) was no higher than those not receiving antivirals (n = 159,386). Analysis of medical records in the UK General Practice Research Database showed that the adjusted relative risk of NPAEs in influenza patients was significantly higher (1.75-fold) than in the general population. Based on literature reports, NPAEs in Japanese and Taiwanese children with influenza have occurred before the initiation of oseltamivir treatment; events were also similar to those occurring after the initiation of oseltamivir therapy. No clinically relevant differences in plasma pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate were noted between Japanese and Caucasian adults or children. Penetration into the CNS of both oseltamivir and oseltamivir carboxylate was low in Japanese and Caucasian adults (cerebrospinal fluid/plasma maximum concentration and area under the plasma concentration-time curve ratios of approximately 0.03), and the capacity for converting oseltamivir to oseltamivir carboxylate in rat and human brains was low. In animal autoradiography and pharmacokinetic studies, brain : plasma radioactivity ratios were generally 20% or lower. Animal studies showed no specific CNS/behavioural effects after administration of doses corresponding to > or =100 times the clinical dose. Oseltamivir or oseltamivir carboxylate did not interact with human neuraminidases or with 155 known molecular targets in radioligand binding and functional assays. A review of the information published to date on functional variations of genes relevant to oseltamivir pharmacokinetics and pharmacodynamics and simulated gene knock-out scenarios did not identify any plausible genetic explanations for the observed NPAEs. The available data do not suggest that the incidence of NPAEs in influenza patients receiving oseltamivir is higher than in those who do not, and no mechanism by which oseltamivir or oseltamivir carboxylate could cause or worsen such events could be identified.
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Rouits E, Charasson V, Pétain A, Boisdron-Celle M, Delord JP, Fonck M, Laurand A, Poirier AL, Morel A, Chatelut E, Robert J, Gamelin E. Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients. Br J Cancer 2008; 99:1239-45. [PMID: 18797458 PMCID: PMC2570505 DOI: 10.1038/sj.bjc.6604673] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
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 6β-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 6β-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 6β-hydroxylation determination could help to determine the optimal dose of irinotecan.
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Affiliation(s)
- E Rouits
- Laboratoire d'Oncopharmacologie, Centre Paul-Papin, 2 rue Moll, Angers 49000, France
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Bandrés E, Zárate R, Ramirez N, Abajo A, Bitarte N, García-Foncillas J. Pharmacogenomics in colorectal cancer: The first step for individualized-therapy. World J Gastroenterol 2007; 13:5888-901. [PMID: 17990354 PMCID: PMC4205435 DOI: 10.3748/wjg.v13.i44.5888] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Interindividual differences in the toxicity and response to anticancer therapies are currently observed in practically all available treatment regimens. A goal of cancer therapy is to predict patient response and toxicity to drugs in order to facilitate the individualization of patient treatment. Identification of subgroups of patients that differ in their prognosis and response to treatment could help to identify the best available drug therapy according the genetic profile. Several mechanisms have been suggested to contribute to chemo-therapeutic drug resistance: amplification or overexpression of membrane transporters, changes in cellular proteins involved in detoxification or in DNA repair, apoptosis and activation of oncogenes or tumor suppressor genes. Colorectal cancer (CRC) is regarded as intrinsically resistant to chemotherapy. Several molecular markers predictive of CRC therapy have been included during the last decade but their results in different studies complicate their application in practical clinical. The simultaneous testing of multiple markers predictive of response could help to identify more accurately the true role of these polymorphisms in CRC therapy. This review analyzes the role of genetic variants in genes involved in the action mechanisms of the drugs used at present in colorectal cancer.
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Kim SR, Sai K, Tanaka-Kagawa T, Jinno H, Ozawa S, Kaniwa N, Saito Y, Akasawa A, Matsumoto K, Saito H, Kamatani N, Shirao K, Yamamoto N, Yoshida T, Minami H, Ohtsu A, Saijo N, Sawada JI. Haplotypes and a novel defective allele of CES2 found in a Japanese population. Drug Metab Dispos 2007; 35:1865-72. [PMID: 17640957 DOI: 10.1124/dmd.107.015339] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Human carboxylesterase 2 (hCE-2) is a member of the serine esterase superfamily and is responsible for hydrolysis of a wide variety of xenobiotic and endogenous esters. hCE-2 also activates an anticancer drug, irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin, CPT-11), into its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). In this study, a comprehensive haplotype analysis of the CES2 gene, which encodes hCE-2, in a Japanese population was conducted. Using 21 single nucleotide polymorphisms (SNPs), including 4 nonsynonymous SNPs, 100C>T (Arg(34)Trp, *2), 424G>A (Val(142)Met, *3), 1A>T (Met(1)Leu, *5), and 617G>A (Arg(206)His, *6), and a SNP at the splice acceptor site of intron 8 (IVS8-2A>G, *4), 20 haplotypes were identified in 262 Japanese subjects. In 176 Japanese cancer patients who received irinotecan, associations of CES2 haplotypes and changes in a pharmacokinetic parameter, (SN-38 + SN-38G)/CPT-11 area under the plasma concentration curve (AUC) ratio, were analyzed. No significant association was found among the major haplotypes of the *1 group lacking nonsynonymous or defective SNPs. However, patients with nonsynonymous SNPs, 100C>T (Arg(34)Trp) or 1A>T (Met(1)Leu), showed substantially reduced AUC ratios. In vitro functional characterization of the SNPs was conducted and showed that the 1A>T SNP affected translational but not transcriptional efficiency. These findings are useful for further pharmacogenetic studies on CES2-activated prodrugs.
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Affiliation(s)
- Su-Ryang Kim
- Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.
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Schiel MA, Green SL, Davis WI, Sanghani PC, Bosron WF, Sanghani SP. Expression and characterization of a human carboxylesterase 2 splice variant. J Pharmacol Exp Ther 2007; 323:94-101. [PMID: 17636009 DOI: 10.1124/jpet.107.127027] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
CPT-11 [7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin or Irinotecan] is a carbamate prodrug that is activated in vivo by carboxylesterase (CES)-2 to SN-38 (7-ethyl-10-hydroxycamptothecin), a potent topoisomerase I inhibitor. There is high interindividual variation when CPT-11 is used in the treatment of colorectal cancer. Several splice variants of CES2 are reported in the expressed sequence tag database. Real-time polymerase chain reaction was used to determine the abundance of the CES2 and splice variant of human carboxylesterase 2 (CES2Delta(458-473)) transcripts in 10 paired samples of human tumor and normal colon tissue. The results showed that the CES2Delta(458-473) transcript accounts for an average of 6% of total CES2 transcripts in colon tissue, and there is large interindividual variation in CES2 expression in both tumor and normal colon samples. The carboxylesterase activity of the colon samples was determined by 4-methylumbelliferyl acetate hydrolysis assays and nondenaturing polyacrylamide gel electrophoresis followed by activity staining. Significant, positive correlations were found between CES2 expression levels and both measures of carboxylesterase activity. We cloned and expressed the CES2Delta(458-473) protein in Sf9 insect cells. The purification profiles and preliminary characterization of the CES2Delta(458-473) protein indicated that the expressed protein is folded and glycosylated like CES2. However, in vitro assays show that the CES2Delta(458-473) protein lacks 4-methylumbelliferyl acetate and irinotecan hydrolase activities. In conclusion, we found that the CES2Delta(458-473) protein is an inactive splice variant of CES2 and that its transcript is spliced at a relatively constant rate in tumor and normal colon tissue.
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Affiliation(s)
- Marissa A Schiel
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Kruzelock RP, Short W. Colorectal Cancer Therapeutics and the Challenges of Applied Pharmacogenomics. Curr Probl Cancer 2007; 31:315-66. [PMID: 17905192 DOI: 10.1016/j.currproblcancer.2007.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Ceppa F, Fontan E, Cremades S, Bihannic R, Bousquet A, Beauvillain L, Burnat P. Implication de la pharmacogénétique dans les traitements des cancers colorectaux. Rev Med Interne 2007; 28:594-602. [PMID: 17624636 DOI: 10.1016/j.revmed.2007.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2006] [Revised: 03/06/2007] [Accepted: 03/12/2007] [Indexed: 01/11/2023]
Abstract
SCOPE Clinical implications associated with polymorphisms in drug-metabolizing genes involved in the chemotherapy of colorectal cancers (5-flurorouracil, oxaliplatin and irinotecan) are reviewed. CURRENT SITUATION AND SALIENT POINTS Treatments of colorectal cancers have been greatly improved last years but patients respond differently to identical medication. Genetic polymorphisms are one of the major causes of these individual responses to drugs associated with sometimes severe adverse effects. Pharmacogenetics is based on all polymorphisms that determine genetic human diversity associated with variable response to anticancer drugs. PERSPECTIVES Morbidity and mortality related to toxicity or inefficacy of these drugs could be reduced by analyzing the pharmacogenetic profile of patients before treatment. Results should be integrated in protocols for monitoring and assessment the dosage of drugs.
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Affiliation(s)
- F Ceppa
- Laboratoire de biochimie, toxicologie et pharmacologie cliniques, HIA Bégin, 69, avenue de Paris, 94163 Saint-Mandé cedex, France.
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Abstract
Irinotecan is widely used in the treatment of metastatic colorectal cancer and extensive small-cell lung cancer. Its use is limited by severe toxicities such as neutropenia and delayed-type diarrhea. Irinotecan is converted to its active metabolite SN-38. SN-38 is further metabolized to SN-38G by various hepatic and extrahepatic UGT1A isozymes, mainly UGT1A1. Impaired glucuronidation activity of the UGT1A1 enzyme has been linked with elevated levels of SN-38, leading to toxicities. UGT1A1*28 involves an extra TA repeat in the UGT1A1 promoter region and is the variant most frequently contributing to interpatient variability in irinotecan pharmacokinetics and toxicities. This information led to the revision of the irinotecan label by the US Food and Drug Administration. Recently, UGT1A1*6 seems to contribute to the risk of toxicity of irinotecan in Asian patients. The pharmacogenetics of irinotecan (irinogenetics) is one of few promising examples of the application of pharmacogenetics to individualized drug therapy. This review summarizes ongoing studies and unanswered questions on irinogenetics.
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Affiliation(s)
- Tae Won Kim
- Section of Oncology, Department of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea
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45
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Parissenti AM, Hembruff SL, Villeneuve DJ, Veitch Z, Guo B, Eng J. Gene expression profiles as biomarkers for the prediction of chemotherapy drug response in human tumour cells. Anticancer Drugs 2007; 18:499-523. [PMID: 17414620 DOI: 10.1097/cad.0b013e3280262427] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Genome profiling approaches such as cDNA microarray analysis and quantitative reverse transcription polymerase chain reaction are playing ever-increasing roles in the classification of human cancers and in the discovery of biomarkers for the prediction of prognosis in cancer patients. Increasing research efforts are also being directed at identifying set of genes whose expression can be correlated with response to specific drugs or drug combinations. Such genes hold the prospect of tailoring chemotherapy regimens to the individual patient, based on tumour or host gene expression profiles. This review outlines recent advances and challenges in using genome profiling for the identification of tumour or host genes whose expression correlates with response to chemotherapy drugs both in vitro and in clinical studies. Genetic predictors of response to a variety of anticancer agents are discussed, including the anthracyclines, taxanes, topoisomerase I and II inhibitors, nucleoside analogs, alkylating agents, and vinca alkaloids.
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Affiliation(s)
- Amadeo M Parissenti
- Tumour Biology Research Program, Sudbury Regional Hospital, Department of Biology, Laurentian University, Sudbury, Ottawa, Ontario, Canada.
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Bellott R, Le Morvan V, Charasson V, Laurand A, Colotte M, Zanger UM, Klein K, Smith D, Bonnet J, Robert J. Functional study of the 830C>G polymorphism of the human carboxylesterase 2 gene. Cancer Chemother Pharmacol 2007; 61:481-8. [PMID: 17483951 DOI: 10.1007/s00280-007-0493-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2007] [Accepted: 04/02/2007] [Indexed: 01/02/2023]
Abstract
PURPOSE Carboxylesterase 2 (CES2) is involved in the activation of the anticancer drug irinotecan to its active metabolite SN-38. We previously identified a single nucleotide polymorphism (SNP), with an allele frequency around 10%, as possibly involved in enzyme expression (Clin Pharmacol Ther 76:528-535, 2004), which could explain the large individual variation in SN-38 disposition. METHODS The 830C>G SNP, located in the 5' untranslated region of the gene, was analysed in various DNA samples extracted from: (1) the National Cancer Institute NCI-60 panel of human tumour cell lines; (2) a collection of 104 samples of normal tissue from colorectal cancer patients; (3) blood samples from a population of 95 normal subjects; (4) a collection of 285 human livers. CES2 genotypes were tentatively related to irinotecan cytotoxicity and CES2 expression in the NCI-60 panel; to response to treatment and event-free survival in colorectal cancer patients; and to CES2 expression and catalytic activity in subsets of the human liver collection. RESULTS No significant relationship was found in the NCI-60 panel between CES2 830C>G genotype and irinotecan cytotoxicity or CES2 expression. No significant relationship was found between CES2 830C>G genotype and the toxicity and therapeutic efficacy (tumour response, event-free survival) of irinotecan in colorectal cancer patients. There was no significant relationship between CES2 830C>G genotype and CES2 expression and catalytic activity determined in a subset of genotype-selected liver samples. CONCLUSION The 830C>G SNP of CES2 is unlikely to have significant functional consequences on CES2 expression, activity or function.
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Affiliation(s)
- Ricardo Bellott
- Laboratoire de Pharmacologie des Agents Anticancéreux, Institut Bergonié, Université Victor Segalen Bordeaux 2, France
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Stoehlmacher J. The impact of genomics and proteomics in the clinic: functional genetic polymorphisms and their value in response and toxicity prediction in solid tumours. Ann Oncol 2006; 17 Suppl 10:x263-8. [PMID: 17018736 DOI: 10.1093/annonc/mdl271] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- J Stoehlmacher
- Technical University, Department of Internal Medicine I, Dresden, Germany
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48
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Satoh T, Hosokawa M. Structure, function and regulation of carboxylesterases. Chem Biol Interact 2006; 162:195-211. [PMID: 16919614 DOI: 10.1016/j.cbi.2006.07.001] [Citation(s) in RCA: 372] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2006] [Revised: 06/14/2006] [Accepted: 07/01/2006] [Indexed: 11/22/2022]
Abstract
This review covers current developments in molecular-based studies of the structure and function of carboxylesterases. To allay the confusion of the classic classification of carboxylesterase isozymes, we have proposed a novel nomenclature and classification of mammalian carboxylesterases on the basis of molecular properties. In addition, mechanisms of regulation of gene expression of carboxylesterases by xenobiotics and involvement of carboxylesterase in drug metabolism and enzyme induction are also described.
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Affiliation(s)
- Tetsuo Satoh
- Graduate School of Pharmaceutical Sciences, Chiba University, Japan.
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49
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Abstract
Colorectal cancer is one of the most common types of cancer in both men and women. Multiple chemotherapy combinations exist; however, there is currently no strategy for individualised therapy selection prior to treatment. Genetic polymorphisms in genes involved in the metabolism, transport or targets for the commonly used chemotherapy drugs (5-fluorouracil, irinotecan and oxaliplatin) have been described. Many require validation in large prospective trials before they can be used as markers for outcome and/or toxicity. This review describes the data available on polymorphisms in key genes that are associated with chemotherapy toxicity and response in colorectal cancer.
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Affiliation(s)
- Sharon Marsh
- Division of Oncology, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8069, St Louis, MO 63110, USA.
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de Jong FA, de Jonge MJA, Verweij J, Mathijssen RHJ. Role of pharmacogenetics in irinotecan therapy. Cancer Lett 2006; 234:90-106. [PMID: 16343744 DOI: 10.1016/j.canlet.2005.04.040] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2005] [Accepted: 04/20/2005] [Indexed: 01/27/2023]
Abstract
In the treatment of advanced colorectal cancer, irinotecan has become one of the most important drugs, despite its sometimes unpredictable adverse effects. To understand why some patients experience severe adverse effects (diarrhea and neutropenia), while others do not, the metabolic pathways of this drug have to be unraveled in detail. Individual variation in expression of several phase I and phase II metabolizing enzymes and ABC-transporters involved in irinotecan metabolism and excretion, at least partly explains the observed pharmacokinetic interpatient variability. Although the difference in expression-level of these proteins to a certain amount is explained by physiologic and environmental factors, the presence of specific genetic determinants also does influence their expression and function. In this review, the role of genetic polymorphisms in the main enzyme-systems (carboxylesterase, cytochrome P450 3A, and uridine diphosphate-glucuronosyltransferase) and ABC-transporters (ABCB1, ABCC2, and ABCG2) involved in irinotecan metabolism, are discussed. Since at this moment the field of pharmacogenetics and pharmacogenomics is rapidly expanding and simultaneously more rapid and cost-effective screening methods are emerging, a wealth of future data is expected to enrich our knowledge of the genetic basis of irinotecan metabolism. Eventually, this may help to truly individualize the dosing of this (and other) anti-cancer agent(s), using a personal genetic profile of the most relevant enzymes for every patient.
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Affiliation(s)
- Floris A de Jong
- Department of Medical Oncology, Daniel den Hoed Cancer Center, Erasmus University Medical Center Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
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