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Memar N, Sherrard R, Sethi A, Fernandez CL, Schmidt H, Lambie EJ, Poole RJ, Schnabel R, Conradt B. The replicative helicase CMG is required for the divergence of cell fates during asymmetric cell division in vivo. Nat Commun 2024; 15:9399. [PMID: 39477966 PMCID: PMC11525967 DOI: 10.1038/s41467-024-53715-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 10/17/2024] [Indexed: 11/02/2024] Open
Abstract
We report that the eukaryotic replicative helicase CMG (Cdc45-MCM-GINS) is required for differential gene expression in cells produced by asymmetric cell divisions in C. elegans. We found that the C. elegans CMG component, PSF-2 GINS2, is necessary for transcriptional upregulation of the pro-apoptotic gene egl-1 BH3-only that occurs in cells programmed to die after they are produced through asymmetric cell divisions. We propose that CMG's histone chaperone activity causes epigenetic changes at the egl-1 locus during replication in mother cells, and that these changes are required for egl-1 upregulation in cells programmed to die. We find that PSF-2 is also required for the divergence of other cell fates during C. elegans development, suggesting that this function is not unique to egl-1 expression. Our work uncovers an unexpected role of CMG in cell fate decisions and an intrinsic mechanism for gene expression plasticity in the context of asymmetric cell division.
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Affiliation(s)
- Nadin Memar
- Research Department Cell and Developmental Biology, Division of Biosciences, University College London, London, UK.
- Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan, South Korea.
| | - Ryan Sherrard
- Faculty of Biology, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany
| | - Aditya Sethi
- Research Department Cell and Developmental Biology, Division of Biosciences, University College London, London, UK
| | - Carla Lloret Fernandez
- Research Department Cell and Developmental Biology, Division of Biosciences, University College London, London, UK
| | - Henning Schmidt
- Institute of Genetics, TU Braunschweig, Braunschweig, Germany
| | - Eric J Lambie
- Research Department Cell and Developmental Biology, Division of Biosciences, University College London, London, UK
| | - Richard J Poole
- Research Department Cell and Developmental Biology, Division of Biosciences, University College London, London, UK
| | - Ralf Schnabel
- Institute of Genetics, TU Braunschweig, Braunschweig, Germany
| | - Barbara Conradt
- Research Department Cell and Developmental Biology, Division of Biosciences, University College London, London, UK.
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Maslarinou A, Manolopoulos VG, Ragia G. Pharmacogenomic-guided dosing of fluoropyrimidines beyond DPYD: time for a polygenic algorithm? Front Pharmacol 2023; 14:1184523. [PMID: 37256234 PMCID: PMC10226670 DOI: 10.3389/fphar.2023.1184523] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 04/19/2023] [Indexed: 06/01/2023] Open
Abstract
Fluoropyrimidines are chemotherapeutic agents widely used for the treatment of various solid tumors. Commonly prescribed FPs include 5-fluorouracil (5-FU) and its oral prodrugs capecitabine (CAP) and tegafur. Bioconversion of 5-FU prodrugs to 5-FU and subsequent metabolic activation of 5-FU are required for the formation of fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate, the active nucleotides through which 5-FU exerts its antimetabolite actions. A significant proportion of FP-treated patients develop severe or life-threatening, even fatal, toxicity. It is well known that FP-induced toxicity is governed by genetic factors, with dihydropyrimidine dehydrogenase (DPYD), the rate limiting enzyme in 5-FU catabolism, being currently the cornerstone of FP pharmacogenomics. DPYD-based dosing guidelines exist to guide FP chemotherapy suggesting significant dose reductions in DPYD defective patients. Accumulated evidence shows that additional variations in other genes implicated in FP pharmacokinetics and pharmacodynamics increase risk for FP toxicity, therefore taking into account more gene variations in FP dosing guidelines holds promise to improve FP pharmacotherapy. In this review we describe the current knowledge on pharmacogenomics of FP-related genes, beyond DPYD, focusing on FP toxicity risk and genetic effects on FP dose reductions. We propose that in the future, FP dosing guidelines may be expanded to include a broader ethnicity-based genetic panel as well as gene*gene and gender*gene interactions towards safer FP prescription.
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Affiliation(s)
- Anthi Maslarinou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
- Individualised Medicine and Pharmacological Research Solutions Center, Alexandroupolis, Greece
| | - Vangelis G. Manolopoulos
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
- Individualised Medicine and Pharmacological Research Solutions Center, Alexandroupolis, Greece
- Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Georgia Ragia
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
- Individualised Medicine and Pharmacological Research Solutions Center, Alexandroupolis, Greece
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Favela-Mendoza AF, Godínez-López AD, Chávez-Arreguin M, Aguilar-Velázquez JA, Martínez-Cortes G, Rangel-Villalobos H. Analysis of the TSER and G>C variants in the TYMS gene: a high frequency of low expression genotypes predicted in the Mexican population. Ann Hum Biol 2023; 50:94-99. [PMID: 36789646 DOI: 10.1080/03014460.2023.2180088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
BACKGROUND In the TYMS gene promoter, there is a repeat polymorphism (TSER) that affects the expression level of the thymidylate synthetase (TS) enzyme involved in the response to some anticancer drugs. The G>C transversion located in the TSER*3R allele decreases the expression level of the TS enzyme avoiding the upstream stimulatory factor (USF-1) binding site. Despite the biomedical impact of the SNP G>C, only TSER has been reported in most worldwide populations. Thus, we studied both TSER and SNP G>C variants in the Mexican population. SUBJECTS AND METHODS A population sample (n = 156) was genotyped for the TSER and G>C variants by PCR and PCR-RFLPs, respectively, followed by PAGE and silver staining. RESULTS For TSER, the most frequent allele was 2 R (52.56%), as well as the genotype 2 R/3R (42.3%). Comparison with Latin American, European, and American (USA) populations suggest a heterogeneous worldwide distribution (FST-value = 0.01564; p-value = 0.0000). When the G>C variant was included (2RG, 3RG, and 3RC), a high frequency of low expression genotypes was observed: 2RG/2RG, 2RG/3RC, and 3RC/3RC (84.6%). CONCLUSION The high frequency of genotypes associated with low TS enzyme expression justifies obtaining the TYMS gene variant profile in Mexican patient's candidates to pharmaceutical treatments like 5'-Fluoracil, methotrexate, and pemetrex.
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Affiliation(s)
- Alma Faviola Favela-Mendoza
- Instituto de Investigación en Genética Molecular, Centro Universitario de la Ciénega, Universidad de Guadalajara (CUCiénega-UdeG), Ocotlán, México
| | - Andrea Dinorah Godínez-López
- Instituto de Investigación en Genética Molecular, Centro Universitario de la Ciénega, Universidad de Guadalajara (CUCiénega-UdeG), Ocotlán, México
| | - Mariana Chávez-Arreguin
- Instituto de Investigación en Genética Molecular, Centro Universitario de la Ciénega, Universidad de Guadalajara (CUCiénega-UdeG), Ocotlán, México
| | - José Alonso Aguilar-Velázquez
- Instituto de Investigación en Genética Molecular, Centro Universitario de la Ciénega, Universidad de Guadalajara (CUCiénega-UdeG), Ocotlán, México
| | - Gabriela Martínez-Cortes
- Instituto de Investigación en Genética Molecular, Centro Universitario de la Ciénega, Universidad de Guadalajara (CUCiénega-UdeG), Ocotlán, México
| | - Héctor Rangel-Villalobos
- Instituto de Investigación en Genética Molecular, Centro Universitario de la Ciénega, Universidad de Guadalajara (CUCiénega-UdeG), Ocotlán, México
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Ulker D, Ozyurt R, Erkasap N, Butun V. Magnetic Targeting of 5-Fluorouracil-Loaded Liposome-Nanogels for In Vivo Breast Cancer Therapy and the Cytotoxic Effects on Liver and Kidney. AAPS PharmSciTech 2022; 23:289. [DOI: 10.1208/s12249-022-02438-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 10/03/2022] [Indexed: 02/06/2023] Open
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Khalij Y, Belaid I, Chouchane S, Amor D, Omezzine A, Ben Rejeb N, Ben Ahmed S, Bouslama A. DPYD and TYMS polymorphisms as predictors of 5 fluorouracil toxicity in colorectal cancer patients. J Chemother 2022:1-10. [PMID: 36137946 DOI: 10.1080/1120009x.2022.2125736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death. 5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for CRC. Our objective was to determine the genotypic frequency of polymorphisms affecting dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthetase (TYMS) genes and to correlate the genetic profile with the toxicity due to 5-FU, also considering nongenetic factors. This is a prospective study that involved 66 patients. We extracted DNA by salting out methods. We carried out the genotyping of the different polymorphisms by simple PCR for the TYMS 5'UTR and by PCR-RFLP for DPYD: 1905 + 1 G > A, 85 T > C, 496 A > G, 1679 T > G, c.483 + 18G > A and the TYMS: 5'UTR VNTR, 5'UTR G > C and 3'UTR. The study of the association of DPYD and TYMS polymorphisms with the various signs of toxicity under 5-FU revealed that the polymorphisms 496 A > G were significantly associated with hepatotoxicity: OR = 3.85 (p = 0.04). In addition, 85 T > C was significantly associated with mucositis and neurotoxicity: OR = 4.35 (p = 0.03), OR = 3.79 (p = 0.02). For TYMS, the only significant association we observed for 5'UTR with vomiting: OR = 3.34 (p = 0.04). The incidence of adverse reactions related to 5-FU appears to be influenced in patients with CRC by the identified DPYD and TYMS gene polymorphisms in the Tunisian population.
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Affiliation(s)
- Yassine Khalij
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia.,University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Imtinen Belaid
- Carcinology Department, Farhat Hached University Hospital, Sousse, Tunisia
| | - Sana Chouchane
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia.,University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Dorra Amor
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia.,University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Asma Omezzine
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia.,University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Nabila Ben Rejeb
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia.,University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Slim Ben Ahmed
- Carcinology Department, Farhat Hached University Hospital, Sousse, Tunisia
| | - Ali Bouslama
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia
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6
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Rezaei-Sameti M, Iraji Borojeni Z. Interaction of 5-fluorouracil anticancer drug with nucleobases: insight from DFT, TD-DFT, and AIM calculations. J Biomol Struct Dyn 2022:1-12. [PMID: 35866624 DOI: 10.1080/07391102.2022.2099976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
In this study, the interaction of 5-fluorouracil (5FU) drug with adenine (A), guanine(G), cytosine(C), uracil (U), and thymine (T) nucleobases of DNA and RNA are surveyed at the ωB97XD/LANL2DZ, M06-2X/6-31G (d, p), MPW1PWQ1/6-31G(d, p), PBEPBE/6-31(d, p) and ωB97XD/6-31G(d, p) levels of density functional theory (DFT). The considered complexes of 5FU drug with nucleobases are optimized at the above level of theories. Max Force and RMS of optimization criteria are 0.00035 (Ha), and 0.0003 respectively. From optimized structures, the adsorption energy, thermodynamic parameters in gas and solvent media, quantum theory atom in molecule (QTAIM), electron localized function (ELF), and reduced density gradient (RDG) are calculated at ωB97XD/LANL2DZ and M06-2X/6-31G (d, p) level of DFT theory. The QTAIM, ELF, and RDG results confirm that the nature of bonding between 5FU drug with A, C, G, U, and T nucleobases is electrostatic or hydrogen bond type. The adsorption and thermodynamic energy results demonstrate that the interaction of the 5FU drug with C and G nucleobases is stronger than other nucleobases. The results of this study can be suggested the mechanism of interaction of the 5FU drug with nucleobases of DNA and RNA.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Mahdi Rezaei-Sameti
- Department of Applied Chemistry, Faculty of Science, Malayer University, Malayer, Iran
| | - Zohre Iraji Borojeni
- Department of Applied Chemistry, Faculty of Science, Malayer University, Malayer, Iran
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7
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Wang L, Shi C, Yu J, Xu Y. FOXM1-induced TYMS upregulation promotes the progression of hepatocellular carcinoma. Cancer Cell Int 2022; 22:47. [PMID: 35093082 PMCID: PMC8801073 DOI: 10.1186/s12935-021-02372-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 11/28/2021] [Indexed: 12/12/2023] Open
Abstract
Abstract
Background
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the major causes of cancer-related death. Thymidylate synthase (TYMS) catalyzes the methylation of deoxy guanosine to deoxy thymidylate, which is a crucial gene for DNA repair and replication. Thus, TYMS was reported to be closely associated with developing a variety of tumors, but it has been poorly studied in HCC.
Materials and methods
We used the cell counting kit-8 (CCK-8), BrdU, and CFSE assay to measure cell proliferation. The flow cytometry assay and the TUNEL assay were used for assessing cell apoptosis. The flow cytometry assay was used to analyze the cell cycle. The Transwell invasion assay and the wound healing assay were conducted to determine the invasive ability of the cells. RT-qPCR and Western blot analyses were performed to evaluate the mRNA and protein expression levels of specific genes, respectively.
Results
TYMS was found to be upregulated in both HCC cells and patient samples. High expression of TYMS was associated with an unfavorable prognosis in HCC patients based on the TCGA-LIHC dataset. Cell proliferation, apoptosis, and invasion assays revealed that TYMS promoted the proliferation and invasion of HCC cells as well as inhibited apoptosis. In addition, TYMS is a downstream target of FOXM1. TYMS knockdown reversed the 5-FU resistance caused by FOXM1 overexpression and re-sensitized HCC cells to 5-FU treatment.
Conclusion
This study suggested that TYMS serves as an oncogene in HCC, and targeting the FOXM1-TYMS axis may help improve the survival of HCC patients as well as provide new insights for treating advanced HCC patients.
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Bae H, Lee W, Song J, Hong T, Kim MH, Ham J, Song G, Lim W. Polydatin Counteracts 5-Fluorouracil Resistance by Enhancing Apoptosis via Calcium Influx in Colon Cancer. Antioxidants (Basel) 2021; 10:antiox10091477. [PMID: 34573109 PMCID: PMC8469995 DOI: 10.3390/antiox10091477] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022] Open
Abstract
Colon cancer is a disease with a high prevalence rate worldwide, and for its treatment, a 5-fluorouracil (5-FU)-based chemotherapeutic strategy is generally used. However, conventional anticancer agents have some limitations, including the development of drug resistance. Therefore, there has recently been a demand for the improvement of antitumor agents using natural products with low side effects and high efficacy. Polydatin is a natural active compound extracted from an annual plant, and widely known for its anticancer effects in diverse types of cancer. However, it is still not clearly understood how polydatin ameliorates several drawbacks of standard anticancer drugs by reinforcing the chemosensitivity against 5-FU, and neither are the intrinsic mechanisms behind this process. In this study, we examined how polydatin produces anticancer effects in two types of colon cancer, called HCT116 and HT-29 cells. Polydatin has the ability to repress the progression of colon cancer, and causes a modification of distribution in the cell cycle by a flow cytometry analysis. It also induces mitochondrial dysfunctions through oxidative stress and the loss of mitochondrial membrane potential. The present study investigated the apoptosis caused by the disturbance of calcium regulation and the expression levels of related proteins through flow cytometry and immunoblotting analysis. It was revealed that polydatin suppresses the signaling pathways of the mitogen-activated protein kinase (MAPK) and PI3K/AKT. In addition, it was shown that polydatin combined with 5-FU counteracts drug resistance in 5-FU-resistant cells. Therefore, this study suggests that polydatin has the potential to be developed as an innovative medicinal drug for the treatment of colon cancer.
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Affiliation(s)
- Hyocheol Bae
- Department of Oriental Biotechnology, College of Life Sciences, Kyung Hee University, Yongin 17104, Korea;
| | - Woonghee Lee
- Institute of Animal Molecular Biotechnology, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea; (W.L.); (J.H.)
| | - Jisoo Song
- Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul 02707, Korea; (J.S.); (T.H.)
| | - Taeyeon Hong
- Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul 02707, Korea; (J.S.); (T.H.)
| | - Myung Hyun Kim
- Department of Food and Nutrition, Sookmyung Women’s University, Seoul 04310, Korea;
| | - Jiyeon Ham
- Institute of Animal Molecular Biotechnology, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea; (W.L.); (J.H.)
| | - Gwonhwa Song
- Institute of Animal Molecular Biotechnology, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea; (W.L.); (J.H.)
- Correspondence: (G.S.); (W.L.); Tel.: +82-2-3290-3881 (G.S.); +82-2-910-4773 (W.L.)
| | - Whasun Lim
- Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul 02707, Korea; (J.S.); (T.H.)
- Correspondence: (G.S.); (W.L.); Tel.: +82-2-3290-3881 (G.S.); +82-2-910-4773 (W.L.)
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Haider K, Rehman S, Pathak A, Najmi AK, Yar MS. Advances in 2-substituted benzothiazole scaffold-based chemotherapeutic agents. Arch Pharm (Weinheim) 2021; 354:e2100246. [PMID: 34467567 DOI: 10.1002/ardp.202100246] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 01/25/2023]
Abstract
Targeted therapy plays a pivotal role in cancer therapeutics by countering the drawbacks of conventional treatment like adverse events and drug resistance. Over the last decade, heterocyclic derivatives have received considerable attention as cytotoxic agents by modulating various signaling pathways. Benzothiazole is an important heterocyclic scaffold that has been explored for its therapeutic potential. Benzothiazole-based derivatives have emerged as potent inhibitors of enzymes such as EGFR, VEGFR, PI3K, topoisomerases, and thymidylate kinases. Several researchers have designed, synthesized, and evaluated benzothiazole scaffold-based enzyme inhibitors. Of these, several inhibitors have entered various phases of clinical trials. This review describes the recent advances and developments of benzothiazole architecture-based derivatives as potent anticancer agents.
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Affiliation(s)
- Kashif Haider
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
| | - Sara Rehman
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
| | - Ankita Pathak
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
| | - Abul K Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
| | - Mohammad S Yar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India
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Ioannou C, Ragia G, Balgkouranidou I, Xenidis N, Amarantidis K, Koukaki T, Biziota E, Kakolyris S, Manolopoulos VG. Gender-dependent association of TYMS-TSER polymorphism with 5-fluorouracil or capecitabine-based chemotherapy toxicity. Pharmacogenomics 2021; 22:669-680. [PMID: 34100299 DOI: 10.2217/pgs-2021-0031] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Aim: TYMS gene encodes for TS enzyme involved in 5-fluorouracil (5-FU) and capecitabine (CAP) metabolism. This study assessed the association of TYMS-TSER and 3RG>C polymorphisms with 5-FU/CAP adverse event (AE) incidence. Materials & methods: TYMS-TSER and 3RG>C polymorphisms were analyzed by use of PCR/PCR-RFLP in 313 5-FU/CAP-treated cancer patients. Results: Female TYMS-TSER 2R carriers were at increased risk for 5-FU/CAP AEs (odds ratio: 2.195; p = 0.032). 2R/2R genotype was the only factor that increased risk for delayed drug administration or therapy discontinuation (odds ratio: 5.049; p = 0.016). No other associations were found. Conclusion: TYMS-TSER 3R/2R polymorphism was associated with incidence of AEs in female cancer patients. This gender-driven association potentially implicates the ER that, in female patients, potentially regulates TS expression.
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Affiliation(s)
- Charalampia Ioannou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece
| | - Georgia Ragia
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece
| | - Ioanna Balgkouranidou
- Department of Medical Oncology, University General Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece
| | - Nikolaos Xenidis
- Department of Medical Oncology, University General Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece
| | - Kyriakos Amarantidis
- Department of Medical Oncology, University General Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece
| | - Triantafyllia Koukaki
- Department of Medical Oncology, University General Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece
| | - Eirini Biziota
- Department of Medical Oncology, University General Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece
| | - Stylianos Kakolyris
- Department of Medical Oncology, University General Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece
| | - Vangelis G Manolopoulos
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, 68100, Greece.,Clinical Pharmacology & Pharmacogenetics Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
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11
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El-Etrawy AAS, Sherbiny FF. Design, synthesis, biological evaluation and molecular modeling investigation of new N'-(2-Thiouracil-5-oyl) hydrazone derivatives as potential anti-breast cancer and anti-bacterial agents. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2021.129993] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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12
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Mohamad KS. Association between 5'-UTR and 3'-UTR Polymorphisms of the TYMS Gene and Breast Cancer in Kurdish Women of Iraq. Asian Pac J Cancer Prev 2021; 22:1557-1560. [PMID: 34048185 PMCID: PMC8408396 DOI: 10.31557/apjcp.2021.22.5.1557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Indexed: 12/03/2022] Open
Abstract
Breast cancer is a common cancer found among women worldwide. Many polymorphisms can play a role in the development of this disease. The study was conducted to evaluate whether 2R/3R and 6bp insertion/deletion polymorphisms of the TYMS gene are associated with breast cancer risk in the Kurdish Iraqi population.
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Affiliation(s)
- Kazhal Shekh Mohamad
- Department of Medical Laboratory Sciences, College of Sciences, University of Raparin, Ranya, Kurdistan Region of Iraq
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13
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Wang L, Wang Q, Xu P, Fu L, Li Y, Fu H, Quan H, Lou L. YES1 amplification confers trastuzumab-emtansine (T-DM1) resistance in HER2-positive cancer. Br J Cancer 2020; 123:1000-1011. [PMID: 32572172 PMCID: PMC7494777 DOI: 10.1038/s41416-020-0952-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 05/21/2020] [Accepted: 06/03/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Trastuzumab-emtansine (T-DM1), one of the most potent HER2-targeted drugs, shows impressive efficacy in patients with HER2-positive breast cancers. However, resistance inevitably occurs and becomes a critical clinical problem. METHODS We modelled the development of acquired resistance by exposing HER2-positive cells to escalating concentrations of T-DM1. Signalling pathways activation was detected by western blotting, gene expression was analysed by qRT-PCR and gene copy numbers were determined by qPCR. The role of Yes on resistance was confirmed by siRNA-mediated knockdown and stable transfection-mediated overexpression. The in vivo effects were tested in xenograft model. RESULTS We found that Yes is overexpressed in T-DM1-resistant cells owing to amplification of chromosome region 18p11.32, where the YES1 gene resides. Yes activated multiple proliferation-related signalling pathways, including EGFR, PI3K and MAPK, and led to cross-resistance to all types of HER2-targeted drugs, including antibody-drug conjugate, antibody and small molecule inhibitor. The outcome of this cross-resistance may be a clinically incurable condition. Importantly, we found that inhibiting Yes with dasatinib sensitised resistant cells in vitro and in vivo. CONCLUSIONS Our study revealed that YES1 amplification conferred resistance to HER2-targeted drugs and suggested the potential application of the strategy of combining HER2 and Yes inhibition in the clinic.
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Affiliation(s)
- Lei Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China
| | - Quanren Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China
| | - Piaopiao Xu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China
| | - Li Fu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China
| | - Yun Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China
| | - Haoyu Fu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China
| | - Haitian Quan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
| | - Liguang Lou
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
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14
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Ntavatzikos A, Spathis A, Patapis P, Machairas N, Vourli G, Peros G, Papadopoulos I, Panayiotides I, Koumarianou A. TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer. World J Gastrointest Oncol 2019; 11:551-566. [PMID: 31367274 PMCID: PMC6657223 DOI: 10.4251/wjgo.v11.i7.551] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/30/2019] [Accepted: 06/12/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Patients with stage II-III colorectal cancer (CRC) treated with adjuvant chemotherapy, gain a 25% survival benefit. In the context of personalized medicine, there is a need to identify patients with CRC who may benefit from adjuvant chemotherapy. Molecular profiling could guide treatment decisions in these patients. Thymidylate synthase (TYMS) gene polymorphisms, KRAS and BRAF could be included in the molecular profile under consideration. AIM To investigate the association of TYMS gene polymorphisms, KRAS and BRAF mutations with survival of CRC patients treated with chemotherapy. METHODS A retrospective study studied formalin-fixed paraffin-embedded tissues (FFPEs) of consecutive patients treated with adjuvant chemotherapy during January/2005-January/2007. FFPEs were analysed with PCR for the detection of TYMS polymorphisms, mutated KRAS (mKRAS) and BRAF (mBRAF). Patients were classified into three groups (high, medium and low risk) according to 5'UTR TYMS polymorphisms Similarly, based on 3'UTR polymorphism ins/loss of heterozygosity (LOH) patients were allocated into two groups (high and low risk of relapse, respectively). Cox regression models examined the associated 5-year survival outcomes. RESULTS One hundred and thirty patients with early stage CRC (stage I-II: 55 patients; stage III 75 patients; colon: 70 patients; rectal: 60 patients) were treated with surgery and chemotherapy. The 5-year disease free survival and overall survival rate was 61.6% and 73.9% respectively. 5'UTR polymorphisms of intermediate TYMS polymorphisms (2RG/3RG, 2RG/LOH, 3RC/LOH) were associated with lower risk for relapse [hazard ratio (HR) 0.320, P = 0.02 and HR 0.343, P = 0.013 respectively] and death (HR 0.368, P = 0.031 and HR 0.394, P = 0.029 respectively). The 3'UTR polymorphism ins/LOH was independently associated with increased risk for disease recurrence (P = 0.001) and death (P = 0.005). mBRAF (3.8% of patients) was associated with increased risk of death (HR 4.500, P = 0.022) whereas mKRAS (39% of patients) not. CONCLUSION Prospective validating studies are required to confirm whether 2RG/3RG, 2RG/LOH, 3RC/LOH, absence of ins/LOH and wild type BRAF may indicate patients at lower risk of relapse following adjuvant chemotherapy.
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Affiliation(s)
- Anastasios Ntavatzikos
- Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Aris Spathis
- Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Paul Patapis
- 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Nikolaos Machairas
- 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Georgia Vourli
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - George Peros
- Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., “I AGIA TRIAS”, Athens 11528, Greece
| | - Iordanis Papadopoulos
- Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., “I AGIA TRIAS”, Athens 11528, Greece
| | - Ioannis Panayiotides
- 2nd Department of Pathology, University of Athens, Medical School, “ATTIKON” University Hospital, Athens 12462, Greece
| | - Anna Koumarianou
- Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
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15
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Guo R, Tian Y, Jin X, Huang X, Yang J. Thymidylate Synthase, a New Myoepithelial Biomarker for Breast Lesions. Int J Surg Pathol 2019; 27:852-858. [PMID: 31234664 DOI: 10.1177/1066896919858403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background. The identification of myoepithelial cells (MECs) can facilitate the differential diagnosis of breast lesions. We previously found thymidylate synthase (TS) expression in the nuclei of MECs in breast tissues, which prompted us to investigate the usefulness of TS as a sensitive and specific biomarker in the differential diagnosis of breast lesions, similar to other MEC biomarkers (ie, tumor protein [P63] and cluster of differentiation 10 [CD10]). Methods. Immunohistochemistry for TS, P63, and CD10 was performed on paraffin sections from 189 breast specimens. Results. The results showed the intensity of the immunoreactive TS signal to be comparable with that of P63 in the nuclei of MECs. Furthermore, the nuclei of MECs stained strongly for TS and P63 in normal breast tissues (obtained adjacent to invasive breast lesions), benign breast lesions, and carcinoma in situ, whereas the cytoplasm of MECs stained strongly for CD10. The immunoreactive TS signal in the cytoplasm of MECs was variable in 22 out of 32 (65.6%) cases of invasive breast carcinoma and 4 out of 20 cases (20.0%) of ductal carcinoma in situ. We found no immunoreactive TS signal in the nuclei of luminal and stromal cells in breast lesions, although there was a weak positive signal in the cytoplasm of luminal and stromal cells. Conclusions. TS is a sensitive and specific MEC biomarker in the differential diagnosis of breast lesions.
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Affiliation(s)
- Rui Guo
- The Second Affiliated Hospital, Xi'an Jiaotong University, Shaanxi Province, China
| | - Yi Tian
- The Second Affiliated Hospital, Xi'an Jiaotong University, Shaanxi Province, China
| | - Xueyuan Jin
- The Second Affiliated Hospital, Xi'an Jiaotong University, Shaanxi Province, China
| | - Xiaozhong Huang
- The Second Affiliated Hospital, Xi'an Jiaotong University, Shaanxi Province, China
| | - Jun Yang
- The Second Affiliated Hospital, Xi'an Jiaotong University, Shaanxi Province, China
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16
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Varghese V, Magnani L, Harada-Shoji N, Mauri F, Szydlo RM, Yao S, Lam EWF, Kenny LM. FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression. Sci Rep 2019; 9:1505. [PMID: 30728402 PMCID: PMC6365533 DOI: 10.1038/s41598-018-38017-0] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 10/07/2018] [Indexed: 12/11/2022] Open
Abstract
Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.
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Affiliation(s)
- Vidhya Varghese
- Department of Surgery and Cancer, Imperial College London, London, USA
| | - Luca Magnani
- Department of Surgery and Cancer, Imperial College London, London, USA
| | | | - Francesco Mauri
- Imperial College Healthcare NHS Trust, Imperial College London, London, USA
| | | | - Shang Yao
- Department of Surgery and Cancer, Imperial College London, London, USA
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, London, USA.
| | - Laura M Kenny
- Department of Surgery and Cancer, Imperial College London, London, USA.
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17
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Wang SM, Zeng WX, Wu WS, Sun LL, Yan D. Genotype and allele frequencies of TYMS rs2790 A > G polymorphism in a Chinese paediatric population with acute lymphoblastic leukaemia. J Clin Pharm Ther 2018; 43:507-512. [PMID: 29500934 DOI: 10.1111/jcpt.12678] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 02/09/2018] [Indexed: 12/16/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Thymidylate synthase (TYMS) is an important target for methotrexate (MTX). Genetic variations in the TYMS gene contribute to the differences in treatment responses to MTX. The aim of this study was to investigate the distribution of a microRNA (miRNA) binding site polymorphism (rs2790 A > G) in the 3'-untranslated region (3'-UTR) of TYMS and its association with MTX concentration and haematological toxicity in Chinese paediatric patients with acute lymphoblastic leukaemia (ALL). METHODS The Sequenom MassARRAY system was used for TYMS rs2790 A > G genotyping in 118 children with ALL. Serum MTX concentrations were measured by a fluorescence polarization immunoassay. Clinical data were extracted from the electronic medical records. RESULTS AND DISCUSSION The minor allele frequency noted in this study (39.8%) was significantly higher than those in the CEU (Utah residents with northern and western Europe ancestry; 16.2%) and YRI (Yoruba in Ibadan, Nigeria; 25.0%) samples reported in the 1000 Genomes Project (P < .01). The frequency of MTX level >40 μmol/L at 24 hours in patients with the AA genotype (36.6%) was significantly higher than that in GG genotype carriers (5.9%, P < .05). However, the incidence rates of haematological toxicity were similar in the three genotype groups. Whereas there was evidence of higher blood levels in the A homozygotes, the evidence for this translating to higher toxicity was lacking. A larger study would be required to answer this. WHAT IS NEW AND CONCLUSION The results of this study confirmed the significant ethnic differences in the distributions of the TYMS rs2790 A > G polymorphism. Whereas there was evidence of differences in MTX blood levels according to genotype, our study was not powered to show whether this would lead to more haematological toxicity.
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Affiliation(s)
- S-M Wang
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - W-X Zeng
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - W-S Wu
- Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - L-L Sun
- Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - D Yan
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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18
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Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: An overview about well-established and recently emerging clinical data. Crit Rev Oncol Hematol 2017; 120:163-179. [DOI: 10.1016/j.critrevonc.2017.11.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 10/20/2017] [Accepted: 11/06/2017] [Indexed: 12/13/2022] Open
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19
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Ntavatzikos A, Spathis A, Patapis P, Machairas N, Peros G, Konstantoudakis S, Leventakou D, Panayiotides IG, Karakitsos P, Koumarianou A. Integrating TYMS, KRAS and BRAF testing in patients with metastatic colorectal cancer. World J Gastroenterol 2017; 23:5913-5924. [PMID: 28932083 PMCID: PMC5583576 DOI: 10.3748/wjg.v23.i32.5913] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 06/22/2017] [Accepted: 07/22/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate the impact of thymidylate synthase (TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy. METHODS Clinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3' untranslated region (UTR) and 5'UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed. RESULTS The analysis recovered 89 patients with mCRC (46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3'UTR polymorphisms are associated with risk for disease progression and death (P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high TYMS expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally, KRAS mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1st line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively). CONCLUSION The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.
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Affiliation(s)
- Anastasios Ntavatzikos
- Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Aris Spathis
- Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Paul Patapis
- 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Nikolaos Machairas
- 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - George Peros
- Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., “I AGIA TRIAS”, 11528 Athens, Greece
| | - Stefanos Konstantoudakis
- 2nd Department of Pathology, University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Danai Leventakou
- Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Ioannis G Panayiotides
- 2nd Department of Pathology, University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Petros Karakitsos
- Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Anna Koumarianou
- Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, 12462 Athens, Greece
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20
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Zhao Y, Chen W, Zhu W, Li J, Su J, Zhao S, Chen M, Zhang J, Guo A, Yan S, Zhou X, Kuang X, Liu Z, Luo D, Knepper TC, He Y, Chen X. Tandem repeats of TSER significantly influence the efficacy of 5-fluorouracil in the treatment of plantar warts. Per Med 2016; 13:233-240. [PMID: 29767611 DOI: 10.2217/pme-2015-0014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
AIM To identify potential genetic risk markers associated with 5-fluorouracil (5-FU) treatment outcomes in plantar warts patients. METHODS In this study, 126 plantar warts patients were treated with an intralesional mixture of 5-FU, lidocaine and epinephrine. Treatment outcomes were compared with DNA mutation analysis. RESULTS More patients with TSER 3R/3R genotype failed 5-FU treatment than TSER 2R/3R+2R/2R (72.1 vs 43.8%; odds ratio: 3.32; 95% CI: 1.26-8.72; p = 0.013). In addition, the regression modeling identified patient age and TSER 3R allele as covariates of the risk of 5-FU treatment failure (p = 0.025). CONCLUSION TSER 3R/3R of TYMS gene was found to be the major risk of treatment failure. This genetic marker provides a potential treatment stratification target to modulate 5-FU treatment in plantar wart patients.
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Affiliation(s)
- Yue Zhao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Dermatology, Heping Hospital, Changzhi Medical College, Changzhi, Shanxi, China
| | - Wangqing Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wu Zhu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jie Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Juan Su
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuang Zhao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mingliang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jianglin Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Aiyuan Guo
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Siyu Yan
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xingchen Zhou
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xinwei Kuang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoqian Liu
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University Changsha, Hunan, China
| | - Dan Luo
- Department of Social Medicine & Health Management, Public Health School, Central South University, Changsha, Hunan, China
| | - Todd C Knepper
- Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Yijing He
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer & Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
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21
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Ghodke-Puranik Y, Puranik AS, Shintre P, Joshi K, Patwardhan B, Lamba J, Niewold TB, Chopra A. Folate metabolic pathway single nucleotide polymorphisms: a predictive pharmacogenetic marker of methotrexate response in Indian (Asian) patients with rheumatoid arthritis. Pharmacogenomics 2015; 16:2019-34. [PMID: 26616421 DOI: 10.2217/pgs.15.145] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
AIM We evaluated the pharmacogenetic influence of genetic polymorphisms in folate pathway genes in Indian rheumatoid arthritis patients receiving methotrexate (MTX). PATIENTS & METHODS Twelve polymorphisms within nine folate pathway genes were analyzed for association with MTX response in 322 Indian rheumatoid arthritis (RA) patients and MTX pharmacokinetics in 94 RA patients. RESULTS Polymorphisms in GGH, SHMT1 and TS were associated with MTX-related adverse events while SNPs in MTHFR and RFC1/SLC19A1 were associated with MTX efficacy. TS5'UTR and SHMT1 polymorphisms were associated with higher plasma levels of MTX. CONCLUSION Polymorphisms in folate-MTX pathway genes contribute to MTX response and affect MTX concentrations in Indian RA patients. A toxicogenetic index could identify patients who develop adverse events to MTX.
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Affiliation(s)
- Yogita Ghodke-Puranik
- Interdisciplinary School of Health Sciences, University of Pune, Pune 411007, India.,Department of Immunology & Division of Rheumatology, Mayo Clinic, Rochester, MN 55901, USA
| | - Amrutesh S Puranik
- Interdisciplinary School of Health Sciences, University of Pune, Pune 411007, India.,Center for Aging, Mayo Clinic, Rochester, MN 55901, USA
| | - Pooja Shintre
- Department of Biotechnology, Sinhgad College of Engineering, Pune 411041, India.,School of Anatomy, Physiology & Human Biology, University of Western Australia, Australia
| | - Kalpana Joshi
- Department of Biotechnology, Sinhgad College of Engineering, Pune 411041, India
| | - Bhushan Patwardhan
- Interdisciplinary School of Health Sciences, University of Pune, Pune 411007, India
| | | | - Timothy B Niewold
- Department of Immunology & Division of Rheumatology, Mayo Clinic, Rochester, MN 55901, USA
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22
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Romão VC, Lima A, Bernardes M, Canhão H, Fonseca JE. Three decades of low-dose methotrexate in rheumatoid arthritis: can we predict toxicity? Immunol Res 2015; 60:289-310. [PMID: 25391609 DOI: 10.1007/s12026-014-8564-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Methotrexate (MTX) is the anchor disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis (RA) treatment. It is used in monotherapy and/or in combination with other synthetic or biological DMARDs, and is known to have the best cost-effectiveness and efficacy/toxicity ratios. However, toxicity is still a concern, with a significant proportion of patients interrupting long-term treatment due to the occurrence of MTX-related adverse drug reactions (ADRs), which are the main cause of drug withdrawal. Despite the extensive accumulated experience in the last three decades, it is still impossible in routine clinical practice to identify patients prone to develop MTX toxicity. While clinical and biological variables, including folate supplementation, partially help to minimize MTX-related ADRs, the advent of pharmacogenomics could provide further insight into risk stratification and help to optimize drug monitoring and long-term retention. In this paper, we aimed to review and summarize current data on low-dose MTX-associated toxicity, its prevention and predictors, keeping in mind practical RA clinical care.
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Affiliation(s)
- Vasco C Romão
- Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon Academic Medical Centre, Edifício Egas Moniz, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal
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23
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Grem JL, Kos ME, Evande RE, Meza JL, Schwarz JK. A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors. Cancer 2015; 121:3862-8. [DOI: 10.1002/cncr.29504] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 04/05/2015] [Accepted: 04/07/2015] [Indexed: 11/08/2022]
Affiliation(s)
- Jean L. Grem
- Section of Oncology/Hematology, Department of Internal Medicine; University of Nebraska Medical Center; Omaha Nebraska
| | - Mary E. Kos
- Early Clinical Trials Unit, Eppley Cancer Institute; University of Nebraska Medical Center; Omaha Nebraska
| | - Ruby E. Evande
- Section of Oncology/Hematology, Department of Internal Medicine; University of Nebraska Medical Center; Omaha Nebraska
| | - Jane L. Meza
- Department of Biostatistics, College of Public Health; University of Nebraska Medical Center; Omaha Nebraska
| | - James K. Schwarz
- Section of Oncology/Hematology, Department of Internal Medicine; University of Nebraska Medical Center; Omaha Nebraska
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Genetic Determinants of Methotrexate Toxicity in Tunisian Patients with Rheumatoid Arthritis: A Study of Polymorphisms Involved in the MTX Metabolic Pathway. Eur J Drug Metab Pharmacokinet 2015; 41:385-93. [DOI: 10.1007/s13318-015-0288-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Thymidylate synthase genetic polymorphism and plasma total homocysteine level in a group of Turkish patients with rheumatoid arthritis: relationship with disease activity and methotrexate toxicity. REVISTA BRASILEIRA DE REUMATOLOGIA 2015; 55:485-92. [PMID: 25687398 DOI: 10.1016/j.rbr.2014.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 12/01/2014] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The polymorphism of thymidylate synthase (TS) gene and homocysteine are reported to have a relationship to methotrexate (MTX) metabolism, with conflicting results. The aim of this study was to determine homocysteine levels and the frequency of TS gene triple repeat (TS3R) and double repeat (TS2R) polymorphisms in a group of Turkish RA patients and evaluate its association with MTX toxicity and disease activity. METHODS Sixty-four patients with RA and 31 control subjects with a mean age of 48.7 ± 12.5 and 46.2 ± 13.4 years, were enrolled to the study. Demographic characteristics were obtained and number of patients with MTX-related adverse affects, were recorded in the patient group. The homocysteine levels and TS2R/TS3R polymorphisms of the TS gene were analyzed and the distribution of genotypes according to MTX toxicity and disease activity, were determined. RESULTS The demographic properties were similar between the patient and control subjects. Folic acid supplementation with a mean dose of 5mg folic acid/week, was present in all patients. Thirty-six of the 64 patients showed adverse effects to MTX treatment. The frequency of TS2R and TS3R polymorphisms were found to be similar in the patient and control groups. TS2R and TS3R gene polymorphisms were found to be similar in patients with and without MTX-related adverse events. The mean homocysteine level was also similar in patients with and without TS gene polymorphism, but was found to be higher (12.45μmol/L vs 10.7μmol/L) in patients with MTX-related side effects than in patients without side effects. The mean level of homocysteine was correlated with levels of ESR in the patient group. CONCLUSIONS In conclusion, homocysteine levels might effect the disease activity and toxicity of MTX but 2R and 3R polymorphisms in the TS gene, were not related with MTX-related toxicity in RA patients receiving folate supplementation. Further studies are needed to illuminate the polymorphisms in other enzymes that might be responsible from the MTX toxicity in patients suffering from RA.
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Germline oncopharmacogenetics, a promising field in cancer therapy. Cell Oncol (Dordr) 2015; 38:65-89. [PMID: 25573079 DOI: 10.1007/s13402-014-0214-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2014] [Indexed: 12/14/2022] Open
Abstract
Pharmacogenetics (PGx) is the study of the relationship between inter-individual genetic variation and drug responses. Germline variants of genes involved in drug metabolism, drug transport, and drug targets can affect individual response to medications. Cancer therapies are characterized by an intrinsically high toxicity; therefore, the application of pharmacogenetics to cancer patients is a particularly promising method for avoiding the use of inefficacious drugs and preventing the associated adverse effects. However, despite continuing efforts in this field, very few labels include information about germline genetic variants associated with drug responses. DPYD, TPMT, UGT1A1, G6PD, CYP2D6, and HLA are the sole loci for which the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) report specific information. This review highlights the germline PGx variants that have been approved to date for anticancer treatments, and also provides some insights about other germline variants with potential clinical applications. The continuous and rapid evolution of next-generation sequencing applications, together with the development of computational methods, should help to refine the implementation of personalized medicine. One day, clinicians may be able to prescribe the best treatment and the correct drug dosage based on each patient's genotype. This approach would improve treatment efficacy, reduce toxicity, and predict non-responders, thereby decreasing chemotherapy-associated morbidity and improving health benefits.
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Hummel R, Sie C, Watson DI, Wang T, Ansar A, Michael MZ, Hoek MVD, Haier J, Hussey DJ. MicroRNA signatures in chemotherapy resistant esophageal cancer cell lines. World J Gastroenterol 2014; 20:14904-14912. [PMID: 25356050 PMCID: PMC4209553 DOI: 10.3748/wjg.v20.i40.14904] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 05/19/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate expression of microRNA (miRNA) and potential targets in chemotherapy resistant esophageal cancer cell lines. METHODS An in-vitro model of acquired chemotherapy resistance in esophageal adeno- (EAC) and squamous cell carcinoma (ESCC) cells was used, and microRNA expression profiles for cisplatin or 5-fluorouracil (5-FU) resistant variants vs chemotherapy sensitive controls were compared using microarray and quantitative real-time polymerase chain reaction (PCR). The expression of chemotherapy-relevant genes potentially targeted by the dysregulated microRNAs in the chemotherapy resistant variants was also evaluated. RESULTS Chemotherapy resistant sublines were found to have specific miRNA signatures, and these miRNA signatures were different for the cisplatin vs 5-FU resistant cells from the same tumor cell line, and also for EAC vs ESCC cells with resistance to the same specific chemotherapy agent. Amongst others, miR-27b-3p, miR-193b-3p, miR-192-5p, miR-378 a-3p, miR-125a-5p and miR-18a-3p were dysregulated, consistent with negative posttranscriptional control of KRAS, TYMS, ABCC3, CBL-B and ERBB2 expression via these miRNAs. CONCLUSION The current study supports the hypothesis that microRNA expression has an impact on chemotherapy resistance in esophageal cancer.
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Lima A, Seabra V, Bernardes M, Azevedo R, Sousa H, Medeiros R. Role of key TYMS polymorphisms on methotrexate therapeutic outcome in portuguese rheumatoid arthritis patients. PLoS One 2014; 9:e108165. [PMID: 25279663 PMCID: PMC4184792 DOI: 10.1371/journal.pone.0108165] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 08/19/2014] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Therapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients. METHODS Clinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches. RESULTS Considering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp- carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp- carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp- alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes. CONCLUSION Our study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences.
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Affiliation(s)
- Aurea Lima
- CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences-North (ISCS-N), Gandra PRD, Portugal
- Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal
- Abel Salazar Institute for the Biomedical Sciences (ICBAS) of University of Porto, Porto, Portugal
- * E-mail:
| | - Vítor Seabra
- CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences-North (ISCS-N), Gandra PRD, Portugal
| | - Miguel Bernardes
- Faculty of Medicine of University of Porto (FMUP), Porto, Portugal
- Rheumatology Department of São João Hospital Center, Porto, Portugal
| | - Rita Azevedo
- Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal
- Faculty of Medicine of University of Porto (FMUP), Porto, Portugal
| | - Hugo Sousa
- Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal
- Faculty of Medicine of University of Porto (FMUP), Porto, Portugal
- Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal
- Abel Salazar Institute for the Biomedical Sciences (ICBAS) of University of Porto, Porto, Portugal
- Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal
- Research Department-Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal
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Pandey S, Garg P, Lee S, Choung HW, Choung YH, Choung PH, Chung JH. Nucleotide biosynthesis arrest by silencing SHMT1 function via vitamin B6-coupled vector and effects on tumor growth inhibition. Biomaterials 2014; 35:9332-42. [PMID: 25132602 DOI: 10.1016/j.biomaterials.2014.07.045] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 07/23/2014] [Indexed: 01/15/2023]
Abstract
Serine hydroxymethyltransferase isoforms (SHMT1 & SHMT2α), which serve as scaffold protein for the formation of a multi-enzyme complex and generate one-carbon unit for the de novo thymidylate biosynthesis pathway during DNA synthesis, are vitamin B6 (VB6)-dependent enzyme. Cancer cells with high proliferation intensity need increased SHMT activation which enforces the facilitated-diffusion of VB6 for the continuous functioning of thymidylate synthase cycle. Therefore, SHMT knockdown presents an alternative approach to prevent DNA synthesis in cancer cells; however, its potential to inhibit cancer growth remains unknown so far. Here we demonstrated that VB6 coupled to poly(ester amine) (VBPEA) enforces a high level of VTC (VB6-transporting membrane carriers)-mediated endocytosis of the complexed SHMT1 siRNA (siSHMT1) to interrupt the thymidylate biosynthesis pathway of cancer cells. The detrimental effect of SHMT1 knockdown on the disintegration of multi-enzyme complex resulted in cell cycle arrest and a decrease in cell's genomic DNA content, leading to enhanced apoptotic events in cancer cells. A reduction in tumor size was observed with constant SHMT1 suppression in xenograft mice. This study illustrates how silencing the SHMT1 expression inhibits cancer growth and the increased VB6 channeling for sustenance of cancer cells promotes VB6-coupled vector to elicit enhanced delivery of siSHMT1.
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Affiliation(s)
- Shambhavi Pandey
- Department of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul 151-921, Republic of Korea
| | - Pankaj Garg
- Department of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul 151-921, Republic of Korea
| | - Somin Lee
- Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Han-Wool Choung
- Department of Oral and Maxillofacial Surgery and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-774, Republic of Korea
| | - Yun-Hoon Choung
- Department of Otalaryngology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea
| | - Pill-Hoon Choung
- Department of Oral and Maxillofacial Surgery and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-774, Republic of Korea.
| | - Jong Hoon Chung
- Department of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul 151-921, Republic of Korea; Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
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Rukov JL, Wilentzik R, Jaffe I, Vinther J, Shomron N. Pharmaco-miR: linking microRNAs and drug effects. Brief Bioinform 2014; 15:648-59. [PMID: 23376192 PMCID: PMC4103536 DOI: 10.1093/bib/bbs082] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 11/19/2012] [Indexed: 12/22/2022] Open
Abstract
MicroRNAs (miRNAs) are short regulatory RNAs that down-regulate gene expression. They are essential for cell homeostasis and active in many disease states. A major discovery is the ability of miRNAs to determine the efficacy of drugs, which has given rise to the field of 'miRNA pharmacogenomics' through 'Pharmaco-miRs'. miRNAs play a significant role in pharmacogenomics by down-regulating genes that are important for drug function. These interactions can be described as triplet sets consisting of a miRNA, a target gene and a drug associated with the gene. We have developed a web server which links miRNA expression and drug function by combining data on miRNA targeting and protein-drug interactions. miRNA targeting information derive from both experimental data and computational predictions, and protein-drug interactions are annotated by the Pharmacogenomics Knowledge base (PharmGKB). Pharmaco-miR's input consists of miRNAs, genes and/or drug names and the output consists of miRNA pharmacogenomic sets or a list of unique associated miRNAs, genes and drugs. We have furthermore built a database, named Pharmaco-miR Verified Sets (VerSe), which contains miRNA pharmacogenomic data manually curated from the literature, can be searched and downloaded via Pharmaco-miR and informs on trends and generalities published in the field. Overall, we present examples of how Pharmaco-miR provides possible explanations for previously published observations, including how the cisplatin and 5-fluorouracil resistance induced by miR-148a may be caused by miR-148a targeting of the gene KIT. The information is available at www.Pharmaco-miR.org.
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Liu JH, Wang T, Zhou WJ, Pang C, Wang L, Chen C, Dai PG. Single tube genotyping of TYMS 1494del6 polymorphism in the Chinese Han population by duplex scorpion primers. Exp Mol Pathol 2014; 96:269-73. [PMID: 24667064 DOI: 10.1016/j.yexmp.2014.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 02/13/2014] [Accepted: 03/17/2014] [Indexed: 11/28/2022]
Abstract
BACKGROUND The development of pharmacogenomics has created an urgent need for robust molecular characterization. And it has become a challenge to develop suitable detecting methods for routine clinical use. AIM The aim of the current study is to develop a simple and reliable TYMS 1494del6 polymorphism genotyping assay by duplex scorpion primers in the Chinese Han population. METHOD We evaluated the performance of the duplex scorpion primer assay in the genotyping of TYMS 1494del6 polymorphism and screened 54 DNA samples of the Chinese Han population. The results were further validated by pyrosequencing. RESULTS The duplex scorpion primer assay showed high specificity and accuracy for genotyping TYMS 1494del6 polymorphism. Complete concordance was observed between the duplex scorpion primer assay and pyrosequencing. The frequency of the TYMS +6 bp allele was 34% and the -6 bp allele was 66% in 54 Chinese Han population DNA samples. CONCLUSION The duplex scorpion primer assay provides a rapid, reliable and high-throughput method to genotype TYMS 1494del6 polymorphism in the Chinese Han population.
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Affiliation(s)
- Jin-hui Liu
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China
| | - Ting Wang
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China
| | - Wen-jing Zhou
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China
| | - Cong Pang
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China
| | - Le Wang
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China; Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China
| | - Chao Chen
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China
| | - Peng-gao Dai
- The National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China.
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Lima A, Azevedo R, Sousa H, Seabra V, Medeiros R. Current approaches for TYMS polymorphisms and their importance in molecular epidemiology and pharmacogenetics. Pharmacogenomics 2013; 14:1337-51. [DOI: 10.2217/pgs.13.118] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
TS is critical for providing the requisite nucleotide precursors in order to maintain DNA synthesis and repair. Furthermore, it is an important target for several drugs such as 5-fluorouracil and methotrexate. However, several mechanisms of resistance to TS inhibitors have been explained as linked to TYMS overexpression. Some authors have described the relationship between genetic polymorphisms on TYMS, in particular rs34743033, rs2853542 and rs34489327, with the development of several diseases and with the clinical response to drug therapy and/or survival. Nevertheless, the obtained results described in the literature are controversial, which has lead to a search strategy to understand the impact of these polymorphisms on molecular epidemiology and pharmacogenetics. With the progress of these scientific areas, early identification of individuals at risk of disease along with improvement in the prediction of patients’ outcome will offer a powerful tool for the translation of TYMS polymorphisms into clinical practice and individualization of treatments.
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Affiliation(s)
- Aurea Lima
- Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua António Bernardino de Almeida, 4200-072, Porto, Portugal
- Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal
- CESPU, Health Sciences Research Center (CICS), Department of Pharmaceutical Sciences, Higher Institute of Health Sciences – North (ISCS-N), Rua Central de Gandra 1317, 4585-116, Gandra PRD, Portugal.
| | - Rita Azevedo
- Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua António Bernardino de Almeida, 4200-072, Porto, Portugal
- Faculty of Medicine of University of Porto (FMUP), Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Hugo Sousa
- Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua António Bernardino de Almeida, 4200-072, Porto, Portugal
- Faculty of Medicine of University of Porto (FMUP), Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Vítor Seabra
- CESPU, Health Sciences Research Center (CICS), Department of Pharmaceutical Sciences, Higher Institute of Health Sciences – North (ISCS-N), Rua Central de Gandra 1317, 4585-116, Gandra PRD, Portugal
| | - Rui Medeiros
- Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua António Bernardino de Almeida, 4200-072, Porto, Portugal
- Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal
- Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua António Bernardino de Almeida, 4200-072, Porto, Portugal
- Research Department – Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalação, 6657, 4200-177, Porto, Portugal
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Liu G, Neumeister M, Reichensperger J, Yang RD. Therapeutic potential of human adipose stem cells in a cancer stem cell-like gastric cancer cell model. Int J Oncol 2013; 43:1301-9. [PMID: 23900519 DOI: 10.3892/ijo.2013.2039] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 06/03/2013] [Indexed: 11/05/2022] Open
Abstract
Cancer stem cells (CSCs) or circulating tumor cells play an important role in tumor initiation, invasion, metastasis and resistance to anticancer therapies. Therapies that target gastric tumor CSCs have potential clinical application for preventing malignant gastric tumor progression and metastasis. We isolated CD44+ gastric cancer cells from the gastric cancer cell line AGS and Hs746T cells and maintained the cells in a novel stem cell culture. The cells were kept in an undifferentiated proliferative state and we characterized their cancer stem cell properties and chemotherapy-resistance behavior. The CD44+ cancer cells were also co-cultured with human adipose stem cells (ADSCs) to determine the chemotherapy-promotion effects of the adipose cells on the CD44+ cancer cells. The CD44+ gastric cancer cell model is a non-adhesion, 3-dimensional, spheroid phenotype. The non-adherent CD44+ cells have cancer stem cell properties and are highly chemo-resistant. However, these cells regained chemo-sensitivity when re-attached to an extracellular matrix-coated attachment surface. The human adipose stem cells significantly promoted the chemo-sensitivity of the non-adherent CD44+ gastric cancer cells. Integrin α2/β2 and the Wnt signaling pathways are involved in the mechanisms. We concluded that the in vitro non-adherent CD44+ gastric cancer cell model resembles the circulating gastric tumor cells in vivo. Introduction of an appropriate attachment surface significantly promotes chemo-sensitivity of the non-adherent CD44+ gastric cancer cells. The human adipose stem cells function as a 'living vehicle surface' for such a purpose in vivo.
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Affiliation(s)
- Guangming Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62794, USA
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Martinez Molina D, Jafari R, Ignatushchenko M, Seki T, Larsson EA, Dan C, Sreekumar L, Cao Y, Nordlund P. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 2013; 341:84-7. [PMID: 23828940 DOI: 10.1126/science.1233606] [Citation(s) in RCA: 1478] [Impact Index Per Article: 123.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The efficacy of therapeutics is dependent on a drug binding to its cognate target. Optimization of target engagement by drugs in cells is often challenging, because drug binding cannot be monitored inside cells. We have developed a method for evaluating drug binding to target proteins in cells and tissue samples. This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins. Using this assay, we validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues. CETSA is likely to become a valuable tool for the validation and optimization of drug target engagement.
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Affiliation(s)
- Daniel Martinez Molina
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
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Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood 2013; 121:5145-53. [PMID: 23652803 DOI: 10.1182/blood-2013-01-480335] [Citation(s) in RCA: 122] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The pharmacogenetics of methotrexate (MTX) was investigated in a large cohort of pediatric patients with acute lymphoblastic leukemia (ALL). Four hundred ninety-nine children with ALL from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial who received 1996 courses of MTX at 5 g/m(2) were genotyped for 8 single nucleotide polymorphisms in 5 candidate genes of the MTX/folate pathway. Patients' MTX pharmacokinetics, MTX toxicities, and outcomes were correlated with the genotypes. The interindividual variability in MTX kinetics had a substantial genetic component between 68% and 75%. The SLCO1B1 rs4149056 variant was significantly associated with MTX kinetics. In a multiple regression model, MTX area under the concentration time curve (AUC)0-48h increased by 26% (P < .001) per SLCO1B1 rs4149056 C allele. MTX AUC0-48h was a significant predictor of overall toxic adverse events during MTX courses (R(2) = 0.043; P < .001), whereas the thymidylate synthase rs34743033 tandem repeat polymorphism was predictive of stomatitis (R(2) = 0.018; P = .009), a frequent side effect of high-dose MTX. Multiple Cox regression analyses revealed an association of minimal residual disease (hazard ratio 7.3; P < .001) and methylenetetrahydrofolate reductase rs1801131 (hazard ratio 3.1; P = .015) with event-free survival in the ALL-BFM 2000 study population. Genetic variations substantially influence the kinetics and response to high-dose MTX therapy in childhood ALL.
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González-Neira A. Pharmacogenetics of chemotherapy efficacy in breast cancer. Pharmacogenomics 2012; 13:677-90. [PMID: 22515610 DOI: 10.2217/pgs.12.44] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Large differences are observed in chemotherapy response between breast cancer patients, with a substantial part of this variability being explained by genetic factors. Polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters and drug targets influence the pharmacokinetics and pharmacodynamics of these anticancer drugs, leading to differences in therapeutic efficacy. Pharmacogenetic investigations of breast cancer therapeutics focused on these candidate loci have been performed. This article summarizes the status of research to identify polymorphisms in genes that influence response to the chemotherapeutic agents used in breast cancer treatment and suggests future directions for this line of research. Understanding the genetic factors that predispose patients to poor treatment outcomes will help guide individualized therapeutic strategies to obtain maximal benefit.
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Affiliation(s)
- Anna González-Neira
- Human Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.
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Abstract
Multiple drug strategies for many cancer types are now readily available and there is a clear need for tools to inform decision making on therapy selection. Although there is still a long way to go before pharmacogenomics achieves the goal of individualized selection of cancer treatment, promising progress is being made. Genetic testing for thiopurine methyltransferase (TPMT) variant alleles in patients prior to mercaptopurine administration, and for UGT1A1*28 in patients prior to administration of irinotecan therapy, along with the instigation of genotype-guided clinical trials (e.g. TYMS) are important advances in cancer pharmacogenomics. Markers for the toxicity and efficacy of many oncology drugs remain unknown; however, the examples highlighted here suggest progress is being made towards the incorporation of pharmacogenomics into clinical practice in oncology.
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Affiliation(s)
- Sharon Marsh
- Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
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Begg EJ, Helsby NA, Jensen BP. Pharmacogenetics of drug-metabolizing enzymes: the prodrug hypothesis. Pharmacogenomics 2012; 13:83-9. [DOI: 10.2217/pgs.11.134] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The hope of individualized drug therapy has been bolstered by the knowledge that drug-metabolizing enzymes can be affected by genetic polymorphisms. The initial flurry of potential examples has been muted somewhat by the failure of most predictions to be translated into clinical practice. Perhaps the only real example with reasonable evidence is that of azathioprine/6-mercaptopurine and thiopurine methyl-transferase. A few other examples such as tamoxifen, clopidogrel, irinotecan and warfarin warrant further discussion. An interesting feature of these drugs is that all except warfarin are prodrugs. We propose the hypothesis that prodrugs are over-represented in drugs that may be affected by genetic polymorphisms. Understanding this may assist our efforts to advance the field.
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Affiliation(s)
| | - Nuala A Helsby
- School of Medical Sciences, University of Auckland, Auckland, New Zealand
| | - Berit P Jensen
- Department of Medicine, University of Otago – Christchurch, Christchurch 8140, New Zealand
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Muhale FA, Wetmore BA, Thomas RS, McLeod HL. Systems pharmacology assessment of the 5-fluorouracil pathway. Pharmacogenomics 2011; 12:341-50. [PMID: 21449674 DOI: 10.2217/pgs.10.188] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
AIM To assess the impact of the 5-fluorouracil (5-FU) drug-pathway genes on cytotoxicity, and determine whether loss-of-function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes. MATERIALS & METHODS Dose-response experiments were used to quantify the phenotype of sensitivity to 5-FU following the specific knockdown of genes selected from the 5-FU PharmGKB drug pathway in three human colorectal cell lines. Changes in sensitivity were considered significant if the IC(50) for shRNA-exposed cells were three standard deviations outside the mean IC(50) for control-treated cells. RESULTS Of the 24 genes analyzed, 13 produced significant changes on the phenotype of sensitivity to 5-FU (DHFR, DPYS, DTYMK, DUT, FPGS, GGH, NME1, NT5C, RRM1, TYMS, UCK2, UNG and UMPS). CONCLUSION The RNAi screening strategy enabled prioritization of the genes from the 5-FU drug pathway. Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples.
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Affiliation(s)
- Filipe A Muhale
- UNC Institute for Pharmacogenomics & Individualized Therapy, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7361, USA
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Liu G, Hu X, Premkumar L, Chakrabarty S. Nifedipine synergizes with calcium in activating the calcium sensing receptor, suppressing the expression of thymidylate synthase and survivin and promoting sensitivity to fluorouracil in human colon carcinoma cells. Mol Carcinog 2011; 50:922-30. [DOI: 10.1002/mc.20752] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2010] [Revised: 01/14/2011] [Accepted: 01/19/2011] [Indexed: 01/09/2023]
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Dibrov S, McLean J, Hermann T. Structure of an RNA dimer of a regulatory element from human thymidylate synthase mRNA. ACTA CRYSTALLOGRAPHICA. SECTION D, BIOLOGICAL CRYSTALLOGRAPHY 2011; 67:97-104. [PMID: 21245530 PMCID: PMC3045271 DOI: 10.1107/s0907444910050900] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2010] [Accepted: 12/04/2010] [Indexed: 11/10/2022]
Abstract
A sequence around the start codon of the mRNA of human thymidylate synthase (TS) folds into a secondary-structure motif in which the initiation site is sequestered in a metastable hairpin. Binding of the protein to its own mRNA at the hairpin prevents the production of TS through a translation-repression feedback mechanism. Stabilization of the mRNA hairpin by other ligands has been proposed as a strategy to reduce TS levels in anticancer therapy. Rapidly proliferating cells require high TS activity to maintain the production of thymidine as a building block for DNA synthesis. The crystal structure of a model oligonucleotide (TS1) that represents the TS-binding site of the mRNA has been determined. While fluorescence studies showed that the TS1 RNA preferentially adopts a hairpin structure in solution, even at high RNA concentrations, an asymmetric dimer of two hybridized TS1 strands was obtained in the crystal. The TS1 dimer contains an unusual S-turn motif that also occurs in the `off' state of the human ribosomal decoding site RNA.
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Affiliation(s)
- Sergey Dibrov
- Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Jaime McLean
- Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Thomas Hermann
- Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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Watson RG, Muhale F, Thorne LB, Yu J, O'Neil BH, Hoskins JM, Meyers MO, Deal AM, Ibrahim JG, Hudson ML, Walko CM, McLeod HL, Auman JT. Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapy. Eur J Cancer 2010; 46:3358-3364. [PMID: 20727737 PMCID: PMC2991554 DOI: 10.1016/j.ejca.2010.07.011] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2010] [Revised: 06/18/2010] [Accepted: 07/14/2010] [Indexed: 12/14/2022]
Abstract
Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Genetic variations and expression alterations in genes involved in 5-FU metabolism and effect have been shown to modulate 5-FU sensitivity in vitro, however these alterations do not fully explain clinical resistance to 5-FU-based chemotherapy. To determine if alterations of DNA copy number in genes involved in 5-FU metabolism-impacted clinical resistance to 5-FU-based chemotherapy, we assessed thymidylate synthetase (TYMS) and thymidine phosphorylase (TYMP) copy number in colorectal liver metastases. DNA copy number of TYMS and TYMP was evaluated using real time quantitative PCR in frozen colorectal liver metastases procured from 62 patients who were pretreated with 5-FU-based chemotherapy prior to surgical resection (5-FU exposed) and from 51 patients who received no pretreatment (unexposed). Gain of TYMS DNA copy number was observed in 18% of the 5-FU exposed metastases, while only 4% of the unexposed metastases exhibited TYMS copy gain (p = 0.036). No significant differences were noted in TYMP copy number alterations between 5-FU-exposed and -unexposed metastases. Median survival time was similar in 5-FU-exposed patients with metastases containing TYMS amplification and those with no amplification. However, TYMS amplification was associated with shorter median survival in patients receiving post-resection chemotherapy (hazard ratio = 2.7, 95% confidence interval = 1.1-6.6; p = 0.027). These results suggest amplification of TYMS amplification as a putative mechanism for clinical resistance to 5-FU-based chemotherapy and may have important ramifications for the post-resection chemotherapy choices for metastatic colorectal cancer.
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Affiliation(s)
- Roshawn G Watson
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Filipe Muhale
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Leigh B Thorne
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Jinsheng Yu
- Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
| | - Bert H O'Neil
- Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Janelle M Hoskins
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Michael O Meyers
- Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Allison M Deal
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Joseph G Ibrahim
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Michael L Hudson
- School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - Christine M Walko
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Howard L McLeod
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - James T Auman
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
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Savas S. Useful genetic variation databases for oncologists investigating the genetic basis of variable treatment response and survival in cancer. Acta Oncol 2010; 49:1217-26. [PMID: 20670087 DOI: 10.3109/0284186x.2010.500297] [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] [Indexed: 11/13/2022]
Abstract
Identification of the genetic basis of variable treatment response, prognosis and survival in cancer patients (i.e. personalized medicine) is an important aim in current medicine. Millions of genetic variations exist in the human genome, some of which are already found to be directly involved in variable treatment response and survival among cancer patients. GENETIC VARIATION DATABASES: Special databases curate, compile, organize and post information related to these genetic variations for the scientific community in a user friendly and free-to-access manner via the World Wide Web. FUTURE DIRECTIONS AND CONCLUSION: Clinicians have a critical role in genetic predictive and prognostic studies. In this review, main public-domain databases on genetic variations, including the two comprehensive genetic variation databases (dbSNP and HapMap), a pharmacogenomics database (PharmGKB), two resequencing-based genetic variation databases (SeattleSNPs and EGP), a population-based genetic variation database (JSNPs), and a copy-number variant database (DGV), and their utility in cancer research are discussed. Utilization of these databases can assist clinicians in their studies related to treatment response and prognosis in cancer patients.
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Affiliation(s)
- Sevtap Savas
- Memorial University of Newfoundland, St. John's, NL, Canada.
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Jin K, He K, Li G, Teng L. Personalized cancer therapy using a patient-derived tumor tissue xenograft model: a translational field worthy of exploring further? Per Med 2010; 7:597-606. [PMID: 29776245 DOI: 10.2217/pme.10.48] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
It has long been observed that interpatient variability in response to anticancer drugs is associated with different outcomes. Oncologists continually hold the desire of matching the right therapeutic regimen with the right cancer patient, which is termed ‘personalized cancer therapy’. Rapid advances in genetics, genomics and related technologies are promising a new era of personalized cancer therapy based on individual molecular biomarkers. However, these molecular predictors of tumor response are far from perfect. Because of the inherent limitations in the current approaches for anticancer drugs response prediction, the need for new techniques to predict tumor response to therapy is urgent. Using a patient-derived human tumor tissue (PDTT) xenograft model to predict tumor response to therapy might be an ideal candidate method to choose. This article provides an overview of the achievements and limitations of genetic, genomic and proteomic molecular markers for personalized cancer therapy, and further discusses the potentials of using a PDTT xenograft model as a candidate strategy for personalized cancer therapy.
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Affiliation(s)
- Ketao Jin
- Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Department of General Surgery, Zhejiang University Teaching Hospital Zhuji Hospital, Zhuji, Zhejiang, China
| | - Kuifeng He
- Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Guangliang Li
- Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy. Br J Cancer 2010; 103:581-9. [PMID: 20628391 PMCID: PMC2939780 DOI: 10.1038/sj.bjc.6605776] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: The impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU. Methods: Genotyping of TYMS (5′TRP and 3′UTR), UGT1A1*28, UGT1A9*22 and UGT1A7*3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study. Their association with response, toxicity and survival was investigated by univariate and multivariate statistical analysis. Results: TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response (OR=5.87, 95% confidence interval (CI)=1.68–20.45; P=0.005). UGT1A1*28/*28 was predictive for haematologic toxicity (OR=6.27, 95% CI=1.09–36.12; P=0.04), specifically for neutropenia alone (OR=6.40, 95% CI=1.11–37.03; P=0.038) or together with diarrhoea (OR=18.87, 95% CI=2.14–166.67; P=0.008). UGT1A9*1/*1 was associated with non-haematologic toxicity (OR=2.70, 95% CI=1.07–6.82; P=0.035). Haplotype VII (all non-favourable alleles) was associated with non-haematologic toxicity (OR=2.11, 95% CI=1.12–3.98; P=0.02). Conclusion: TYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients. A genetic-based algorithm to optimise treatment individualisation is proposed.
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Savas S, Younghusband HB. dbCPCO: a database of genetic markers tested for their predictive and prognostic value in colorectal cancer. Hum Mutat 2010; 31:901-7. [DOI: 10.1002/humu.21285] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Henríquez-Hernández LA, Pérez LF, Hernández AG, de León AC, Díaz-Chico B, Rosales AM. TYMS, MTHFR, p53 and MDR1 gene polymorphisms in breast cancer patients treated with adjuvant therapy. Cancer Epidemiol 2010; 34:490-3. [PMID: 20371218 DOI: 10.1016/j.canep.2010.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2009] [Revised: 02/25/2010] [Accepted: 03/08/2010] [Indexed: 01/15/2023]
Abstract
PURPOSE The distribution of TSER (TYMS), C677T (MTHFR), Arg72Pro (p53) and C3435T (MDR1) gene polymorphisms was investigated in 80 consecutive breast cancer patients treated with adjuvant chemotherapy. RESULTS Observed allelic frequencies were: TSER, (2) 0.55 and (3) 0.45; MTHFR C677T, (C) 0.65 and (T) 0.35; p53 Arg72Pro, (Arg) 0.76 and (Pro) 0.24; MDR1 C3435T, (C) 0.51 and (T) 0.49. MTHFR C677T was found to be a strong predictor of the presence of multifocal tumour (odds ratio, 4.1; 95% CI, 1.1-15.7; P=0.035). CONCLUSION Our data indicate that breast cancer patients with the C/C variant may present multifocal tumour most frequently.
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Liu G, Hu X, Chakrabarty S. Vitamin D mediates its action in human colon carcinoma cells in a calcium-sensing receptor-dependent manner: downregulates malignant cell behavior and the expression of thymidylate synthase and survivin and promotes cellular sensitivity to 5-FU. Int J Cancer 2010; 126:631-9. [PMID: 19621386 DOI: 10.1002/ijc.24762] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Vitamin D (VD) protects against colon carcinogenesis by mechanisms not fully understood. We had earlier reported on the similarity in the biologic action of VD and that of the calcium-sensing receptor (CaSR) in human colon carcinoma cells. At the molecular level, the CaSR gene contains 2 VD response elements and VD stimulates the expression of CaSR. In this study, we investigated on the relationship between VD action and CaSR function. We determined and compared the action of VD in human colon carcinoma cells (CBS, Moser, Caco-2 and HCT116) and their CaSR knocked-down counterparts. VD inhibited cellular proliferation, cellular invasion, and anchorage-independent growth and stimulated the expression of p21/Waf1 but not in CaSR knocked-down cells. These results demonstrate, for the first time, that the known tumor-suppressive function of VD requires functional CaSR and knocking down CaSR expression abrogated this function of VD. We recently reported that activation of CaSR in human colon carcinoma cells downregulated the expression of thymidylate synthase (TS) and survivin and promoted a significant increase in sensitivity to cytotoxic drugs. We now demonstrate, for the first time, that VD suppressed the expression of TS and survivin, TS and survivin gene transcriptional activities and promoted a cytotoxic response to 5-FU in a CaSR-dependent manner. Ectopic expression of wild-type CaSR in colon carcinoma cells also inhibited the expression of TS and survivin and enhanced cellular sensitivity to 5-FU. VD, however, could no longer enhance cellular sensitivity to 5-FU in cells overexpressing CaSR.
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Affiliation(s)
- Guangming Liu
- Department of Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794-9677, USA
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Cuesta R, Gupta M, Schneider RJ. The regulation of protein synthesis in cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2009; 90:255-92. [PMID: 20374744 DOI: 10.1016/s1877-1173(09)90007-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Translational control of cancer is a multifaceted process, involving alterations in translation factor levels and activities that are unique to the different types of cancers and the different stages of disease. Translational alterations in cancer include adaptations of the tumor itself, of the tumor microenvironment, an integral component in disease, and adaptations that occur as cancer progresses from development to local disease and ultimately to metastatic disease. Adaptations include the overexpression and increased activity of specific translation factors, the physical or functional loss of translation regulatory components, increased production of ribosomes, selective mRNA translation, and alteration of signal transduction pathways to permit unfettered activation of protein synthesis. There is intense clinical interest to capitalize on the emerging new understanding of translational control in cancer by targeting specific components of the translation apparatus that are altered in disease for the development of specific cancer therapeutics. Clinical trial data are nascent but encouraging, suggesting that translational control constitutes an important new area for drug development in human cancer.
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Affiliation(s)
- Rafael Cuesta
- Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA
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