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Pirvu LC, Stefaniu A, Nita S, Radu N, Neagu G. In Silico and In Vitro Analyses of Strawberry-Derived Extracts in Relation to Key Compounds' Metabolic and Anti-Tumor Effects. Int J Mol Sci 2025; 26:3492. [PMID: 40331930 PMCID: PMC12026510 DOI: 10.3390/ijms26083492] [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: 02/23/2025] [Revised: 04/04/2025] [Accepted: 04/05/2025] [Indexed: 05/08/2025] Open
Abstract
Plant extracts contain many small molecules that are less investigated. The present paper aims to study in silico physical-chemical, pharmacokinetic, medicinal chemistry and lead/drug-likeness properties and the ability to interfere with the activity of P-glycoprotein (P-gp) transporter and cytochrome P450 (CYP) oxidase system in humans of phloridzin, phloretin, 4-methylchalcone metabolic series alongside the top three compounds found in the ethanolic extract from strawberries (S), namely 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one, 2-pyrrolidinone 5-(cyclohexylmethyl) and hexadecanoic acid. The phloridzin derivatives also were studied for their inhibitory potential upon Bcl-2, TNKS1 and COX-2 molecular targets. In vitro, Caco-2 studies analyzed the cytoprotective and anti-proliferative activity of S and the three phloridzin derivatives (pure compounds) in comparison with their combination 1:1 (GAE/pure compound, w/w), in the range 1 to 50 µg active compounds per test sample. Altogether, it was concluded that phloretin (Phl) can be used alone or in combination with S to support intestinal cell health in humans. Phloridzin (Phd) and phloridzin combined with S were proven ineffective. 4-methylchalcone (4-MeCh) combined with S indicated no advantages, while the pure compound exhibited augmented inhibitory effects, becoming a candidate for combinations with anticancer drugs. Overall, in silico studies revealed possible limitations in the practical use of phloridzin derivatives due to their potential to interfere with the activity of several major CYP enzymes.
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Affiliation(s)
- Lucia Camelia Pirvu
- Department of Pharmaceutical Biotechnologies, National Institute for Chemical Pharmaceutical Research and Development (INCDCF-ICCF), 112 Vitan, 031299 Bucharest, Romania;
| | - Amalia Stefaniu
- Department of Pharmaceutical Biotechnologies, National Institute for Chemical Pharmaceutical Research and Development (INCDCF-ICCF), 112 Vitan, 031299 Bucharest, Romania;
| | - Sultana Nita
- Department of Physical-Chemical Analysis and Quality Control, National Institute for Chemical Pharmaceutical Research and Development (INCDCF-ICCF), 112 Vitan, 031299 Bucharest, Romania;
| | - Nicoleta Radu
- Biotechnology Faculty, University of Agronomic Sciences and Veterinary Medicine of Bucharest, 59 Marasti, District 1, 011464 Bucharest, Romania;
- Department of Biotechnology, National Institute of Chemistry and Petrochemistry Research and Development, 202 Splaiul Independentei, 060021 Bucharest, Romania
| | - Georgeta Neagu
- Department of Pharmacology, National Institute for Chemical Pharmaceutical Research and Development (INCDCF-ICCF), 112 Vitan, 031299 Bucharest, Romania
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Moric-Janiszewska E, Smolik S, Szydłowski L, Kapral M. Associations between Selected ADRB1 and CYP2D6 Gene Polymorphisms in Children with Ventricular and Supraventricular Arrhythmias. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2057. [PMID: 38138160 PMCID: PMC10744405 DOI: 10.3390/medicina59122057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/13/2023] [Accepted: 11/17/2023] [Indexed: 12/24/2023]
Abstract
Background and Objectives: Tachycardia is a common cardiovascular disease. Drugs blocking β1-adrenergic receptors (ADRB1) are used in the therapy of arrhythmogenic heart diseases. Disease-related polymorphisms can be observed within the ADRB1 gene. The two most important are Ser49Gly and Arg389Gly, and they influence the treatment efficacy. The family of the cytochrome P450 system consists of the isoenzyme CYP2D6 (Debrisoquine 4-hydroxylase), which is involved in phase I metabolism of almost 25% of clinically important drugs, including antiarrhythmic drugs. A study was conducted to detect the ADRB1 and CYP2D6 gene polymorphisms. Materials and Methods: The material for the test was whole blood from 30 patients with ventricular and supraventricular tachycardia and 20 controls. The samples were obtained from the Department of Pediatric Cardiology. The first to be made was the extraction of DNA using a GeneMATRIX Quick Blood DNA Purification Kit from EURx. The selected ADRB1 and CYP2D6 gene polymorphisms were detected by high-resolution melting polymerase chain reaction (HRM-PCR) analysis. Results: Based on the analysis of melt profile data for each PCR product, the identification of polymorphisms was carried out. Heterozygotes and homozygotes were found in the examined alleles. Conclusions: The frequency of the Arg389Gly polymorphism differs statistically significantly between the control group and patients with supraventricular and ventricular arrhythmias, as well as between these two groups of patients. Moreover, the Arg389Gly polymorphism was statistically more prevalent in the group of girls with SVT arrhythmia compared to girls with VT. A few carriers of homozygous and heterozygous systems of the S49G polymorphism were detected among patients with arrhythmias, as well as control group. The percentage of individuals carrying the CYP2D6 4 allele as either homozygous or heterozygous was observed in the study and control groups. The high prevalence of the CYP2D6*4 allele carriers in both groups prompts the optimization of beta-1 blocker therapy.
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Affiliation(s)
- Ewa Moric-Janiszewska
- Department of Biochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jedności 8B, 41-200 Sosnowiec, Poland
| | - Sławomir Smolik
- Department of Biochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jedności 8B, 41-200 Sosnowiec, Poland
| | - Lesław Szydłowski
- Department of Pediatric Cardiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Medyków 16, 40-752 Katowice, Poland
| | - Małgorzata Kapral
- Department of Biochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jedności 8B, 41-200 Sosnowiec, Poland
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Asif M, Alvi SS, Azaz T, Khan AR, Tiwari B, Hafeez BB, Nasibullah M. Novel Functionalized Spiro [Indoline-3,5'-pyrroline]-2,2'dione Derivatives: Synthesis, Characterization, Drug-Likeness, ADME, and Anticancer Potential. Int J Mol Sci 2023; 24:ijms24087336. [PMID: 37108498 PMCID: PMC10139052 DOI: 10.3390/ijms24087336] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 03/29/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
A highly stereo-selective, one-pot, multicomponent method was chosen to synthesize the novel functionalized 1, 3-cycloaddition spirooxindoles (SOXs) (4a-4h). Synthesized SOXs were analyzed for their drug-likeness and ADME parameters and screened for their anticancer activity. Our molecular docking analysis revealed that among all derivatives of SOXs (4a-4h), 4a has a substantial binding affinity (∆G) -6.65, -6.55, -8.73, and -7.27 Kcal/mol with CD-44, EGFR, AKR1D1, and HER-2, respectively. A functional study demonstrated that SOX 4a has a substantial impact on human cancer cell phenotypes exhibiting abnormality in cytoplasmic and nuclear architecture as well as granule formation leading to cell death. SOX 4a treatment robustly induced reactive oxygen species (ROS) generation in cancer cells as observed by enhanced DCFH-DA signals. Overall, our results suggest that SOX (4a) targets CD-44, EGFR, AKR1D1, and HER-2 and induces ROS generation in cancer cells. We conclude that SOX (4a) could be explored as a potential chemotherapeutic molecule against various cancers in appropriate pre-clinical in vitro and in vivo model systems.
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Affiliation(s)
- Mohd Asif
- Department of Chemistry, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Sahir Sultan Alvi
- Department of Immunology and Microbiology, South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Tazeen Azaz
- Department of Biological and Synthetic Chemistry, Centre of Biomedical Research, SGPGIMS-Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India
| | - Abdul Rahman Khan
- Department of Chemistry, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Bhoopendra Tiwari
- Department of Biological and Synthetic Chemistry, Centre of Biomedical Research, SGPGIMS-Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India
| | - Bilal Bin Hafeez
- Department of Immunology and Microbiology, South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Malik Nasibullah
- Department of Chemistry, Integral University, Lucknow 226026, Uttar Pradesh, India
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Asif M, Aqil F, Alasmary FA, almalki AS, Khan AR, Nasibullah M. Lewis base-catalyzed synthesis of highly functionalized spirooxindole-pyranopyrazoles and their in vitro anticancer studies. Med Chem Res 2023. [DOI: 10.1007/s00044-023-03053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
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Asif M, Saquib M, Rahman Khan A, Aqil F, salem Almalki A, Ali Alasmary F, Singh J, Nasibullah M. Synthesis of Functionalized 2′,5‐Oxo‐spiro[furan‐2,3′‐indoline]‐3‐carboxylate Derivatives as Antiproliferative Agents: ADMET Studies, and Molecular Docking against P2Y12 Inhibitors. ChemistrySelect 2023. [DOI: 10.1002/slct.202204536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Affiliation(s)
- Mohd Asif
- Department of Chemistry Integral University Lucknow 226026, U.P. India
| | - Mohammad Saquib
- Department of Chemistry University of Allahabad Prayagraj (Allahabad) 211002 India
| | - Abdul Rahman Khan
- Department of Chemistry Integral University Lucknow 226026, U.P. India
| | - Farrukh Aqil
- UofL Health-Brown Cancer Center and Department of Medicine University of Louisville Louisville KY40202 USA
| | - Amani salem Almalki
- Chemistry Department College of Science King Saud University Riyadh 11451 Saudi Arabia
| | - Fatmah Ali Alasmary
- Chemistry Department College of Science King Saud University Riyadh 11451 Saudi Arabia
| | - Jaya Singh
- Department of Chemistry LRPG College Sahibabad Ghaziabad 201005 India
| | - Malik Nasibullah
- Department of Chemistry Integral University Lucknow 226026, U.P. India
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Chakravarty D, Johnson A, Sklar J, Lindeman NI, Moore K, Ganesan S, Lovly CM, Perlmutter J, Gray SW, Hwang J, Lieu C, André F, Azad N, Borad M, Tafe L, Messersmith H, Robson M, Meric-Bernstam F. Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol 2022; 40:1231-1258. [PMID: 35175857 DOI: 10.1200/jco.21.02767] [Citation(s) in RCA: 123] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors. CLINICAL CONTEXT An increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers. However, there is a lack of clarity as to when tumor genomic sequencing should be ordered, what type of assays should be performed, and how to interpret the results for treatment selection. PROVISIONAL CLINICAL OPINION Patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel-based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumor mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase (NTRK) fusions provide a rationale for genomic testing for all solid tumors. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and expected efficacy of genomic biomarker-linked options relative to other approved or investigational treatments.Additional information is available at www.asco.org/assays-and-predictive-markers-guidelines.
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Affiliation(s)
| | | | | | - Neal I Lindeman
- Brigham and Womens' Hospital, Harvard Medical School, Boston, MA
| | | | | | | | | | | | | | | | - Fabrice André
- PRISM, Precision Medicine Center, Institut Gustave Roussy, Villejuif, France
| | | | | | - Laura Tafe
- Dartmouth-Hitchcock Medical Center and The Geisel School of Medicine at Dartmouth, Darmouth, NH
| | | | - Mark Robson
- Memorial Sloan Kettering Cancer Center, New York City, NY
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Pang H, Zhang G, Yan N, Lang J, Liang Y, Xu X, Cui Y, Wu X, Li X, Shan M, Wang X, Meng X, Liu J, Tian G, Cai L, Yuan D, Wang X. Evaluating the Risk of Breast Cancer Recurrence and Metastasis After Adjuvant Tamoxifen Therapy by Integrating Polymorphisms in Cytochrome P450 Genes and Clinicopathological Characteristics. Front Oncol 2021; 11:738222. [PMID: 34868931 PMCID: PMC8639703 DOI: 10.3389/fonc.2021.738222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 10/25/2021] [Indexed: 11/13/2022] Open
Abstract
Tamoxifen (TAM) is the most commonly used adjuvant endocrine drug for hormone receptor-positive (HR+) breast cancer patients. However, how to accurately evaluate the risk of breast cancer recurrence and metastasis after adjuvant TAM therapy is still a major concern. In recent years, many studies have shown that the clinical outcomes of TAM-treated breast cancer patients are influenced by the activity of some cytochrome P450 (CYP) enzymes that catalyze the formation of active TAM metabolites like endoxifen and 4-hydroxytamoxifen. In this study, we aimed to first develop and validate an algorithm combining polymorphisms in CYP genes and clinicopathological signatures to identify a subpopulation of breast cancer patients who might benefit most from TAM adjuvant therapy and meanwhile evaluate major risk factors related to TAM resistance. Specifically, a total of 256 patients with invasive breast cancer who received adjuvant endocrine therapy were selected. The genotypes at 10 loci from three TAM metabolism-related CYP genes were detected by time-of-flight mass spectrometry and multiplex long PCR. Combining the 10 loci with nine clinicopathological characteristics, we obtained 19 important features whose association with cancer recurrence was assessed by importance score via random forests. After that, a logistic regression model was trained to calculate TAM risk-of-recurrence score (TAM RORs), which is adopted to assess a patient's risk of recurrence after TAM treatment. The sensitivity and specificity of the model in an independent test cohort were 86.67% and 64.56%, respectively. This study showed that breast cancer patients with high TAM RORs were less sensitive to TAM treatment and manifested more invasive characteristics, whereas those with low TAM RORs were highly sensitive to TAM treatment, and their conditions were stable during the follow-up period. There were some risk factors that had a significant effect on the efficacy of TAM. They were tissue classification (tumor Grade < 2 vs. Grade ≥ 2, p = 2.2e-16), the number of lymph node metastases (Node-Negative vs. Node < 4, p = 5.3e-07; Node < 4 vs. Node ≥ 4, p = 0.003; Node-Negative vs. Node ≥ 4, p = 7.2e-15), and the expression levels of estrogen receptor (ER) and progesterone receptor (PR) (ER < 50% vs. ER ≥ 50%, p = 1.3e-12; PR < 50% vs. PR ≥ 50%, p = 2.6e-08). The really remarkable thing is that different genotypes of CYP2D6*10(C188T) show significant differences in prediction function (CYP2D6*10 CC vs. TT, p < 0.019; CYP2D6*10 CT vs. TT, p < 0.037). There are more than 50% Chinese who have CYP2D6*10 mutation. So the genotype of CYP2D6*10(C188T) should be tested before TAM therapy.
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Affiliation(s)
- Hui Pang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Guoqiang Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Na Yan
- Department of Science, Geneis (Beijing) Co., Ltd., Beijing, China
- Department of Science, Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Jidong Lang
- Department of Science, Geneis (Beijing) Co., Ltd., Beijing, China
- Department of Science, Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Yuebin Liang
- Department of Science, Geneis (Beijing) Co., Ltd., Beijing, China
- Department of Science, Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Xinyuan Xu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yaowen Cui
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xueya Wu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xianjun Li
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ming Shan
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiaoqin Wang
- Department of Science, Geneis (Beijing) Co., Ltd., Beijing, China
| | - Xiangzhi Meng
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaxiang Liu
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Geng Tian
- Department of Science, Geneis (Beijing) Co., Ltd., Beijing, China
- Department of Science, Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Li Cai
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dawei Yuan
- Department of Science, Geneis (Beijing) Co., Ltd., Beijing, China
| | - Xin Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Ahmad P, Alvi SS, Iqbal J, Khan MS. Identification and evaluation of natural organosulfur compounds as potential dual inhibitors of α-amylase and α-glucosidase activity: an in-silico and in-vitro approach. Med Chem Res 2021. [DOI: 10.1007/s00044-021-02799-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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9
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Maggadani BP, Harahap Y, Harmita, Haryono SJ, Untu CWP. Analysis of tamoxifen and its metabolites in dried blood spot and volumetric absorptive microsampling: comparison and clinical application. Heliyon 2021; 7:e07275. [PMID: 34179536 PMCID: PMC8213905 DOI: 10.1016/j.heliyon.2021.e07275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/22/2021] [Accepted: 06/07/2021] [Indexed: 10/29/2022] Open
Abstract
This research was conducted to develop the Dried Blood Spot (DBS) and Volumetric Absorptive Microsampling (VAMS) method in the analysis of Tamoxifen (TAM) and its metabolites endoxifen (END), 4-hydroxytamoxifen (4-HT), and N-desmethyltamoxifen (NDT) using Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). This method was then applied to monitor TAM and its metabolites in breast cancer patients. The UPLC-MS/MS method was developed and validated with propranolol as the internal standard. The recovery and matrix effects on DBS and VAMS were investigated. The validation requirements were fulfilled by the methodology of analysis and sample preparation described in this study. Both VAMS and DBS extraction recoveries were satisfactory, with low variability. Extraction recovery in the VAMS sample was found to be slightly higher than in the DBS sample. Sample stability in DBS and VAMS was demonstrated for up to 2 months. Both of these methods were successfully applied for the analysis of TAM and metabolites in clinical patients. The mean concentrations obtained from the two methods were not significantly different.
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Affiliation(s)
| | - Yahdiana Harahap
- Faculty of Pharmacy, Universitas Indonesia, Depok, 16424, Indonesia
- Indonesia Defense University, Bogor 16810, West Java, Indonesia
| | - Harmita
- Faculty of Pharmacy, Universitas Indonesia, Depok, 16424, Indonesia
| | - Samuel J. Haryono
- Surgical Oncology Division, SJH Initiative-MRCCC Siloam Hospital, Jakarta, Indonesia
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10
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African genetic diversity and adaptation inform a precision medicine agenda. Nat Rev Genet 2021; 22:284-306. [PMID: 33432191 DOI: 10.1038/s41576-020-00306-8] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2020] [Indexed: 01/29/2023]
Abstract
The deep evolutionary history of African populations, since the emergence of modern humans more than 300,000 years ago, has resulted in high genetic diversity and considerable population structure. Selected genetic variants have increased in frequency due to environmental adaptation, but recent exposures to novel pathogens and changes in lifestyle render some of them with properties leading to present health liabilities. The unique discoverability potential from African genomic studies promises invaluable contributions to understanding the genomic and molecular basis of health and disease. Globally, African populations are understudied, and precision medicine approaches are largely based on data from European and Asian-ancestry populations, which limits the transferability of findings to the continent of Africa. Africa needs innovative precision medicine solutions based on African data that use knowledge and implementation strategies aligned to its climatic, cultural, economic and genomic diversity.
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Możdżeń E, Babińska I, Wójcikowski J, Antkiewicz-Michaluk L. 1-Methyl-1,2,3,4-tetrahydroisoquinoline - The toxicological research on an exo/endogenous amine with antidepressant-like activity - In vivo, in vitro and in silico studies. Pharmacol Rep 2019; 71:1140-1146. [PMID: 31655278 DOI: 10.1016/j.pharep.2019.06.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 06/08/2019] [Accepted: 06/28/2019] [Indexed: 11/23/2022]
Abstract
BACKGROUND 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) demonstrates significant neuroprotective activity. It can interact with agonistic conformation of dopamine (DA) receptors. 1MeTIQ inhibits the formation of 3,4-dihydroxyphenylacetic acid as well as production of free radicals and shifts DA catabolism toward COMT-dependent O-methylation. 1MeTIQ inhibits both MAO-A and B enzymes activity and increases neurotransmitters levels in the brain. It shows significant antidepressant-like effect in forced swim test (FST) in rats. This compound might be effective for depression therapy in a clinical setting but its success is determined not only by good efficacy, but also by an acceptable its ADMET profile. The use of combination in silico prediction with in vivoand in vitro studies greatly simplifies the search for new, safer and effectively acting drugs. METHODS The aim of this study was to investigate the degree of histopathological changes in different rats tissues after acute and chronic administration of 1MeTIQ. Additionally, prediction of its properties in terms of absorption, distribution, metabolism, elimination and toxicity in the human body was performed. RESULTS The obtained data did not show extensive and significant toxic effects of tested substance in in vivo and in vitro studies in rats, and in silico ADMET prediction. CONCLUSIONS These results can help to discover a new effective and safe antidepressant substance and have important significance in the treatment of depression in clinic. Additionally, the use in the treatment of depression substance with neuroprotective, antioxidant and antidepressant-like effects in the CNS and existing endogenously might be also beneficial in controlling the adverse CNS inflammatory processes accompanying depression.
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Affiliation(s)
- Edyta Możdżeń
- Department of Neurochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
| | - Izabela Babińska
- Department of Pathophysiology, Forensic and Administration of Veterinary Medicine, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Jacek Wójcikowski
- Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
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Impact of CYP2D6 polymorphisms on endoxifen concentrations and breast cancer outcomes. THE PHARMACOGENOMICS JOURNAL 2017; 18:201-208. [DOI: 10.1038/tpj.2017.36] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 06/03/2017] [Accepted: 06/07/2017] [Indexed: 12/27/2022]
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13
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Bag A, Ghorai PK. Enhancement of biocompatibility and photoacoustic contrast activity of metal clusters. J Mol Graph Model 2017; 75:220-232. [PMID: 28601707 DOI: 10.1016/j.jmgm.2017.05.011] [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: 02/28/2017] [Revised: 05/12/2017] [Accepted: 05/16/2017] [Indexed: 01/23/2023]
Abstract
Organometallic carbonyl clusters (OMCC) of group VIII elements are water soluble, bio-compatible and stable high-contrast photoacoustic agents for live cell imaging. But, they have limited application due to weak absorption within 700-1000nm wavelength which is known as the biological window of absorption. In this article, we report that hexa-nuclear iron (Fe6) carbonyl cluster derivatized with sodium thio-propanoate has very good absorption within 700-1600nm wave length. This modeled compound is water soluble and bio-compatible. The bio-compatibility of this compound is tested through cytotoxicity, LogP and metabolic probability at CYP450-2D6 enzyme.
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Affiliation(s)
- Arijit Bag
- Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur 741246, WB, India
| | - Pradip Kr Ghorai
- Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur 741246, WB, India.
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14
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Delaney SK, Hultner ML, Jacob HJ, Ledbetter DH, McCarthy JJ, Ball M, Beckman KB, Belmont JW, Bloss CS, Christman MF, Cosgrove A, Damiani SA, Danis T, Delledonne M, Dougherty MJ, Dudley JT, Faucett WA, Friedman JR, Haase DH, Hays TS, Heilsberg S, Huber J, Kaminsky L, Ledbetter N, Lee WH, Levin E, Libiger O, Linderman M, Love RL, Magnus DC, Martland A, McClure SL, Megill SE, Messier H, Nussbaum RL, Palaniappan L, Patay BA, Popovich BW, Quackenbush J, Savant MJ, Su MM, Terry SF, Tucker S, Wong WT, Green RC. Toward clinical genomics in everyday medicine: perspectives and recommendations. Expert Rev Mol Diagn 2016; 16:521-32. [PMID: 26810587 PMCID: PMC4841021 DOI: 10.1586/14737159.2016.1146593] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Precision or personalized medicine through clinical genome and exome sequencing has been described by some as a revolution that could transform healthcare delivery, yet it is currently used in only a small fraction of patients, principally for the diagnosis of suspected Mendelian conditions and for targeting cancer treatments. Given the burden of illness in our society, it is of interest to ask how clinical genome and exome sequencing can be constructively integrated more broadly into the routine practice of medicine for the betterment of public health. In November 2014, 46 experts from academia, industry, policy and patient advocacy gathered in a conference sponsored by Illumina, Inc. to discuss this question, share viewpoints and propose recommendations. This perspective summarizes that work and identifies some of the obstacles and opportunities that must be considered in translating advances in genomics more widely into the practice of medicine.
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Affiliation(s)
- Susan K Delaney
- a Coriell Institute for Medical Research , Camden , NJ , USA
| | - Michael L Hultner
- b Lockheed Martin , Information Systems & Global Solutions , Rockville , MD , USA
| | - Howard J Jacob
- c HudsonAlpha Institute for Biotechnology , Huntsville , AL , USA
| | | | - Jeanette J McCarthy
- e Duke University , Center for Applied Genomics and Precision Medicine , Durham , NC , USA
| | | | - Kenneth B Beckman
- g University of Minnesota , Genomics Center ,, Minneapolis , MN , USA
| | - John W Belmont
- h Baylor College of Medicine , Children's Nutrition Research Center , Houston , TX , USA
| | - Cinnamon S Bloss
- i University of California, San Diego , School of Medicine , La Jolla , CA , USA
| | | | | | - Stephen A Damiani
- k Mission Massimo Foundation , Elsternwick , VIC , Australia .,l Mission Massimo Foundation Inc ., Westlake Village , CA , USA
| | | | | | - Michael J Dougherty
- o The American Society of Human Genetics , Bethesda , MD , USA.,p Department of Pediatrics , University of Colorado School of Medicine , Aurora , CO , USA
| | - Joel T Dudley
- q Icahn School of Medicine at Mount Sinai , New York , NY , USA
| | | | - Jennifer R Friedman
- r University of California, San Diego , Departments of Neurosciences and Pediatrics and Rady Children's Hospital , San Diego , CA , USA
| | | | - Tom S Hays
- t University of Minnesota , Department of Genetics, Cell Biology and Development , Minneapolis , MN , USA
| | | | - Jeff Huber
- u Google Inc ., Mountain View , CA , USA
| | | | | | | | - Elissa Levin
- q Icahn School of Medicine at Mount Sinai , New York , NY , USA
| | | | | | | | - David C Magnus
- y Stanford Center for Biomedical Ethics , Stanford School of Medicine , Stanford , CA , USA
| | | | | | | | - Helen Messier
- ab Healix Health, Ltd , West Vancouver , BC , Canada
| | | | | | | | | | | | | | - Michael M Su
- ai Anthem Blue Cross , Woodland Hills , CA , USA
| | | | - Steven Tucker
- ak Novena Specialist Center , Singapore , Republic of Singapore
| | | | - Robert C Green
- am Division of Genetics, Department of Medicine, Brigham and Women's Hospital , the Broad Institute, Harvard Medical School and Partners Healthcare Personalized Medicine , Boston , MA , USA
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15
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Hu XX, Yuan LJ, Fang P, Mao YH, Zhan YY, Li XY, Dai DP, Cai JP, Hu GX. Effect of CYP2D6 genetic polymorphism on the metabolism of citalopram in vitro. Drug Metab Pharmacokinet 2016; 31:133-8. [PMID: 27016952 DOI: 10.1016/j.dmpk.2016.01.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 12/21/2015] [Accepted: 01/14/2016] [Indexed: 12/17/2022]
Abstract
Genetic polymorphisms of CYP2D6 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. We aimed at investigating the role of CYP2D6 in the metabolism of citalopram and identifying the effect of 24 CYP2D6 allelic variants we found in Chinese Han population on the metabolism of citalopram in vitro. These CYP2D6 variants expressed by insect cells system were incubated with 10-1000 μM citalopram for 30 min at 37 °C and the reaction was terminated by cooling to -80 °C immediately. Citalopram and its metabolites were analyzed by high-performance liquid chromatography (HPLC). The intrinsic clearance (Vmax/Km) values of the variants toward citalopram metabolites were significantly altered, 38-129% for demethylcitalopram and 13-138% for citalopram N-oxide when compared with CYP2D6*1. Most of the tested rare alleles exhibited significantly decreased values due to increased Km and/or decreased Vmax values. We conclude that recombinant system could be used to investigate the enzymes involved in drug metabolism and these findings suggest that more attention should be paid to subjects carrying these CYP2D6 alleles when administering citalopram in the clinic.
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Affiliation(s)
- Xiao-Xia Hu
- Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ling-Jing Yuan
- Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ping Fang
- Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yong-Hui Mao
- Department of Nephrology, Beijing Hospital, Ministry of Health, Beijing, China
| | - Yun-Yun Zhan
- Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiang-Yu Li
- Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Da-Peng Dai
- The Key Laboratory of Geriatrics, Beijing Hospital, Beijing Institute of Geriatrics, Ministry of Health, Beijing, China
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Hospital, Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.
| | - Guo-Xin Hu
- Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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16
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Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort. THE PHARMACOGENOMICS JOURNAL 2015; 16:566-572. [PMID: 26503815 DOI: 10.1038/tpj.2015.76] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 08/20/2015] [Accepted: 09/08/2015] [Indexed: 11/08/2022]
Abstract
The relationship between genetic variation in CYP2D6 and variable drug response represents a potentially powerful pharmacogenetic tool. However, little is known regarding this relationship in the genetically diverse South African population. The aim was therefore to evaluate the relationship between predicted and measured CYP2D6 phenotype. An XL-PCR+Sequencing approach was used to determine CYP2D6 genotype in 100 healthy volunteers and phenotype was predicted using activity scores. With dextromethorphan as the probe drug, metabolic ratios served as a surrogate measure of in vivo CYP2D6 activity. Three-hour plasma metabolic ratios of dextrorphan/dextromethorphan were measured simultaneously using semi-automated online solid phase extraction coupled with tandem mass spectrometry. Partial adaptation of the activity score system demonstrated a strong association between genotype and phenotype, as illustrated by a kappa value of 0.792, inter-rater discrepancy of 0.051 and sensitivity of 72.7%. Predicted phenotype frequencies using the modified activity score were 1.3% for poor metabolisers (PM), 7.6% for intermediate metabolisers (IM) and 87.3% for extensive metabolisers (EM). Measured phenotype frequencies were 1.3% for PM, 13.9% for IM and 84.8% for EM. Comprehensive CYP2D6 genotyping reliably predicts CYP2D6 activity in this South African cohort and can be utilised as a valuable pharmacogenetic tool.
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Markopoulos C, Kykalos S, Mantas D. Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen. World J Clin Oncol 2014; 5:374-381. [PMID: 25114852 PMCID: PMC4127608 DOI: 10.5306/wjco.v5.i3.374] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 03/10/2014] [Accepted: 06/03/2014] [Indexed: 02/06/2023] Open
Abstract
Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.
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18
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Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype. Breast 2014; 23:400-6. [DOI: 10.1016/j.breast.2014.02.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Revised: 02/12/2014] [Accepted: 02/22/2014] [Indexed: 11/22/2022] Open
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19
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Marcsisin SR, Sousa JC, Reichard GA, Caridha D, Zeng Q, Roncal N, McNulty R, Careagabarja J, Sciotti RJ, Bennett JW, Zottig VE, Deye G, Li Q, Read L, Hickman M, Dhammika Nanayakkara NP, Walker LA, Smith B, Melendez V, Pybus BS. Tafenoquine and NPC-1161B require CYP 2D metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds. Malar J 2014; 13:2. [PMID: 24386891 PMCID: PMC3893421 DOI: 10.1186/1475-2875-13-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 12/22/2013] [Indexed: 12/03/2022] Open
Abstract
Background Tafenoquine (TQ) is an 8-aminoquinoline (8AQ) that has been tested in several Phase II and Phase III clinical studies and is currently in late stage development as an anti-malarial prophylactic agent. NPC-1161B is a promising 8AQ in late preclinical development. It has recently been reported that the 8AQ drug primaquine requires metabolic activation by CYP 2D6 for efficacy in humans and in mice, highlighting the importance of pharmacogenomics in the target population when administering primaquine. A logical follow-up study was to determine whether CYP 2D activation is required for other compounds in the 8AQ structural class. Methods In the present study, the anti-malarial activities of NPC-1161B and TQ were assessed against luciferase expressing Plasmodium berghei in CYP 2D knock-out mice in comparison with normal C57BL/6 mice (WT) and with humanized/CYP 2D6 knock-in mice by monitoring luminescence with an in vivo imaging system. These experiments were designed to determine the direct effects of CYP 2D metabolic activation on the anti-malarial efficacy of NPC-1161B and TQ. Results NPC-1161B and TQ exhibited no anti-malarial activity in CYP 2D knock-out mice when dosed at their ED100 values (1 mg/kg and 3 mg/kg, respectively) established in WT mice. TQ anti-malarial activity was partially restored in humanized/CYP 2D6 knock-in mice when tested at two times its ED100. Conclusions The results reported here strongly suggest that metabolism of NPC-1161B and TQ by the CYP 2D enzyme class is essential for their anti-malarial activity. Furthermore, these results may provide a possible explanation for therapeutic failures for patients who do not respond to 8AQ treatment for relapsing malaria. Because CYP 2D6 is highly polymorphic, variable expression of this enzyme in humans represents a significant pharmacogenomic liability for 8AQs which require CYP 2D metabolic activation for efficacy, particularly for large-scale prophylaxis and eradication campaigns.
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Affiliation(s)
- Sean R Marcsisin
- Division of Experimental Therapeutics, Military Malaria Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910, USA.
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20
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Slaughter RL. Pharmacokinetic behavior presents drug therapy challenges. Expert Rev Clin Pharmacol 2013; 6:627-39. [PMID: 24164611 DOI: 10.1586/17512433.2013.849196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
There are conditions that cause a substantial change in drug clearance to such a degree that how a specific drug is managed to optimize drug response and minimize drug toxicity presents a challenge. This review will focus on recent literature (within the past 5 years) that evaluates pathophysiologic and genetic conditions and drug interactions which can change drug clearance to the magnitude that response is affected. Situations discussed that cause an increase in drug clearance will include: augmented renal clearance in critically ill patients; ultrafast drug metabolism caused by gene duplication; and enzyme induction interactions caused by rifampin. Situations discussed that result in a reduction in clearance will include: multiple organ failure in critically ill, patients with non-functioning CYP2D6 and CYP2C8/9 alleles, and CYP3A4 drug interactions with erythromycin and clarithromycin. In each case evaluated clearance is changed to the magnitude such that managing drug therapy can be difficult.
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Affiliation(s)
- Richard L Slaughter
- Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, 259 Mack Ave, Detroit, MI 48201, USA +313 577 1574
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21
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Abstract
The past decade has brought together substantial advances in human genome analysis and a maturation of understanding of tumor biology. Although there is much progress still to be made, there are now several prominent examples in which tumor-associated somatic mutations have been used to identify cellular signaling pathways in tumors. This in turn has led to the development of targeted therapies, with somatic mutations serving as genomic predictors of tumor response and providing new leads for drug development. There is also a realization that germline DNA variants can help optimize cancer drug dosing and predict the susceptibility of patients to the adverse side effects of these drugs-knowledge that ultimately can be used to improve the benefit:risk ratio of cancer treatment for individual patients.
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Affiliation(s)
- Howard L McLeod
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC 27599, USA.
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22
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Newman WG, Flockhart D. Breast cancer pharmacogenomics: where we are going. Pharmacogenomics 2012; 13:629-31. [PMID: 22515602 DOI: 10.2217/pgs.12.37] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
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