Clinical Trial: CYP2D6 Related Dose Escalation of Tamoxifen in Breast Cancer Patients With Iranian Ethnic Background Resulted in Increased Concentrations of Tamoxifen and Its Metabolites

Introduction: The polymorphic enzyme cytochrome P450 2D6 (CYP2D6) catalyzes a major step in the bioactivation of tamoxifen. Genotyping of clinically relevant CYP2D6 alleles and subsequent dose adjustment is a promising approach to individualize breast cancer therapy. The aim of this study was to investigate the relationship between the plasma levels of tamoxifen and its metabolites and different CYP2D6 genotypes under standard (20 mg/d) and dose-adjusted therapy (Registration ID in Iranian Registry of Clinical Trials: IRCT2015082323734N1). Material and methods: Using TaqMan® assays common alleles of CYP2D6 (*1, *2, *4, *5, *6, *10, *17 and *41) and gene duplication were identified in 134 breast cancer patients. Based on CYP2D6 genotypes patients with an activity score 1 (n=15) and 0 to 0.5 (n=2) were treated with tamoxifen adjusted dosage of 30 and 40 mg/d, respectively. The concentration of tamoxifen and its metabolites before and after 4 and 8 months of dose adjustment were measured using LC-MS/MS technology. Results: At baseline, (Z)-endoxifen plasma concentrations (33 ± 15.5, 28.1 ± 14, 26.6 ± 23.4, 14.3 ± 8.6 and 10.7 ± 5.5 for EM/EM, EM/IM, EM/PM, IM/IM and PM/PM, respectively) and the metabolic ratio (Z)-Endoxifen / N-desmethyltamoxifen (0.0558 ± 0.02, 0.0396 ± 0.0111, 0.0332 ± 0.0222, 0.0149 ± 0.0026 and 0.0169 ± 0.0177 for EM/EM, EM/IM, EM/PM, IM/IM and PM/PM, respectively) correlated with C...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research

Related Links:

Authors: Cheng G, Zielonka J, Hardy M, Ouari O, Chitambar CR, Dwinell MB, Kalyanaraman B Abstract We demonstrate that combined treatment with metformin (Met) or its mitochondria-targeted analog, mito-metformin (Mito-Met), and various iron chelators synergistically inhibits proliferation of pancreatic and triple-negative breast cancer cells. Previously, we reported that Met (at millimolar levels) and Mito-Met (at micromolar levels) inhibited pancreatic cancer cell proliferation. Inhibition of mitochondrial complex I and mitochondrial oxidative phosphorylation (OXPHOS) through stimulation of mitochondrial redox signa...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
AbstractPurpose of reviewThis paper will focus on novel breast cancer therapies used in clinical practice today, as well as review our understanding of standard therapies and their potential impact on cardiovascular health.Recent findingsEstablished and novel treatments such as anthracyclines, HER2-targeted agents, and immunotherapy have contributed to improvements in breast cancer outcomes; however, these treatments may be associated with an increased risk of cardiovascular injury. The number of available breast cancer treatments continues to expand, as does the need for health care providers to understand the potential i...
Source: Current Treatment Options in Cardiovascular Medicine - Category: Cardiology Source Type: research
In this study, we identified a natural compound 3-deoxy-2β,16-dihydroxynagilactone E (B6) from the traditional Chinese medicinal plant Podocarpus nagi as a potent inhibitor of STAT3 signaling. B6 preferentially inhibited the phosphorylation of STAT3 by interacting with and inactivating JAK2, the main upstream kinase of STAT3. B6 dose-dependently inhibited IL-6-induced STAT3 signaling with an IC50 of 0.2 μM. In contrast to other JAK2 inhibitors, B6 did not interact with the catalytic domain but instead with the FERM-SH2 domain of JAK2. This interaction was JAK-specific since B6 had little effect on other tyro...
Source: Acta Pharmacologica Sinica - Category: Drugs & Pharmacology Authors: Tags: Acta Pharmacol Sin Source Type: research
In this study, based on nucleolin’s active transport property to the nucleus and its affinity with aptamer, we developed a nuclear-targeted delivery system to circumvention of drug resistance in breast cancer (MCF-7/Adr). Dox·HCl inserted in the aptamer AS1411 (Ap-Dox) was encapsulated in the aqueous interior of liposome (Lip(Ap-Dox)). In vitro studies showed that after the Lip(Ap-Dox) diffusing into MCF-7/Adr cells, Ap-Dox complex bound with nucleolin strongly and eventually entered the cell nuclei. By using this drug delivery system, Dox·HCl can efficiently accumulated in the nuclei to effectively kill the cancer cells.
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
Deleted in Breast Cancer 1 (DBC1/CCAR2) is a regulatory protein involved in cell survival and cancer progression. Herein, we focused on summarizing the overall prognostic value of DBC1 for digestive system cancers. Therefore, we conducted a meta-analysis based on 9 studies with 2391 patients to generated combined hazard ratios (HR) or odds ratio (OR) with its 95% confidence intervals (CI) for overall survival (OS) and clinicopathological features. Positive DBC1 expression was significantly associated with poor OS of digestive system cancers (pooled HR=1.650, 95% CI=1.087-2.504, P
Source: Journal of Cancer - Category: Cancer & Oncology Authors: Tags: Research Paper Source Type: research
Publication date: Available online 11 June 2019Source: Journal of Geriatric OncologyAuthor(s): Meghan S. Karuturi, Mina S. Sedrak, Allison Magnuson, Rachel Freedman, Aminah Jatoi, Bejamin D. Smith, Gretchen G. KimmickAbstractWith the aging of the US population, the number of individuals age 65 or older who will be diagnosed with breast cancer is expected to rise. Despite this, older adults with breast cancer remain severely under-represented in cancer clinical trials. Numerous studies have highlighted disparites in care experienced by older patients with breast cancer. Dr. Arti Hurria was one of the most influential leader...
Source: Journal of Geriatric Oncology - Category: Cancer & Oncology Source Type: research
In this study, based on nucleolin's active transport property to the nucleus and its affinity with aptamer, we developed a nuclear-targeted delivery system to circumvention of drug resistance in breast cancer (MCF-7/Adr). Dox·HCl inserted in the aptamer AS1411 (Ap-Dox) was encapsulated in the aqueous interior of liposome (Lip(Ap-Dox)). In vitro studies showed that after the Lip(Ap-Dox) diffusing into MCF-7/Adr cells, Ap-Dox complex bound with nucleolin strongly and eventually entered the cell nuclei. By using this drug delivery system, Dox·HCl can efficiently accumulated in the nuclei to effectively kill the ...
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - Category: Drugs & Pharmacology Authors: Tags: Biomed Pharmacother Source Type: research
In this study, we found differences in mitochondrial morphology in breast cancer cells when compared to a non-tumorigenic cell line and differences in mitochondrial function among breast cancer subtypes when exploring gene-expression data from the TCGA tumor dataset. Interestingly, we found increased ROS levels in triple negative breast cancer (TNBC) cell lines and a dependency on ROS for survival since antioxidant treatment induced cell death in TNBC cells but not in an estrogen receptor positive (ER+) cell line. Moreover, we identified the mitochondria as the main source of ROS in TNBC cell lines. Our results indicate a ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Abstract Cullin-1 (CUL1) is an important factor for tumor growth and a potential therapeutic target for breast cancer therapy, but the molecular mechanism in triple-negative breast cancer (TNBC) is unknown. In the present study, CUL1 shRNA was transfected into BT549 and MDA-MB-231 breast cancer cells. Cell morphology, adhesion, invasion, and migration assays were carried out in the CUL1 knockdown cells. Additionally, protein expression levels of epithelial-mesenchymal transition (EMT)-related factors, Akt phosphorylation at S473 (pAkt), glycogen synthase kinase-3β phosphorylation at ser9 (pGSK3β), cytopl...
Source: Pathology Oncology Research - Category: Pathology Authors: Tags: Pathol Oncol Res Source Type: research
Abstract Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. Disrupting the EZH2-EED interaction, which is required for PRC2 enzymatic activity, is a promising strategy for cancer treatment. However, this kind of inhibitors are still limited. The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology. Co-immunoprecipitation (Co-IP), protein thermal shift assay (PTSA), and cellular thermal shift assay (CETSA) were performed to investigate th...
Source: Acta Pharmacologica Sinica - Category: Drugs & Pharmacology Authors: Tags: Acta Pharmacol Sin Source Type: research
More News: Breast Cancer | Cancer | Cancer & Oncology | Cancer Therapy | Clinical Trials | Drugs & Pharmacology | Genetics | Iran Health | Study | Tamoxifen