ABCB1 유전적 다형성이 만성 골수성 백혈병 환자의 Imatinib 치료 반응에 미치는 영향: 체계적 문헌고찰 및 메타분석

하혜민,천부순,Ha, Hye Min,Chun, Pusoon 대한약학회 2016 약학회지 Vol.60 No.3

A growing number of studies have demonstrated that ABCB1 gene polymorphisms are associated with the variability of responses to imatinib. However, the effects of ABCB1 polymorphisms on imatinib response in chronic myeloid leukemia (CML) are inconsistent. The aim of the present study was to clarify the associations between ABCB1 polymorphisms and imatinib response in CML. A systematic literature review was performed. The databases of PubMed, Embase, and Cochrane Library were searched for all published studies from inception to December 2015. The following terms were used with functions of 'AND' and 'OR': 'chronic myeloid leukemia', 'CML', 'ABCB1', 'MDR1', 'polymorphism', 'SNP', and 'imatinib'. Using the Review Manager 5, odds ratios (ORs) were pooled to estimate the effect of ABCB1 polymorphisms on imatinib response in CML. The pooled analysis showed that ABCB1 2677 G allele was significantly associated with poor response to imatinib in African and Asian patients (GG vs TT, OR: 0.32, p<0.0001; GG+GT vs TT, OR: 0.44, p=0.0005). In subgroup analyses, African patients carrying ABCB1 1236 C allele exhibited higher risk for worse response, whereas Asian patients with 1236 C allele showed better response (CC+CT vs TT, OR: 0.41, p=0.008 for African; OR: 1.65, p=0.03 for Asian). There was no association between C3435T polymorphisms and imatinib response in African, Asian, and Caucasian CML patients.

Effect of <i>ABCB1</i> (<i>MDR1</i>) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects

Kim, Kyoung-Ah,Park, Pil-Whan,Park, Ji-Young Blackwell Scientific Publications 2007 British journal of clinical pharmacology Vol.63 No.1

<P>Aim</P><P>We aimed to investigate the effect of the <I>ABCB1</I> gene on the pharmacokinetics of amlodipine.</P><P>Methods</P><P>Based on polymorphisms of the <I>ABCB1</I> gene at positions 2677 and 3435, 26 healthy male participants were divided into three groups: subjects with 2677GG/3435CC (<I>n</I> = 9), 2677GT/3435CT (<I>n</I> = 9) and 2677TT/3435TT (<I>n</I> = 8). After a single-dose administration of 5 mg amlodipine, plasma concentrations of amlodipine were measured and its pharmacokinetic characteristics were compared according to <I>ABCB1</I> genotype.</P><P>Results</P><P>The area under the plasma concentration–time curve was significantly lower in subjects with 2677TT/3435TT (140.8 ± 35.6 ng h<SUP>−1</SUP> ml<SUP>−1</SUP>) and 2677GT/3435CT (149.8 ± 40.1 ng h<SUP>−1</SUP> ml<SUP>−1</SUP>) than in those with 2677GG/3435CC (208.6 ± 39.2 ng h<SUP>−1</SUP> ml<SUP>−1</SUP>) [95% confidence interval (CI) on the difference, 2677GG/3435CC <I>vs.</I> 2677GT/3435CT 12.0, 105.6, <I>P</I> < 0.01; 2677GG/3435CC <I>vs.</I> 2677TT/3435TT 19.6, 116.0, <I>P</I> < 0.01; 2677GT/3435CT <I>vs.</I> 2677TT/3435TT − 39.2, 57.2, <I>P</I> > 0.05]. The peak plasma concentrations were highest in subjects with 2677GG/3435CC (3.8 ± 0.5 ng ml<SUP>−1</SUP>), lower in subjects with 2677GT/3435CT (3.2 ± 0.5 ng ml<SUP>−1</SUP>) and 2677TT/3435TT (2.7 ± 0.5 ng ml<SUP>−1</SUP>) in rank and showed a significant difference between those with 2677GG/3435CC and with 2677TT/3435TT (95% CI on the difference 0.4, 2.0, <I>P</I> < 0.01). However, the oral clearance was higher in subjects with 2677TT/3435TT (37.7 ± 10.2 l h<SUP>−1</SUP>) than in those with 2677GT/3435CT (35.7 ± 9.9 l h<SUP>−1</SUP>) and with 2677GG/3435CC (24.8 ± 5.4 l h<SUP>−1</SUP>) and exhibited a significant difference between <I>ABCB1</I> genotype groups (95% CI on the difference, 2677GG/3435CC <I>vs.</I> 2677GT/3435CT − 21.5, − 0.3, <I>P</I> < 0.05; 2677GG/3435CC <I>vs.</I> 2677TT/3435TT − 23.8, − 2.0, <I>P</I> < 0.05).</P><P>Conclusion</P><P>Amlodipine pharmacokinetics was affected by the genetic polymorphisms of the <I>ABCB1</I> gene in humans. These findings may provide a plausible explanation for interindividual variation in the disposition of amlodipine, although our study could not explain the exact mechanism(s) by which the polymorphic <I>ABCB1</I> gene paradoxically reduces the plasma levels of amlodipine. Further evaluation is thus warranted.</P>

Impact of ABCB1 C3435T Polymorphism on Treatment Response of Vitamin K Antagonists: A Systematic Review and Meta-analysis

이수연,안숙희 한국임상약학회 2022 한국임상약학회지 Vol.32 No.3

Objective: The aim of this study was to examine the impact of ATP-binding cassette subfamily B member 1 (ABCB1) C3435Tpolymorphism on the treatment response of patients to vitamin K antagonists (VKAs). Methods: In this systematic review and metaanalysis,the PubMed/Medline, Embase, and Cochrane Library databases were searched for eligible articles for the period up toNovember 2020. Articles that reported treatment response to VKAs according to the ABCB1 C3435T polymorphism were includedin this study. Results: A total of 13 and 9 articles were included in the systematic review and meta-analysis, respectively. The weeklymaintenance dose of warfarin was significantly lower in patients with the ABCB1 3435CT or TT polymorphism type than in thosewith the ABCB1 3435CC type (weighted mean difference [WMD], −2.53 mg/week; 95% confidence interval [CI], −3.64 to −1.43,p<0.001). However, the weekly maintenance dose of acenocoumarol was not significantly associated with the ABCB1 C3435Tpolymorphism (WMD, 1.02; 95% CI, −0.61 to 2.65, p=0.22). Conclusion: The ABCB1 C3435T polymorphism was significantlyassociated with the weekly maintenance dose of warfarin. Further research is needed to confirm the association between the ABCB1C3435T polymorphism and the incidence rate of bleeding events.

ABCB1, FCGR2A, and FCGR3A Polymorphisms in Patients with HER2-Positive Metastatic Breast Cancer Who Were Treated with First-Line Taxane plus Trastuzumab Chemotherapy

Kim, Ji-Won,Kim, Jee Hyun,Im, Seock-Ah,Kim, Yu Jung,Han, Hye-Suk,Kim, Jin-Soo,Han, Sae-Won,Jeon, Yoon Kyung,Oh, Do-Youn,Han, Wonshik,Kim, Tae-You,Park, In Ae,Noh, Dong-Young,Bang, Yung-Jue S. Karger AG 2012 Oncology Vol.83 No.4

<P>Abstract</P><P><B><I>Objective:</I></B> The aim of this study was to elucidate clinical implications of ABCB1, FCGR2A, and FCGR3A polymorphisms in patients with HER2-positive metastatic breast cancer (MBC) after taxane plus trastuzumab (TH) chemotherapy. <B><I>Methods:</I></B> Using genomic DNA samples extracted from mononuclear cells of consecutive patients with HER2-positive MBC who received first-line TH, we analyzed five polymorphisms (ABCB1 1236C>T, ABCB1 2677G>T/A, ABCB1 3435C>T, FCGR2A 131H/R, and FCGR3A 158V/F) and then correlated them with the response rate, progression-free survival (PFS), overall survival (OS), and adverse events of patients. <B><I>Results:</I></B> A total of 57 women were analyzed. The median age was 46 years (range 27–72). ABCB1 2677T carriers had a longer PFS (p = 0.037) along with a tendency toward a longer OS (p = 0.057). ABCB1 3435CC genotype carriers had a shorter PFS (p = 0.039) along with a tendency toward a shorter OS (p = 0.093). In combined analysis, PFS was significantly longer in ABCB1 1236CC and/or 2677TT carriers compared to the others (p = 0.006). FCGR2A 131H/R and FCGR3A 158V/F polymorphisms were not significantly associated with response rate, PFS, and OS. <B><I>Conclusions:</I></B> Our data support that ABCB1 polymorphisms may predict PFS after first-line TH chemotherapy in patients with HER2-positive MBC. In contrast, FCGR2A 131H/R and FCGR3A 158V/F polymorphisms could not predict treatment outcomes.</P><P>Copyright © 2012 S. Karger AG, Basel</P>

ABCB1 and BMI1 mRNA expression in patients with chronic myeloid leukemia: impact on imatinib efficacy

Ahmed M. L. Bedewy,Shereen M. Elmaghraby,Noha S. Kandil 대한혈액학회 2019 Blood Research Vol.54 No.1

BackgroundATP-binding cassette transporters are important in the mechanism of multidrug resistance. ABCB1 displays a high affinity for imatinib. BMI1 is a polycomb group protein thought to be overexpressed in leukemic cells.MethodsThis study was conducted to investigate the prognostic value of ABCB1 and BMI1 ex-pressions in chronic myeloid leukemia (CML). Expression levels were measured in 81 patients newly diagnosed with CML and 20 healthy controls by real time reverse tran-scription-PCR. ResultsThe ABCB1 expression levels did not differ between patients with CML and controls. Low ABCB1 mRNA levels were observed in patients who achieved an optimal response com-pared to suboptimal and resistant cases (P=0.005). Non-responders showed the highest ABCB1 levels. ABCB1 expression did not affect the progression-free survival (PFS) of patients. BMI1 expression was higher in patients than that in controls (P=0.001). Patients in advanced phases expressed higher levels of BMI1 than those in the chronic phase (P=0.004). High BMI1 expression was associated with a shorter PFS.ConclusionABCB1 mRNA expression may serve as a predictor of the optimal response to imatinib treatment in patients with CML. BMI1 expression was higher in the accelerated and blastic crisis phases of CML and associated with a shorter PFS.

Ginsenoside Rg5 overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter: in vitro and in vivo study

Sen-Ling Feng,Hai-Bin Luo,Liang Cai,Jie Zhang,Dan Wang,Ying-Jiang Chen,Huan-Xing Zhan,Zhi-Hong Jiang,Ying Xie 고려인삼학회 2020 Journal of Ginseng Research Vol.44 No.2

Background: Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinicalcancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediatedby ABCB1 transporter in vitro and in vivo. Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrateswere carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. Theexpressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cellxenograft model was established to investigate the MDR reversal activity of Rg5 in vivo. Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation ofABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPaseand reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 bindingsite which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 anddocetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizingeffect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXTtreatment significantly suppressed the growth of drug-resistant tumors without increase in toxicitywhen compared to TXT given alone at same dose. Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvantchemotherapy, which encourages further pharmacokinetic and clinical studies.

ABCB1 and BMI1 mRNA expression in patients with chronic myeloid leukemia: impact on imatinib efficacy

Ahmed M. L. Bedewy,Shereen M. Elmaghraby,Noha S. Kandil 대한혈액학회 2019 Blood Research Vol.54 No.1

BackgroundATP-binding cassette transporters are important in the mechanism of multidrug resistance. ABCB1 displays a high affinity for imatinib. BMI1 is a polycomb group protein thought to be overexpressed in leukemic cells.MethodsThis study was conducted to investigate the prognostic value of ABCB1 and BMI1 ex-pressions in chronic myeloid leukemia (CML). Expression levels were measured in 81 patients newly diagnosed with CML and 20 healthy controls by real time reverse tran-scription-PCR. ResultsThe ABCB1 expression levels did not differ between patients with CML and controls. Low ABCB1 mRNA levels were observed in patients who achieved an optimal response com-pared to suboptimal and resistant cases (P=0.005). Non-responders showed the highest ABCB1 levels. ABCB1 expression did not affect the progression-free survival (PFS) of patients. BMI1 expression was higher in patients than that in controls (P=0.001). Patients in advanced phases expressed higher levels of BMI1 than those in the chronic phase (P=0.004). High BMI1 expression was associated with a shorter PFS.ConclusionABCB1 mRNA expression may serve as a predictor of the optimal response to imatinib treatment in patients with CML. BMI1 expression was higher in the accelerated and blastic crisis phases of CML and associated with a shorter PFS.

Ginsenoside Rg5 overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter: in vitro and in vivo study

Feng, Sen-Ling,Luo, Hai-Bin,Cai, Liang,Zhang, Jie,Wang, Dan,Chen, Ying-Jiang,Zhan, Huan-Xing,Jiang, Zhi-Hong,Xie, Ying The Korean Society of Ginseng 2020 Journal of Ginseng Research Vol.44 No.2

Background: Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinical cancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediated by ABCB1 transporter in vitro and in vivo. Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 in vivo. Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose. Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.

Association between ABCB1 Immunohistochemical Expression and Overall Survival in Gastric Cancer Patients

de Oliveira, Juliana,Felipe, Aledson Vitor,Neto, Ricardo Artigiani,Oshima, Celina Tizuko,de Souza Silva, Marcelo,Forones, Nora Manoukian Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.16

Gastric cancer (GC) is one of the most common malignancies worldwide. The ABCB1 protein, a member of the ATP-binding cassette (ABC) transporter family, encoded by the ABCB1 gene, considerably influences the distribution of drugs across cell membranes as well as multidrug resistance (MDR) of antineoplastic drugs. In contrast to the extensive knowledge on the pharmacological action of ABCB1 protein, the correlation between the clinical-pathological data and ABCB1 protein expression in patients with GC remains unclear. The aim was to investigate association between ABCB1 expression and overall survival in GC patients. Human tumor fragments from 57 GC patients were examined by immunohistochemistry assay. We observed lower survival rate of patients with GC who were positive for ABCB1 expression (p=0.030). Based on these observations, we conclude that GC patients with positive ABCB1 protein immunohistochemical expression in their tumors suffer shorter overall survival.

Novel insertion mutation of ABCB1 gene in an ivermectin-sensitive Border Collie

한재익,Hyoung-Won Son,Seung-Cheol Park,Ki-Jeong Na 대한수의학회 2010 Journal of Veterinary Science Vol.11 No.4

P-glycoprotein (P-gp) is encoded by the ABCB1 gene and acts as an efflux pump for xenobiotics. In the Border Collie, a nonsense mutation caused by a 4-base pair deletion in the ABCB1 gene is associated with a premature stop to P-gp synthesis. In this study, we examined the fulllength coding sequence of the ABCB1 gene in an ivermectinsensitive Border Collie that lacked the aforementioned deletion mutation. The sequence was compared to the corresponding sequences of a wild-type Beagle and seven ivermectin-tolerant family members of the Border Collie. When compared to the wild-type Beagle sequence, that of the ivermectin-sensitive Border Collie was found to have one insertion mutation and eight single nucleotide polymorphisms (SNPs) in the coding sequence of the ABCB1 gene. While the eight SNPs were also found in the family members' sequences, the insertion mutation was found only in the ivermectin-sensitive dog. These results suggest the possibility that the SNPs are species-specific features of the ABCB1 gene in Border Collies, and that the insertion mutation may be related to ivermectin intolerance.