Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy

Dj, Erdilyi; Kámory, Enikő; Csókay, Béla; Andrikovics, Hajnalka; Tordai, Attila; Kiss, Csongor; Semsei, Ágnes F.; Janszky, Imre; Zalka, A; Fekete, György; Falus, András; Gt, Kovács; Szalai, Csaba

doi:10.1038/sj.tpj.6500480

Cited by 40 publications

(24 citation statements)

References 33 publications

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“…Yet, exceptions do occur as demonstrated by a recent study showing that Bcrp is rate-limiting for several phytoestrogens at murine BBB (Enokizono et al, 2007). Another speculation regarding the role of Bcrp at the BBB is that Bcrp and P-gp work together to limit the brain penetration of therapeutic agents (de Vries et al, 2007) or CNS toxic effects (Erdilyi et al, 2008). The present results also raise the related question of the specific role of organic anion transporters in the overall barrier function at the blood-brain interface.…”

Section: Discussionmentioning

confidence: 98%

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

Zhao¹,

Raub²,

Sawada³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Expression of breast cancer resistance protein (Bcrp) at the bloodbrain barrier (BBB) has been revealed recently. To investigate comprehensively the potential role of Bcrp at the murine BBB, a chemically diverse set of model compounds (cimetidine, alfuzosin, dipyridamole, and LY2228820) was evaluated using a multiexperimental design. Bcrp1 stably transfected MDCKII cell monolayer transport studies demonstrated that each compound had affinity for Bcrp and that polarized transport by Bcrp was abolished completely by the Bcrp inhibitor chrysin. However, none of the compounds differed in brain uptake between Bcrp wild-type and knockout mice under either an in situ brain perfusion or a 24-h subcutaneous osmotic minipump continuous infusion experimental paradigm. In addition, alfuzosin and dipyridamole were shown to undergo transport by P-glycoprotein (P-gp) in an MDCKII-MDR1 cell monolayer model. Alfuzosin brain uptake was 4-fold higher in mdr1a(؊/؊) mice than in mdr1a(؉/؉) mice in in situ and in vivo studies, demonstrating for the first time that it undergoes P-gpmediated efflux at the BBB. In contrast, P-gp had no effect on dipyridamole brain penetration in situ or in vivo. In fact, in situ BBB permeability of these solutes appeared to be primarily dependent on their lipophilicity in the absence of efflux transport, and in situ brain uptake clearance correlated with the intrinsic transcellular passive permeability from in vitro transport and cellular accumulation studies. In summary, Bcrp mediates in vitro transport of various compounds, but seems to play a minimal role at the BBB in vivo.The blood-brain barrier (BBB) is composed of brain capillary endothelial cells, which are characterized by highly developed tight junctions, a lack of fenestrations, and a paucity of pinocytic and transcytotic activities. Expression of metabolic enzymes and efflux transporters in these and associated glial cells provides additional limiting factors at the BBB. Insufficient drug exposure at the pharmacologic target within the brain, as a consequence of limited flux from blood to brain, represents a major obstacle for effective treatment of central nervous system (CNS) disorders (Begley, 2004;Pardridge, 2005). It is widely accepted that P-glycoprotein (P-gp) is expressed abundantly at the BBB and functions as an efflux pump that extrudes toxic substances and therapeutic agents in the brain-to-blood direction, representing a functional barrier to brain uptake (Schinkel, 1999). The potential role of other members of the ATP-binding cassette (ABC) efflux transporter family, such as multidrug resistance-associated proteins (Mrps) and breast cancer resistance protein (Bcrp), at the BBB is less clear, although the proteins appear to be expressed at the BBB in various species (Yousif et al., 2007).Bcrp is a recently identified member of the ABC efflux transporter family encoded by gene Abcg2 (Doyle et al., 1998). Bcrp is widely expressed in the intestine, liver, mammary gland, and placenta. The functional efficiency of Bcrp in the...

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Section: Discussionmentioning

confidence: 98%

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

Zhao¹,

Raub²,

Sawada³

et al. 2009

Drug Metab Dispos

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“…The combined effect of BCRP and other ABC transporters actually has also been found in a clinical study, in which children with acute lymphoblastic leukemia who were treated with chemotherapy had a significantly increased chance of encephalopathy when they had a specific combination of BCRP and MARP1 polymorphisms compared to when they only had a predisposing genotype for one of the transporters [19]. …”

Section: Introductionmentioning

confidence: 84%

Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases

Iorio¹,

Ros²,

Fantappiè³

et al. 2016

ACAMC

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The treatment of brain tumors and neurodegenerative diseases, represents an ongoing challenge. In Central Nervous System (CNS) the achievement of therapeutic concentration of chemical agents is complicated by the presence of distinct set of efflux proteins, such as ATP-Binding Cassette (ABC) transporters localized on the Blood-Brain Barrier (BBB). The activity of ABC transporters seems to be a common mechanism that underlies the poor response of CNS diseases to therapies.The molecular characterization of Breast Cancer Resistance Protein (BCRP/ABCG2), as an ABC transporter conferring multidrug resistance (MDR), has stimulated many studies to investigate its activity on the BBB, its involvement in physiology and CNS diseases and its role in limiting the delivery of drugs in CNS.In this review, we highlight the activity and localization of BCRP on the BBB and the action that this efflux pump has on many conventional drugs or latest generation molecules used for the treatment of CNS tumors and other neurodegenerative diseases.

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“…Selected genes of interest are summarized in [26,27,49,50]) have been studied. Two recently published, excellent reviews provide exhaustive details and discussions on this topic [6,7] and the authors' general comment on these investigations is given in the Expert commentary.…”

Section: Candidate-gene Approachesmentioning

confidence: 99%

Antileukemic drug effects in childhood acute lymphoblastic leukemia

Pottier¹,

Cheok

Kager

2008

Expert Review of Clinical Pharmacology

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Cancer is the second most common cause of death in children between 1 and 15 years of age in industrialized countries. Although acute lymphoblastic leukemia (ALL) is still among the leading causes of death in childhood cancer, remarkable progress in treatment results has been made with this disease. With current antileukemic therapy, more than 80% of children with ALL can be cured. Antileukemic medications, however, are generally toxic and can cause significant adverse drug reactions. Moreover, some patients have leukemia cell clones that are resistant to conventional antileukemic treatment. Overall, a fifth of children with ALL will not be cured despite intensified therapy, including allogeneic stem cell transplantation. Pharmacogenomics aims to elucidate functionally relevant genomic determinants for drug disposition and response in order to establish valid pharmacogenomic models that can help to select medications and their dose based on a patient's genetic make-up. This review focuses on investigations that provide important basic insights into ALL pharmacogenomics and/or hold great promise in providing clinically valuable pharmacogenomic models that can help to improve childhood ALL treatment by facilitating appropriate dose individualization, optimal treatment selection and drug discovery.

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Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy

Cited by 40 publications

References 33 publications

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases

Antileukemic drug effects in childhood acute lymphoblastic leukemia

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