Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

Tanaka, Yoïchi; Manabe, Atsushi; Fukushima, Hiroko; Suzuki, Ryoko; Nakadate, Hisaya; Kondoh, Kensuke; Nakamura, Kozue; Koh, Katsuyoshi; Fukushima, Tatsuya; Tsuchida, Masahiro; Koike, Kenichi; Kiyokawa, Nobutaka; Noguchi, Emiko; Sumazaki, Ryo; Komiyama, Tomoyoshi

doi:10.1038/tpj.2014.74

Cited by 42 publications

(39 citation statements)

References 25 publications

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“…It was also observed that patients with the AA or AG genotype had higher intracellular 6-thioguanine nucleotides concentration and were at higher risk of leukopenia (Ban et al, 2010). Moreover, it was shown in the Japanese childhood acute lymphoblastic leukemia (ALL) population that the homozygous variant allele in any of the ABCC4 2269G.A, 912C.A, and 559G.T variants was in correlation with reduced 6-MP dose (Tanaka et al, 2014). More recently, Gao et al (2015) reported that 559G.T was significantly associated with decreased intraocular pressure in response to latanoprost.…”

Section: Pharmacogenomics Of Mrp4mentioning

confidence: 86%

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

Wen

Luo

Huang

et al. 2015

J Pharmacol Exp Ther

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Multidrug-resistant protein 4 (MRP4), a member of the C subfamily of ATP-binding cassette transporters, is distributed in a variety of tissues and a number of cancers. As a drug transporter, MRP4 is responsible for the pharmacokinetics and pharmacodynamics of numerous drugs, especially antiviral drugs, antitumor drugs, and diuretics. In this regard, the functional role of MRP4 is affected by a number of factors, such as genetic mutations; tissue-specific transcriptional regulations; post-transcriptional regulations, including miRNAs and membrane internalization; and substrate competition. Unlike other C family members, MRP4 is in a pivotal position to transport cellular signaling molecules, through which it is tightly connected to the living activity and physiologic processes of cells and bodies. In the context of several cancers in which MRP4 is overexpressed, MRP4 inhibition shows striking effects against cancer progression and drug resistance. In this review, we describe the role of MRP4 more specifically in both healthy conditions and disease states, with an emphasis on its potential as a drug target.

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Section: Pharmacogenomics Of Mrp4mentioning

confidence: 86%

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

Wen

Luo

Huang

et al. 2015

J Pharmacol Exp Ther

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“…Guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) are currently being updated to include dosing recommendations for patients with NUDT15 variants [74]. Other genes implicated in differential risk of myelosuppression, that appear to be relevant primarily in persons of East Asian ancestry include multi-drug resistance protein 4 (MRP4) and inosine triphosphate pyrophosphatase (ITPA) [62,75].…”

Section: Hematologic Toxicitymentioning

confidence: 99%

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

Maxwell

Cole

2017

Curr Hematol Malig Rep

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Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

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“…ABCC4 encodes multiple drug resistance protein 4 (MRP4), which belongs to the ATP-binding cassette (ABC) transporter family and assists in the efflux of a large variety of therapeutic agents, including 6-MP [24]. Of the 11 missense variants that have been investigated, compared to the wild-type MRP4, the Y556C variant has been associated with significantly higher transport of 6-MP, whereas the V776I, and the rs9516519 T>G polymorphisms have been associated with significantly lower transport 6-MP [25].…”

Section: Pharmacogenetic Considerations For 6-mpmentioning

confidence: 99%

The Promise of Pharmacogenomics in Reducing Toxicity during Acute Lymphoblastic Leukemia Maintenance Treatment

Rudin

Marable

Huang

2017

Genomics, Proteomics &Amp; Bioinformatics

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Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), and potentially inosine triphosphatase (ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) and dihydrofolate reductase (DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1) and thymidylate synthetase (TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

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Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

Cited by 42 publications

References 25 publications

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

The Promise of Pharmacogenomics in Reducing Toxicity during Acute Lymphoblastic Leukemia Maintenance Treatment

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