Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia

Drenberg, Christina D.; Paugh, Steven W.; Pounds, Stanley; Shi, Lei; Orwick, Shelley; Li, Lie; Hu, Shuiying; Gibson, Alice A.; Ribeiro, Raul C.; Rubnitz, Jeffrey E.; Evans, William E.; Sparreboom, Alex; Baker, Sharyn D.

doi:10.1002/cpt.315

Cited by 28 publications

(24 citation statements)

References 52 publications

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“…Endogenous substrates for OATP1B1 and OATP1B3 include bilirubin, bile salts, thyroid hormones, and steroid sex hormones and their conjugates, whereas exogenous substrates include 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, angiotensin II receptor antagonists, rifampicin, and methotrexate (Hagenbuch and Gui, 2008;Giacomini et al, 2010). The important role of OATP1B1 for systemic pharmacokinetics and treatment outcome has recently been highlighted for chemotherapy in pediatric patients with acute myeloid leukemia (Drenberg et al, 2015). In this study, patients homozygous for a SLCO1B1 genetic variant had significantly more favorable survival outcomes, likely because of reduced clearance and thus increased exposure to chemotherapeutic agents that are OATP1B1substrates.…”

Section: Introductionmentioning

confidence: 74%

Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver

Thomson

Hines

Schuetz

2016

Drug Metabolism and Disposition

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Determining appropriate pharmacotherapy in young children can be challenging due to uncertainties in the development of drug disposition pathways. With knowledge of the ontogeny of drugmetabolizing enzymes and an emerging focus on drug transporters, the developmental pattern of the uptake transporters organic anion transporting polypeptide (OATP) 1B1 and 1B3 was assessed by relative protein quantification using Western blotting in 80 human pediatric liver specimens covering an age range from 9 days to 12 years. OATP1B3 exhibited high expression at birth, which declined over the first months of life, and then increased again in the preadolescent period. In comparison with children 6-12 years of age, the relative protein expression of highly glycosylated (total) OATP1B3 was 235% (357%) in children <3 months of age, 33% (64%) in the age group from 3 months to 2 years, and 50% (59%) in children 2-6 years of age. The fraction of highly glycosylated to total OATP1B3 increased with age, indicating ontogenic processes not only at the transcriptional level but also at the post-translational level. Similar to OATP1B3, OATP1B1 showed high interindividual variability in relative protein expression but no statistically significant difference among the studied age groups.

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Section: Introductionmentioning

confidence: 74%

Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver

Thomson

Hines

Schuetz

2016

Drug Metabolism and Disposition

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“…Interestingly, we recently reported that the presence of a functional polymorphic germline variant in the OCTN1 gene (rs1050152; c.1507C>T; L503F) (40) is significantly correlated with febrile neutropenia, the major dose-limiting toxicity of cytarabine, in a cohort of 164 pediatric patients with AML receiving cytarabine-based therapy (41). Expression of this mutant OCTN1 in HEK293 cells (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues

et al. 2017

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Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analog cytarabine. Cell biological studies confirmed OCTN1-mediated transport of cytarabine and various structurally-related cytidine analogs, such as 2′deoxycytidine and gemcitabine, occurs through a saturable process that is highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside (NBMPR). Our findings have immediate clinical implications given the potential of the identified transport system to help refine strategies that could improve patient survival across multiple cancer types where nucleoside analogs are used in cancer treatment.

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“…These data together suggest that OATP1A2, OATP1B1, and OATP1B3 are all involved in doxorubicin transport. The related agents daunorubicin and mitoxantrone are transported by OATP1B1 in vitro, and deficiency of mouse Oatp1b2 results in significantly increased plasma AUC of both drugs (Drenberg et al, 2016).…”

Section: The Role Of Oatp Transporters In Chemotherapy Dispositionmentioning

confidence: 99%

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology

Schulte

2019

Molecular Pharmacology

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The organic anion transporting polypeptides (OATPs) are a superfamily of drug transporters involved in the uptake and disposition of a wide array of structurally divergent endogenous and exogenous substrates, including steroid hormones, bile acids, and commonly used drugs, such as anti-infectives, antihypertensives, and cholesterol lowering agents. In the past decade, OATPs, primarily OATP1A2, OATP1B1, and OATP1B3, have emerged as potential mediators of chemotherapy disposition, including drugs such as methotrexate, doxorubicin, paclitaxel, docetaxel, irinotecan and its important metabolite 7-ethyl-10-hydroxycamptothecin, and certain tyrosine kinase inhibitors. Furthermore, OATP family members are polymorphic and numerous studies have shown OATP variants to have differential uptake, disposition, and/or pharmacokinetics of numerous drug substrates with important implications for interindividual differences in efficacy and toxicity. Additionally, certain OATPs have been found to be overexpressed in a variety of human solid tumors, including breast, liver, colon, pancreatic, and ovarian cancers, suggesting potential roles for OATPs in tumor development and progression and as novel targets for cancer therapy. This review focuses on the emerging roles for selected OATPs in cancer pharmacology, including preclinical and clinical studies suggesting roles in chemotherapy disposition, the pharmacogenetics of OATPs in cancer therapy, and OATP overexpression in various tumor tissues with implications for OATPs as therapeutic targets.

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Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia

Cited by 28 publications

References 52 publications

Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver

Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver

OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology

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