4106 ORAL Polymorphisms in Methotrexate Transport Pathway – a New Tool for Toxicity Prevention in Pediatric Acute Lymphoblastic Leukemia

López-López, Elixabet; Martín-Guerrero, Idoia; Santos, Bianca Pozza dos; Andoin, Nagore García de; Pifian, M.A.; Garcı́a-Miguel, P; Navajas, Aurora; Garcı́a-Orad, Africa

doi:10.1016/s0959-8049(11)71284-9

Cited by 30 publications

(66 citation statements)

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“…Methotrexate effects are influenced by interindividual variation in its plasma clearance, leading some to implement an approach that targets systemic exposure based on clearance. [101][102][103] Genome-wide analyses identified multiple common genomic variants in SLCO1B1 that were associated with methotrexate clearance, 104 a finding that has been replicated in several studies 50,99,105,106 and confirmed in preclinical models. 107,108 The high degree of replication for SLCO1B1 variants as a determinant of methotrexate clearance stands in contrast to the lack of replicated findings using a candidate-gene approach.…”

Section: Vincristinementioning

confidence: 83%

Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama

Relling

Yang

2015

Blood

128

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Although somatically acquired genomic alterations have long been recognized as the hallmarks of acute lymphoblastic leukemia (ALL), the last decade has shown that inherited genetic variations (germline) are important determinants of interpatient variability in ALL susceptibility, drug response, and toxicities of ALL therapy. In particular, unbiased genome-wide association studies have identified germline variants strongly associated with the predisposition to ALL in children, providing novel insight into the mechanisms of leukemogenesis and evidence for complex interactions between inherited and acquired genetic variations in ALL. Similar genome-wide approaches have also discovered novel germline genetic risk factors that independently influence ALL prognosis and those that strongly modify host susceptibility to adverse effects of antileukemic agents (eg, vincristine, asparaginase, glucocorticoids). There are examples of germline genomic associations that warrant routine clinical use in the treatment of childhood ALL (eg, TPMT and mercaptopurine dosing), but most have not reached this level of actionability. Future studies are needed to integrate both somatic and germline variants to predict risk of relapse and host toxicities, with the eventual goal of implementing genetics-driven precision-medicine approaches in ALL treatment.

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Section: Vincristinementioning

confidence: 83%

Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama

Relling

Yang

2015

Blood

128

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“…Polymorphisms in OAT1, OAT3, and MRP2 are more common among miners exhibiting toxicity from mercury-containing vapors (50). Additionally, OAT3 polymorphisms have been associated with altered cephalosporin handling (87), and suggestive evidence indicates the possible involvement of OATs in antiviral and methotrexate elimination (88,89). One of the better-studied examples of drug transporter polymorphisms affecting renal drug elimination is that of OCT2 (SLC22A2).…”

Section: Pharmacogenomic and Toxicogenomic Considerationsmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

228

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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“…We found this result very interesting because in a previous study published by our group [2], we analyzed the association between 14 SNPs in SLC19A1 and MTX plasma levels in 151 Spanish children diagnosed with ALL. Three SNPs out of 14 showed significant associations with MTX plasma levels.…”

mentioning

confidence: 66%