Pharmacogenetics of methotrexate in acute lymphoblastic leukaemia: why still at the bench level?

Kodidela, Sunitha; Pradhan, S.C.; Dubashi, Biswajit

doi:10.1007/s00228-013-1623-4

Cited by 39 publications

(39 citation statements)

References 41 publications

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“…92,93,95,96 Methotrexate There have been extensive pharmacogenetic studies of methotrexate in ALL. 97,98 Candidate-gene studies have focused on common variants in genes clearly involved in the folate pathway, such as MTHFR, SLC19A1, TYMS, and DHFR. 50,99 Despite multiple candidate-gene studies for toxicity, results have been conflicting (or based on single, nonreplicated small studies), and thus it is currently not possible to recommend changes to methotrexate dosing based on inherited variants in these candidate genes.…”

Section: Vincristinementioning

confidence: 99%

“…50,99 Despite multiple candidate-gene studies for toxicity, results have been conflicting (or based on single, nonreplicated small studies), and thus it is currently not possible to recommend changes to methotrexate dosing based on inherited variants in these candidate genes. 97,98 Genome-wide studies identified variants associated with leukoencephalopathy, 100 but these findings have not yet been replicated. Methotrexate effects are influenced by interindividual variation in its plasma clearance, leading some to implement an approach that targets systemic exposure based on clearance.…”

Section: Vincristinementioning

confidence: 99%

“…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. 97,98 Perspectives Studies of germline genomic determinants in ALL have multiple objectives, one of which is to gain new biological insights into the mechanisms of leukemogenesis or ALL response (desired antileukemic effects or host toxicities) that could eventually yield improvements in diagnosis or therapy. Another, more elusive objective, is to discover genetic variation that can itself be used as a diagnostic or therapeutic test.…”

Section: Vincristinementioning

confidence: 99%

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Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama

Relling

Yang

2015

Blood

127

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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: 99%

Section: Vincristinementioning

confidence: 99%

Section: Vincristinementioning

confidence: 99%

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Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama

Relling

Yang

2015

Blood

127

View full text Add to dashboard Cite

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“…It catalyzes the conversion of 5,10-methylene-tetrahydrofolate to 5-methyl-tetrahydrofolate, which serves as a methyl donor to convert homocysteine to methionine [71]. Two SNPs, C677T ( rs1901133 ) resulting in substitution of alanine with valine at codon 222 (Ala222Val) [72] and A1298C ( rs1801131 ) resulting in substitution of alanine for glutamic acid at codon 429 (Glu429Ala) [73] have been related to reduced activity of MTHFR and increased MTX level.…”

Section: Methotrexate (Mtx)mentioning

confidence: 99%

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy

Mei¹,

Ontiveros²,

Griffiths³

et al. 2015

Blood Reviews

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Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30 years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20–40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including L-asparaginase, glucocorticoids, 6-mercaptopruine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapy.

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“…The outcome of ALL has improved significantly over the past six decades, with the 5-year survival rates increased from about 10-20 to 70-80 % [1][2][3]. There are about three phases in most chemotherapy protocols: induction, consolidation and maintenance [4]. And, methotrexate (MTX) is the key agent in most chemotherapy protocols.…”

Section: Introductionmentioning

confidence: 99%

Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

Yang

Shen

2015

Tumor Biol.

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The antifolate drug methotrexate (MTX) is widely used in the treatment of various neoplastic diseases, including acute lymphoblastic leukemia (ALL). MTX significantly increases cure rates and improves patients' prognosis. Despite that it achieved remarkable clinical success, a large number of patients still suffer from treatment toxicities or side effects. Even to this date, chemotherapeutic regiments have not been personalized because of interindividual differences that affect MTX response, especially polymorphisms in key genes. The pharmacological pathway of MTX in cells is useful to identify gene polymorphisms that influence the process of treatment. The aim of this review was to discuss the gene polymorphisms of drug-metabolizing enzymes in the MTX pathway and their toxicities on ALL treatment.

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Pharmacogenetics of methotrexate in acute lymphoblastic leukaemia: why still at the bench level?

Abstract: Prospective pharmacogenetic studies which consider all of the above-mentioned factors should be undertaken to facilitate the design of personalized MTX treatment for ALL patients.

Cited by 39 publications

References 41 publications

Inherited genetic variation in childhood acute lymphoblastic leukemia

Inherited genetic variation in childhood acute lymphoblastic leukemia

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy

Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

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