Functional variants of gene encoding folate metabolizing enzyme and methotrexate-related toxicity in children with acute lymphoblastic leukemia

Kałużna, Ewelina; Strauss, Ewa; Zając‐Spychała, Olga; Gowin, Ewelina; Świątek-Kościelna, Bogna; Nowak, Jerzy; Fichna, Marta; Mańkowski, Przemysław; Januszkiewicz‐Lewandowska, Danuta

doi:10.1016/j.ejphar.2015.10.058

Cited by 24 publications

(23 citation statements)

References 32 publications

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“…There is great inter-individual variability in MTX response [4, 5, 16, 17]. Several SNPs in genes involved in the MTX transporter pathway have been implicated in the kinetics and effects of MTX in previous studies [9–15], but some results are ambiguous.…”

Section: Discussionmentioning

confidence: 99%

“…Of these, 117 patients were classified as having SR ALL, and 205 as having IR ALL. Details of the stratification and treatment regimens of the two protocols have been published previously [16] and are outlined in Table 1. At a median follow-up time of 75 months (range, 1.0–115.0), 278 patients were in first remission, 33 patients had relapsed, five had died of severe infection (one patient before the first HDMTX), two had died of severe HDMTX toxicity, and four patients had been lost follow-up before the first HDMTX.…”

Section: Methodsmentioning

confidence: 99%

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Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia

et al. 2017

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High-dose methotrexate (HDMTX) plays an important role in the treatment of acute lymphoblastic leukemia (ALL) although there is great inter-patient variability in the efficacy and toxicity of MTX. The relationship between polymorphisms in genes encoding MTX transporters and MTX response is controversial. In the present study, 322 Chinese children with standard- and intermediate-risk ALL were genotyped for 12 polymorphisms. SLCO1B1 rs10841753 showed a significant association with plasma MTX levels at 48 h (P = 0.017). Patients who had the ABCB1 rs1128503 C allele had longer duration of hospitalization than did those with the TT genotype (P = 0.006). No association was found between oral mucositis and any polymorphism. Long-term outcome was worse in patients with the SLCO1B1 rs4149056 CC genotype than in patients with TT or TC (5-year event-free survival [EFS] 33.3 ± 19.2% vs. 90.5 ± 1.7%, P < 0.001), and was worse in patients with the SCL19A1 rs2838958 AA genotype than in patients with AG or GG (5-year EFS 78.5 ± 4.6% vs. 92.2 ± 1.8%, P = 0.008). Multiple Cox regression analyses revealed associations of minimal residual disease (MRD) at day 33 (hazard ratio 3.458; P = 0.002), MRD at day 78 (hazard ratio 6.330; P = 0.001), SLCO1B1 rs4149056 (hazard ratio 12.242; P < 0.001), and SCL19A1 rs2838958 (hazard ratio 2.324; P = 0.019) with EFS. Our findings show that polymorphisms in genes encoding MTX transporters substantially influence the kinetics and response to HDMTX therapy in childhood ALL.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia

et al. 2017

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“…Six cohort studies reported nephrotoxicity secondary to methotrexate, with outcomes reported across Europe and Asia (Supplementary Table S1)). Three studies investigated MTHFR and found C677T SNP was associated with nephrotoxicity . Of these, two also found an association with A1298C .…”

Section: Resultsmentioning

confidence: 99%

“…Three studies investigated MTHFR and found C677T SNP was associated with nephrotoxicity. 55,64,65 Of these, two also found an association with A1298C. 64,65 Two further studies investigated solute carrier organic anion transporter family member 1B1 (SLCO1B1) with rs11045879 66 and rs4149035 18 associated with nephrotoxicity.…”

Section: Nephrotoxicitymentioning

confidence: 99%

Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients

Conyers

Devaraja

Elliott

2017

Pediatric Blood & Cancer

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Many paediatric patients with cancer experience significant chemotherapy side effects. Predisposition to drug reactions is governed by single nucleotide polymorphisms (SNPs). We performed a systematic review of the literature from 2006 through 2016. Outcomes of interest included patient characteristics, cancer type drug of interest, genes investigated, toxicity identified and genetic polymorphisms implicated. The primary toxicities studied were neurotoxicity cardiotoxicity, osteonecrosis, and thromboembolism and hypersensitivity reactions. The retrieved studies were grouped according to toxicity reported and SNP associations. This review highlights the discoveries to date in pharmacogenomics and paediatric oncology along with highlighting some of the important limitations in the area.

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“…Fluorouracil-5 is a pyrimidine analog that acts as a suicide inhibitor by irreversibly binding to the thymidylate synthase enzyme [117]. These drugs have been studied for treating various cancers, but have been shown some limited success partly due to toxicity and patient tolerance issues [118, 119]. …”

Section: Clinical Application Of Precision Ovarian Cancer Medicinementioning

confidence: 99%

Precision targeted therapy of ovarian cancer

Sapiezynski

Taratula

Rodrı́guez-Rodrı́guez

et al. 2016

Journal of Controlled Release

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Functional variants of gene encoding folate metabolizing enzyme and methotrexate-related toxicity in children with acute lymphoblastic leukemia

Cited by 24 publications

References 32 publications

Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia

Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia

Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients

Precision targeted therapy of ovarian cancer

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