<i>ABCC1</i> polymorphisms in anthracycline‐induced cardiotoxicity in childhood acute lymphoblastic leukaemia

Semsei, Ágnes F.; Erdélyi, Dániel; Ungvári, Ildikó; Cságoly, E.; Hegyi, Márta; Kiszel, Petra; Lautner-Csorba, Orsolya; Szabolcs, Judit; Masát, Péter; Fekete, György; Falus, András; Szalai, Csaba; Kovàcs, Gabór

doi:10.1042/cbi20110264

Cited by 107 publications

(76 citation statements)

References 25 publications

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“…The solute carrier family (SLC) is responsible for anthracycline transport into the cell, while ABC (ATP-binding cassette) transporters are involved in energy-dependent anthracycline efflux from the cell. Significant associations have been found between ACT and SNPs in various SLC and ABC genes [33,[43][44][45].…”

Section: Cardiotoxicitymentioning

confidence: 98%

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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Section: Cardiotoxicitymentioning

confidence: 98%

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

Maxwell

Cole

2017

Curr Hematol Malig Rep

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“…Accumulating case-control cohort clinical studies have shown that several MRP1 single nucleotide polymorphisms are related to susceptibility to cardiotoxicity observed in many cancer patients treated with anthracyclines such as DOX (Wojnowski et al, 2005;Semsei et al, 2012;Visscher et al, 2012). These single nucleotide polymorphisms may affect efflux of not only DOX but also other important endobiotics (Jungsuwadee et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Loss of Multidrug Resistance–Associated Protein 1 Potentiates Chronic Doxorubicin-Induced Cardiac Dysfunction in Mice

Zhang

Deng

Sunkara

et al. 2015

J Pharmacol Exp Ther

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Doxorubicin (DOX), an effective cancer chemotherapeutic agent, induces dose-dependent cardiotoxicity, in part due to its ability to cause oxidative stress. We investigated the role of multidrug resistance-associated protein 1 (Mrp1/Abcc1) in DOX-induced cardiotoxicity in C57BL wild-type (WT) mice and their Mrp1 null (Mrp1 2/2 ) littermates. Male mice were administered intraperitoneal DOX (3 or 2 mg/kg body weight) or saline twice a week for 3 weeks and examined 2 weeks after the last dose (protocol A total dose: 18 mg/kg) or for 5 weeks, and mice were examined 48 hours and 2 weeks after the last dose (protocol B total dose: 20 mg/kg). Chronic DOX induced body weight loss and hemotoxicity, adverse effects significantly exacerbated in Mrp1 2/2 versus WT mice. In the heart, significantly higher basal levels of glutathione (1.41-fold 6 0.27-fold) and glutathione disulfide (1.35-fold 6 0.16-fold) were detected in Mrp1 2/2 versus WT mice, and there were comparable decreases in the glutathione/glutathione disulfide ratio in WT and Mrp1 2/2 mice after DOX administration. Surprisingly, DOX induced comparable increases in 4-hydroxynonenal glutathione conjugate concentration in hearts from WT and Mrp1 2/2 mice. However, more DOX-induced apoptosis was detected in Mrp1 2/2 versus WT hearts (P , 0.05) (protocol A), and cardiac function, assessed by measurement of fractional shortening and ejection fraction with echocardiography, was significantly decreased by DOX in Mrp1 2/2 versus WT mice (P , 0.05; 95% confidence intervals of 20.0%-24.3% versus 23.7%-29.5% for fractional shortening, and 41.5%-48.4% versus 47.7%-56.7% for ejection fraction; protocol B). Together, these data indicate that Mrp1 protects the mouse heart against chronic DOX-induced cardiotoxicity.

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“…Semsei et al observed an association between the rs246221 T-allele and LVEF. Patients with TC or TT genotypes displayed reduced LVEF compared with patients carrying the CC genotype [10]. In our study, heterozygous carriers of the rs246221 T-allele in ABCC1 were significantly associated with a LVEF decline of [10 % relative to homozygous carriers of the T-allele (OR 1.59, 95 % CI 1.1-2.3, p = 0.02), suggesting that we independently confirmed the observations by Semsei et al However, rare homozygous carriers of the C-allele did not significantly correlate with a LVEF decline [10 % (OR 0.72, 95 % CI 0.29-1.8).…”

Section: Discussionmentioning

confidence: 96%

“…We now conducted a Pubmed search (May 2014; keywords: single nucleotide polymorphisms and cardiotoxicity) to identify published associations between SNPs and ACT. We identified 10 SNPs, which were all genotyped in 2011, in 6 genes of interest (Table 1) [10][11][12][13][14][15][16][17]. For exploratory analyses, we selected in our genetic database an additional 11 SNPs in genes that are related to the metabolism, toxicity, or outcome of anthracyclines (Table 2) [9].…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

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Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients

Vulsteke

Pfeil

Maggen

et al. 2015

Breast Cancer Res Treat

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Anthracycline-induced cardiotoxicity (ACT) is a well-known serious adverse drug reaction leading to substantial morbidity. The purpose of this study was to assess ACT occurrence and clinical and genetic risk factors in early breast cancer patients. In 6 genes of interest (ABCC1, ABCC2, CYBA, NCF4, RAC2, SLC28A3), 10 single nucleotide polymorphisms (SNPs) involved in ACT were selected based on a literature search. Eight hundred and seventy-seven patients treated between 2000 and 2010 with 3-6 cycles of (neo) adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were genotyped for these SNPs using Sequenom MassARRAY. Main outcome measures were asymptomatic decrease of left ventricular ejection fraction (LVEF) > 10 % and cardiac failure grade 3-5 (CTCAE 4.0). To evaluate the impact of these 10 SNPs as well as clinical factors (age, relative dose intensity of epirubicin, left-sided radiotherapy, occurrence of febrile neutropenia, and planned and received cycles of epirubicin) on decrease of LVEF and cardiac failure, we performed uni- and multivariable logistic regression analysis. Additionally, exploratory analyses including 11 additional SNPs related to the metabolism of anthracyclines were performed. After a median follow-up of 3.62 years (range 0.40-9.60), a LVEF decline of > 10 % occurred in 153 patients (17.5 %) and cardiac failure in 16 patients (1.8 %). In multivariable analysis, six cycles of FEC compared to three cycles received and heterozygous carriers of the rs246221 T-allele in ABCC1 relative to homozygous carriers of the T-allele were significantly associated with LVEF decline of > 10 % (OR 1.3, 95 % CI 1.1-1.4, p < 0.001 and OR 1.6, 95 % CI 1.1-2.3, p = 0.02). Radiotherapy for left-sided breast cancer was associated with cardiac failure (OR 3.7, 95 % CI 1.2-11.5, p 0.026). The other 9 SNPs and clinical factors tested were not significantly associated. In our exploratory analysis, no other SNPs related to anthracycline metabolism were retained in the multivariate model for prediction of LVEF decline. ACT in breast cancer patients is related to number of received cycles of epirubicin and left-sided radiotherapy. Additional studies should be performed to independently confirm the potential association between rs246221 in ABCC1 and LVEF.

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ABCC1 polymorphisms in anthracycline‐induced cardiotoxicity in childhood acute lymphoblastic leukaemia

Cited by 107 publications

References 25 publications

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

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

Loss of Multidrug Resistance–Associated Protein 1 Potentiates Chronic Doxorubicin-Induced Cardiac Dysfunction in Mice

Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients

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