Genetic polymorphisms and response to 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

Tęcza, Karolina; Pamuła‐Piłat, Jolanta; Łanuszewska, Joanna; Grzybowska, Ewa

doi:10.18632/oncotarget.11053

Cited by 21 publications

(19 citation statements)

References 38 publications

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“…Our results from Western blot assay displayed that MRP2 was overexpressed at similar levels in ABCC2 1249G and ABCC2 1249A cell systems. Our results are consistent with previous studies in vivo, 22,25 but disagree with other researches. 26,27 As one of the usual in vitro methods to help transporter observation to data, recombinant cell systems over-expressing MRP2 have some limitations, for instance, the different expression levels of MRP2 in different laboratories may result in altered results, and endogenous efflux activity in cells might also complicate the interpretation of results.…”

Section: Discussionsupporting

confidence: 66%

In vitro Transport Ability of ABCC2 (G1249A) Polymorphic Variant Towards Anticancer Drugs

Guo

Yuan

Gao

2020

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Objective: Multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene, is involved in the efflux of certain anticancer drugs. Here we observed whether the ABCC2 (G1249A) polymorphism impacts the transport abilities of MRP2-dependent paclitaxel, docetaxel, and doxorubicin in recombinant LLC-PK1 cell lines. Methods: LLC-PK1 cell lines transfected with ABCC2 1249G wild-type and ABCC2 1249A variant alleles were used to evaluate the sensitivity, intracellular accumulation, and transmembrane transport of paclitaxel, docetaxel, and doxorubicin. Results: The recombinant ABCC2 1249A variant cell line showed higher IC 50 values for paclitaxel and doxorubicin than ABCC2 1249G wild-type cell system (p<0.01). Intracellular accumulations of paclitaxel and doxorubicin in cells transfected with ABCC2 1249A variant allele were significantly decreased compared to cells transfected with ABCC2 1249G wild-type allele (p<0.01). The efflux ratios of paclitaxel and doxorubicin across ABCC2 1249A cell line were significantly increased compared with ABCC2 1249G cell system (p<0.01). However, ABCC2 (G1249A) polymorphism had no effect on the transport activity of MRP2-mediated docetaxel. Conclusion: Our results indicate that ABCC2 (G1249A) polymorphism affects the transport activities of MRP2-dependent paclitaxel and doxorubicin, resulting in greater efflux of these anticancer drugs.

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Section: Discussionsupporting

confidence: 66%

In vitro Transport Ability of ABCC2 (G1249A) Polymorphic Variant Towards Anticancer Drugs

Guo

Yuan

Gao

2020

OTT

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“…BC patients (61.5% HER2-positive) with GG + GT + GA genotypes of the ABCB1-G2677T/A gene polymorphism treated with the fluorouracil-doxorubicincyclophosphamide scheme, showed higher resistance to treatment than TT + TA patients. The multivariate analysis showed an OR of 3.19 (95% CI: 0.98 -10.39; p = 0.053) [20].…”

Section: Abcb1-2677 G>t/amentioning

confidence: 96%

ABCB1 gene polymorphisms and response to chemotherapy in breast cancer patients: A meta-analysis

et al. 2017

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The ABCB1 gene encodes the P-glycoprotein, an efflux pump for some antineoplastic agents which acts as a resistance mechanism to chemotherapy. Three SNPs (C3435T, C1236T and G2677T/A), are the most widely studied in ABCB1. The inconsistent conclusions about the association of these polymorphisms and the response to chemotherapy in breast cancer (BC) patients prompted us to conduct a meta-analysis. A total of nine (770 patients), five (566 patients) and three studies (367 patients) relating the ABCB1 C3435T, C1236T and G2677T/A polymorphisms respectively, were included. The main analysis revealed a lack of association between ABCB1 polymorphisms and response to chemotherapy in every genetic model: C3435T (dominant OR: 0.888; 95%CI: 0.558-1.413), C1236T (dominant OR: 1.968; 95%CI: 0.609-6.362) and G2677T/A (GG vs GT + GA + TT + TA + AA OR: 0.854; 95%CI: 0.418-1.744). Stratification by ethnicity, cancer type and response criteria did not change the pattern of results. The available evidence indicates that three polymorphisms within ABCB1; C3435T, C1236T and G2677T/A, cannot be considered a reliable predictor of response to chemotherapy in BC patients.

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“…In our previous work we presented the multifactorial polymorphic genetic model of the response to FAC chemotherapy in breast cancer patients [ 27 ]. In the present study we focused on the analysis of the relations between the polymorphic variants in genes with known or potential role in the activity on FAC drugs and different symptoms of FAC-induced toxicity.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

et al. 2018

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The differences in patients’ response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy.In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (ABCB1, ABCC2, ABCG2,SLC22A16), metabolism (ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS), DNA damage recognition, repair and cell cycle control (ATM, ERCC1, ERCC2, TP53, XRCC1).The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life.

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Genetic polymorphisms and response to 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

Cited by 21 publications

References 38 publications

<p>In vitro Transport Ability of <em>ABCC2</em> (G1249A) Polymorphic Variant Towards Anticancer Drugs</p>

<p>In vitro Transport Ability of <em>ABCC2</em> (G1249A) Polymorphic Variant Towards Anticancer Drugs</p>

ABCB1 gene polymorphisms and response to chemotherapy in breast cancer patients: A meta-analysis

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

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