Role of pharmacogenetic factors in the development of side effects of methotrexate in the treatment of malignant tumors: A review

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Methotrexate (MTX) is one of the main chemotherapeutic agents that has determined the high effectiveness of protocols for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphomas. The reverse side of the high anti-tumor activity of MTX is the adverse reactions, which require accompanying preventive therapy. But even modern accompanying therapy in some cases does not avoid severe toxicity from the skin and mucous membranes, nervous system, kidneys, liver. MTX pharmacokinetics exhibits significant individual variability, which may be a reflection of genetic variability. Numerous pharmacogenetic studies have evaluated the effect of polymorphism of various genes involved in MTX metabolism on MTX pharmacokinetics and the development of toxic manifestations in order to improve patient outcomes and decrease drug toxicity. This review presents impact of key metabolic MTX genes (ATIC, DHFR, GGH, FPGS, MTHFR, MTR, MTRR, TYMS) and transporter proteins genes (ABCB1, ABCG2, ABCC2, ABCC4, SLC19A1, SLCO1B1) in the development of MTX side effects. Polymorphic markers in SLCO1B1 gene have the most influence with MTX pharmacokinetic.

作者简介

Timur Valiev

Blokhin National Medical Research Center of Oncology; Sechenov First Moscow State Medical University (Sechenov University)

编辑信件的主要联系方式.
Email: timurvaliev@mail.ru
ORCID iD: 0000-0002-1469-2365

D. Sci. (Med.), Prof.

俄罗斯联邦, Moscow

Vera Semenova

Blokhin National Medical Research Center of Oncology; Engelhardt Institute of Molecular Biology

Email: sulpiridum@yandex.ru
ORCID iD: 0000-0002-9705-1001

Graduate Student

俄罗斯联邦, Moscow

Anna Ikonnikova

Engelhardt Institute of Molecular Biology

Email: timurvaliev@mail.ru
ORCID iD: 0000-0002-8434-5916

junior researcher

俄罗斯联邦, Moscow

Alisa Petrova

Engelhardt Institute of Molecular Biology

Email: alisa7397396@gmail.com
ORCID iD: 0000-0002-7536-5683

Student

俄罗斯联邦, Moscow

Tatiana Belysheva

Blokhin National Medical Research Center of Oncology

Email: klinderma@bk.ru
ORCID iD: 0000-0001-5911-553X

D. Sci. (Med.)

俄罗斯联邦, Moscow

Tatiana Nasedkina

Engelhardt Institute of Molecular Biology

Email: tanased06@rambler.ru
ORCID iD: 0000-0002-2642-4202

D. Sci. (Biol.)

俄罗斯联邦, Moscow

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2. Fig. 1. Simplified scheme of intracellular metabolism of MTX. MTX enters the cell trough SLC19A1, after that, MTX is transformed into polyglutamate form and inhibits DHFR, TYMS, ATIC. The removal of MTX from the cell is performed by means of membrane transporters ABC (adapted [17]).

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