The use of L-asparaginase for the treatment of solid tumors: data from experimental studies and clinical trials

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Abstract

Drug therapy is one of the main strategies of cancer treatment. L-asparaginase, the enzyme that hydrolyzes asparagine, has been included in the treatment regimens for acute lymphoblastic leukemia and other hematological malignancies since more than 50 years ago, but its use for the treatment of solid tumors is still extremely limited. This review analyzes experimental data on the sensitivity of cell lines and xenografts of solid tumors to L-asparaginase, examines the results of clinical trials. Among the mechanisms of the cytotoxic effect of L-asparaginase on tumor cells, such processes as depletion of aspartic and glutamic acids, influence on the internal and external pathways of apoptosis, inhibition of cellular processes through a decrease in the activity of the mTOR protein, and weakening of the expression of the telomerase gene are discussed. Separately, molecular markers are considered, which can be used to suggest the effectiveness of future therapy with L-asparaginase in solid tumors. These markers include expression levels of asparagine synthetase and glutamine synthetase genes, degree of methylation of the ASNS gene promoter region, PTEN protein activity and autophagy, bone marrow environment of tumor cells, as well as expression of genes associated with asparaginase resistance (such as the μ1 opioid receptor gene and the huntingtin-associated protein 1 gene).

About the authors

Il’ya A. Kislyak

Peoples’ Friendship University of Russia

Author for correspondence.
Email: kislyal.ilya.98@mail.ru
ORCID iD: 0000-0002-6042-9795
Russian Federation, 6 Miklukho-Maklaya street, 117198 Moscow

Marina V. Pokrovskaya

Institute of Biomedical Chemistry

Email: ivan1190@yandex.ru
ORCID iD: 0009-0008-2726-3632

Cand.  Sci. (Bio.)

Russian Federation, Moscow

Darya Yu. Zhanturina

Peoples’ Friendship University of Russia

Email: dashazh@gmail.com
ORCID iD: 0009-0005-6521-3220
Russian Federation, 6 Miklukho-Maklaya street, 117198 Moscow

Vadim S. Pokrovsky

Peoples’ Friendship University of Russia; N.N. Blokhin National Medical Research Center of Oncology

Email: v.pokrovsky@ronc.ru
ORCID iD: 0000-0003-4006-9320
SPIN-code: 4552-1226

MD, Dr. Sci. (Med.)

Russian Federation, Moscow; 6 Miklukho-Maklaya street, 117198 Moscow; 24 Kashirskoe shosse, Moscow 115478

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2. Fig. 1. Mechanisms of the antitumor action of L-asparaginase (L-ASNase).

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3. Fig. 2. Involvement of PTEN in the PI3K–Akt–mTOR signaling pathway.

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4. Fig. 3. Inhibition of GSK3 (glycogen synthase kinase 3) sensitizes leukemic cells to the action of asparaginase.

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Согласие на обработку персональных данных с помощью сервиса «Яндекс.Метрика»

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2. Категории обрабатываемых данных: файлы «cookies» (куки-файлы). Файлы «cookie» – это небольшой текстовый файл, который веб-сервер может хранить в браузере Пользователя. Данные файлы веб-сервер загружает на устройство Пользователя при посещении им Сайта. При каждом следующем посещении Пользователем Сайта «cookie» файлы отправляются на Сайт Оператора. Данные файлы позволяют Сайту распознавать устройство Пользователя. Содержимое такого файла может как относиться, так и не относиться к персональным данным, в зависимости от того, содержит ли такой файл персональные данные или содержит обезличенные технические данные.

3. Цель обработки персональных данных: анализ пользовательской активности с помощью сервиса «Яндекс.Метрика».

4. Категории субъектов персональных данных: все Пользователи Сайта, которые дали согласие на обработку файлов «cookie».

5. Способы обработки: сбор, запись, систематизация, накопление, хранение, уточнение (обновление, изменение), извлечение, использование, передача (доступ, предоставление), блокирование, удаление, уничтожение персональных данных.

6. Срок обработки и хранения: до получения от Субъекта персональных данных требования о прекращении обработки/отзыва согласия.

7. Способ отзыва: заявление об отзыве в письменном виде путём его направления на адрес электронной почты Оператора: info@rcsi.science или путем письменного обращения по юридическому адресу: 119991, г. Москва, Ленинский просп., д.32А

8. Субъект персональных данных вправе запретить своему оборудованию прием этих данных или ограничить прием этих данных. При отказе от получения таких данных или при ограничении приема данных некоторые функции Сайта могут работать некорректно. Субъект персональных данных обязуется сам настроить свое оборудование таким способом, чтобы оно обеспечивало адекватный его желаниям режим работы и уровень защиты данных файлов «cookie», Оператор не предоставляет технологических и правовых консультаций на темы подобного характера.

9. Порядок уничтожения персональных данных при достижении цели их обработки или при наступлении иных законных оснований определяется Оператором в соответствии с законодательством Российской Федерации.

10. Я согласен/согласна квалифицировать в качестве своей простой электронной подписи под настоящим Согласием и под Политикой обработки персональных данных выполнение мною следующего действия на сайте: https://journals.rcsi.science/ нажатие мною на интерфейсе с текстом: «Сайт использует сервис «Яндекс.Метрика» (который использует файлы «cookie») на элемент с текстом «Принять и продолжить».