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Успехи молекулярной онкологии

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Трабектедин – лиганд узкой бороздки ДНК

https://doi.org/10.17650/2313-805X.2015.2.2.41-49

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Аннотация

Трабектедин (Trabectedin, ET-743, Yondelis) – алкалоид, который был выделен из беспозвоночного обитателя Карибского бассейна Ecteinascidia turbinate, в настоящее время производится синтетически. Его молекула содержит 3 тетрагидроизохинолиновых функциональных домена, 2 из которых ковалентно связываются с гуанином узкой бороздки ДНК и изгибают молекулу в сторону широкой бороздки, а 3-я находится вне дуплекса и препятствует взаимодействию транскрипционных факторов с ДНК. В результате этого индуцируется каскад событий, нарушающих связывание транскрипционных факторов с ДНК и процессы эксцизионной репарации. Трабектедин, связываясь с обеими цепями ДНК, вызывает межнитевые сшивки, а кроме того, ингибирует работу топоизомераз. Аддукты трабектедина связывают белки эксцизионной репарации, препятствуя их нормальному функционированию и индуцируя разрывы ДНК. Клетки, дефектные по гомологичной рекомбинации, которая репарирует двойные разрывы, особо чувствительны к трабектедину. По этой причине к трабектедину чувствителен ряд опухолей, и в первую очередь миксоидные липосаркомы, а также рак яичников и молочной железы с мутантными генами BRCA1 и BRCA2. У больных с рецидивами сарком, ставшими резистентными к производным платины, трабектедин также оказал терапевтическое действие. Кроме воздействия на опухолевые клетки, трабектедин ингибирует воспалительный процесс путем апоптоза моноцитов и опухолеассоциированных макрофагов, а также опосредованного воздействия на продукцию провоспалительных медиаторов: цитокинов и хемокинов. Трабектедин также ингибирует экспрессию гена MDR-1, ответственного за резистентность опухолевых клеток к химиопрепаратам, и препятствует ангиогенезу.

Об авторах

Геннадий Альтерович Белицкий
НИИ канцерогенеза ФГБНУ «РОНЦ им. Н. Н. Блохина»
Россия
Россия, 115478, Москва, Каширское шоссе, 24


К. И. Кирсанов
НИИ канцерогенеза ФГБНУ «РОНЦ им. Н. Н. Блохина»
Россия
Россия, 115478, Москва, Каширское шоссе, 24


Е. А. Лесовая
НИИ канцерогенеза ФГБНУ «РОНЦ им. Н. Н. Блохина»
Россия
Россия, 115478, Москва, Каширское шоссе, 24


М. Г. Якубовская
НИИ канцерогенеза ФГБНУ «РОНЦ им. Н. Н. Блохина»
Россия
Россия, 115478, Москва, Каширское шоссе, 24


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Для цитирования:


Белицкий Г.А., Кирсанов К.И., Лесовая Е.А., Якубовская М.Г. Трабектедин – лиганд узкой бороздки ДНК. Успехи молекулярной онкологии. 2015;2(2):41-49. https://doi.org/10.17650/2313-805X.2015.2.2.41-49

For citation:


Belitsky G.A., Kirsanov K.I., Lesovaya E.A., Yakubovskaya M.G. Trabectedin – the DNA minor groove binder. Advances in molecular oncology. 2015;2(2):41-49. (In Russ.) https://doi.org/10.17650/2313-805X.2015.2.2.41-49

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ISSN 2313-805X (Print)
ISSN 2413-3787 (Online)