Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press142710.17650/1726-9784-2024-23-1-10-18REVIEWОБЗОР ЛИТЕРАТУРЫCombretastatins A-4 and A-1 and their derivatives: ReviewКомбретастатины А-4 и А-1 и их производные: обзорhttps://orcid.org/0000-0002-3579-1733NemtsovaE. R.НемцоваЕ. Р.
Russian Federation

Elena R. Nemtsova, 

3, 2nd Botkinskiy pr., Moscow, 125284.

Екатерина Романовна Немцова,

125284, Москва, 2-й Боткинский пр., 3.

nemtz@yandex.ruhttps://orcid.org/0000-0002-7159-805XMorozovaN. B.МорозоваН. Б.
Russian Federation

Natalia B. Morozova, 

3, 2nd Botkinskiy pr., Moscow, 125284.

Н.Б. Морозова,

125284, Москва, 2-й Боткинский пр., 3.

 

https://orcid.org/0000-0002-6898-2931PlyutinskayaA. D.ПлютинскаяА. Д.
Russian Federation

Anna D. Plyutinskaya, 

3, 2nd Botkinskiy pr., Moscow, 125284.

А.Д. Плютинская,

125284, Москва, 2-й Боткинский пр., 3.

https://orcid.org/0000-0003-2245-4946NoevA. N.НоевА. Н.
Russian Federation

Alexey N. Noev, 

3, 2nd Botkinskiy pr., Moscow, 125284.

А.Н. Ноев,

125284, Москва, 2-й Боткинский пр., 3.

https://orcid.org/0000-0001-7291-9743PankratovA. A.ПанкратовА. А.
Russian Federation

Andrey A. Pankratov, 

3, 2nd Botkinskiy pr., Moscow, 125284.

А.А. Панкратов,

125284, Москва, 2-й Боткинский пр., 3.

https://orcid.org/0000-0001-9755-1164ShegayP. V.ШегайП. В.
Russian Federation

Peter V. Shegay,

3, 2nd Botkinskiy pr., Moscow, 125284.

П.В. Шегай,

125284, Москва, 2-й Боткинский пр., 3.

Hertsen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre, Ministry of Health of RussiaМосковский научно-исследовательский онкологический институт им. П.А. Герцена – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава России2303202423110182203202422032024https://bioterapevt.abvpress.ru/jour/article/view/1427

This modern literature review covers the results of study of the tubulin inhibitors, mainly combretastatins A-4 and A-1 (CA-4 and CA-1) or colhicinoids. The article presents data of SAR (Structure Activity Relation) study of numerous CA-4 analogues as well as mechanisms of their action evaluated in vitro (using cultured tumor cells) and in vivo (using animals with transplanted murine tumors or with xenografts of human tumors of various histogenesis). The phosphate CA-4 derivative (CA-4P) is characterized as a vascular disrupting agent (VDAs). Approaches are described for developing CA-4 analogues stable in cis-configuration as well as methods for enhancing hydrophility of promising derivatives along with retention of their high cytotoxicity. The results of various clinical trials both of CA-4P and CA-1P administered individually or in combination with chemotherapeutic drugs are also presented. Our conclusion is that despite numerous studies performed during the last thirty years no ideal water-soluble molecule with stable cis-configuration and high cytotoxic activity has been obtained which could become the basis of an active anti-tumor medicine.

The aim of the review is to present the systematic data on antitumor activity of combretastatin CA-4 and CA-1 analogues as well as the modes of their modification and therapeutic usage.

В обзоре литературы рассмотрены результаты исследований различных ингибиторов тубулина (основного компонента микротрубочек), преимущественно колхициноподобных соединений – комбретастатинов А-4 и А-1 (СА-4 и СА-1). Представлены данные исследований SAR (structure activity relation), механизмов действия, оцененных в системах in vitro (на культурах опухолевых клеток) и in vivo (у животных с привитыми опухолями мышей и ксенографтами опухолей человека различного гистогенеза), охарактеризовано фосфатное производное комбретастатина А-4 как vascular disrupting agent (VDAs), описаны подходы к получению аналогов СА-4, стабильных в cis-конфигурации, и способы повышения гидрофильности перспективных производных при сохранении их высокой цитотоксичности. Приведены данные о результатах клинических испытаний СА-4Р и СА-1Р, назначаемых индивидуально или в комбинации с химиопрепаратами. На основании анализа имеющихся результатов исследований производных комбретастатинов А-4 и А-1 сделан вывод об отсутствии среди них в  настоящее время идеального водорастворимого вещества со стабильной cis-конфигурацией молекулы и высокой цитотоксической активностью, на основе которого можно создать активное противоопухолевое лекарственное средство. Целью обзора является систематизация данных о противоопухолевой активности, путях модификации и возможностях терапевтического использования соединений на основе комбретастатинов (СА-4 и СА-1) и их производных.

 

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