vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2020-10-2-96-110vedomostiregmed-295Research ArticleОБЗОРЫREVIEWSПротивоопухолевые лекарственные препараты: планирование доклинических исследований по оценке эффективности и безопасностиAnti-Tumour Drugs: Planning Preclinical Efficacy and Safety Studieshttps://orcid.org/0000-0002-5009-1508БезбородоваО. А.BezborodovaO, A.

Безбородова Ольга Алексеевна - доктор биологических наук.

2-й Боткинский проезд, д. 3, Москва, 125284

Olga A. Bezborodova - Dr. Sci. (Biol.).  

3 2nd Botkinsky Drive, Moscow 125284

olgabezborodova@yandex.ruhttps://orcid.org/0000-0001-7291-9743ПанкратовА. А.PankratovA. A.

Панкратов Андрей Александрович - кандидат биологических наук.

2-й Боткинский проезд, д. 3, Москва, 125284

Andrey A. Pankratov - Cand. Sci. (Biol.).

3 2nd Botkinsky Drive, Moscow 125284

andreimnioi@yandex.ruhttps://orcid.org/0000-0002-3579-1733НемцоваЕ. Р.NemtsovaE. R.

Немцова Елена Романовна - доктор биологических наук. 

2-й Боткинский проезд, д. 3, Москва, 125284

Elena  R. Nemtsova - Dr. Sci. (Biol.).  

3 2nd Botkinsky Drive, Moscow 125284

nemtz@yandex.ruhttps://orcid.org/0000-0003-0909-4202ВенедиктоваЮ. Б.VenediktovaYu. B.

Венедиктова Юлия Борисовна. 

2-й Боткинский проезд, д. 3, Москва, 125284

Yulia B. Venediktova

3 2nd Botkinsky Drive, Moscow 125284

uluaz@yandex.ruhttps://orcid.org/0000-0002-9320-1746ВоронцоваМ. С.VorontsovaM. S.

Воронцова Мария Сергеевна. 

2-й Боткинский проезд, д. 3, Москва, 125284

Maria S. Vorontsova

3 2nd Botkinsky Drive, Moscow 125284

vapireshouse@mail.ruhttps://orcid.org/0000-0001-5121-0858ЕнгалычеваГ. Н.EngalychevaG. N.

Енгалычева Галина Нинелевна - кандидит биологических наук.

Петровский б-р, д. 8, стр. 2, Москва, 127051

Galina N. Engalycheva, Cand. Sci. (Biol.).

8/2 Petrovsky Blvd, Moscow 127051

engalycheva@expmed.ruhttps://orcid.org/0000-0002-6729-2349СюбаевР. Д.SyubaevR. D.

Сюбаев Рашид Даутович - доктор медицинских наук.

Петровский б-р, д. 8, стр. 2, Москва, 127051

Rashid D. Syubaev - Dr. Sci. (Med.). 

8/2 Petrovsky Blvd, Moscow 127051

rds651@mail.ruМосковский научно-исследовательский онкологический институт им. П. А. Герцена — филиал Федерального государственного бюджетного учреждения «Национальный медицинский исследовательский центр радиологии» Министерства здравоохранения Российской ФедерацииРоссияP.A. Hertsen Moscow Oncology Research Centre, Branch of the National Medical Radiology Research CentreRussian FederationФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation20202106202010296110Copyright © Безбородова О.А., Панкратов А.А., Немцова Е.Р., Венедиктова Ю.Б., Воронцова М.С., Енгалычева Г.Н., Сюбаев Р.Д., 20202020Безбородова О.А., Панкратов А.А., Немцова Е.Р., Венедиктова Ю.Б., Воронцова М.С., Енгалычева Г.Н., Сюбаев Р.Д.Bezborodova O.A., Pankratov A.A., Nemtsova E.R., Venediktova Y.B., Vorontsova M.S., Engalycheva G.N., Syubaev R.D.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/295

Расшифровка структуры ДНК и разработка новых молекулярных методов ее анализа, идентификация специфических геномных изменений, ответственных за неопластическую трансформацию, стали поворотными моментами в разработке инновационных лекарственных средств — таргетных противоопухолевых агентов, направленных на молекулярные и генетические мишени опухолевого роста. Переход от эмпирического скрининга агентов, механизм действия которых основан на ингибировании пролиферации опухолевых клеток, к молекулярно-нацеленным методам анализа привел к возникновению ряда важных методологических вопросов, связанных с доклинической разработкой инновационных лекарственных средств. Цель работы — анализ общих принципов и особенностей доклинических исследований эффективности и безопасности современных противоопухолевых препаратов различных классов для усовершенствования существующих национальных методических рекомендаций. В работе рассмотрены вопросы доклинических исследований различных классов противоопухолевых лекарственных средств (синтетических химиотерапевтических препаратов, гормонов и антагонистов гормонов, препаратов алкилирующего действия, антиметаболитов, препаратов микробного и растительного происхождения, а также моноклональных антител). Приведены общие принципы изучения их фармакологической активности в системах in vitro, ex vivo и in vivo, определения фармакокинетических параметров, описаны используемые методы и модели исследований. Указаны особенности определения генотоксичности, канцерогенности, репродуктивной токсичности, мутагенности, острой и хронической токсичности препаратов разных групп, перечислены критерии выбора доз для токсикокинетических исследований. Необходимость гармонизации национальных требований к проведению доклинических исследований с европейскими нормами влечет за собой унификацию терминологии и дальнейшую разработку общих алгоритмов выбора доз и определения необходимых объемов исследования. Использование биомаркеров в доклинических исследованиях позволит исключить дальнейшие исследования неэффективных соединений.

The decoding of the DNA structure and development of new molecular methods of its analysis, as well as identification of specific genomic changes responsible for malignant transformation, have become the turning points in elaboration of novel anti-tumour drugs directed against molecular and genetic targets of tumor growth. Transition from empirical screening of agents inhibiting tumour cell proliferation to molecule-targeted analytical methods has raised a number of serious methodological issues regarding preclinical evaluation of novel medicines. The objective of this paper was to analyse general principles and features of preclinical efficacy and safety studies of different classes of modern anti-tumour drugs with a view to improve existing national guidelines. The paper reviews various aspects of preclinical studies of different classes of anti-tumour drugs (small molecule chemotherapy drugs, hormones and hormone antagonists, alkylating agents and antimetabolites, microbial and herbal medicines, as well as monoclonal antibodies). The article explores general principles of studying the drugs’ pharmacological activity in vitro, ex vivo, and in vivo, and evaluating their pharmacokinetic parameters. It describes various methods and models of research, summarises specific aspects of determination of genotoxicity, carcinogenicity, reproductive toxicity, mutagenicity, acute and chronic toxicity of various groups of medicines. It also lists criteria for selecting drug doses for toxicokinetic studies. The need for harmonisation of national requirements for conducting preclinical studies with the European standards entails alignment of terminology and further development of general algorithms for selecting doses and determining the necessary scope of research. The use of biomarkers in preclinical studies will make it possible to exclude inefficient compounds from further research.

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The authors declare that there are no conflicts of interest present.