Toxicological characteristic of novel antitumour multitargeted agent anthrafuran

Introduction. One of the modern approaches to development of antitumor drugs is based on oriented search of specific tumor cells molecular targets inhibitors. The application of such therapeutic agents will improve selectivity of action and decrease side effects of antineoplastic therapy. Novel antitumor multitargeted drug anthrafuran (LCTA-2034), obtained in Gause Institute of new antibiotics, represents a derivative of anthra[2,3-b]furan-3-carboxamide. Compound exhibits pronounced antitumor activity in vivo. Objective. The objective of the present study was to investigate the toxicity of LCTA-2034. Materials and methods. Toxicological study was performed in male outbred rats. The drug was administrated intraperitoneally at the total doses of MTD and LD₅₀ (14 x 3 mg/kg or 14 x 4.5 mg/kg with 24-h interval). Dynamics of body weight, hematological parameters, blood biochemical parameters, electrocardiography and urinalysis were performed for all animals. 5 animals in each group were sacrificed 1 and 30 days post treatment. The mass coefficients of heart, kidneys, liver, spleen and thymus were calculated. The internal organs were subjected to histological evaluation. Results. The results of the study demonstrate that the intraperitoneal injections of LCTA-2034 don't produce any changes in examined clinical-laboratory parameters. The treatment with LCTA-2034 in total dose of MTD had no effect on morphological structure of the internal organs of rats. The reversible structural damages in liver, kidneys and small intestine were found in group of rats, treated with high dose of the drug. Signs of cardiotoxicity were documented by microscopic pathology observation on day 30 post treatment in individual animals. Conclusion. Dose dependence and reversibility of toxic effects of LCTA-2034 allows us to recommend it to further advance.

антрафуран, ЛХТА-2034, хроническая токсичность, кардиотоксичность, крысы, anthrafuran, LCTA-2034, chronic toxicity, cardiotoxicity, rats

1. Руководство по химиотерапии опухолевых заболеваний. Под ред. Н.И. Переводчиковой. М.: Практическая медицина, 2015. 686 с.

2. Nadas J., Sun D. Anthracyclines as effective anticancer drugs. Expert Opin Drug Discov 2006; 1: 549-568. PMID: 23506066. DOI: 10.1517/17460441.1.6.549.

3. Raj S., Franco V.I., Lipshultz S.E. Anthracycline-induced cardiotoxicity: a review of pathophysiology, diagnosis, and treatment. Curr Treat Options Cardiovasc Med 2014; 16: 315. PMID: 24748018.

4. Корман Д.Б. Основы противоопухолевой химиотерапии. М.: Практическая медицина, 2006. 503 с.

5. Переводчикова Н.И. Новые препараты группы антрациклинов. В кн.: Новые цитостатики в лечении злокачественных опухолей. Под ред. В.А. Горбуновой. М.: Медицина, 1998. С. 61-73.

6. Johnson R.K., Zee-Cheng R.K., Lee W.W. et al. Experimental antitumor activity of aminoantraquinones. Cancer Treat Rep 1979; 63: 425-39. PMID: 427824.

7. Von Hoff D.D., Pollard E., Kuhn J. et al. Phase I clinical investigation of 1,4-dihy-droxy-5,8-bis(2-(2-hydroxyethyl)-ami-no)-9,10-anthracenedione dihydrochloride, a new antracenedione. Cancer Res 1980; 40: 83-7. PMID: 7370989.

8. Shchekotikhin A.E., Dezhenkova L.G., Tsvetkov V.B. et al. Discovery of antitumor anthra[2,3-b]furan-3-carboxamides: Optimization of synthesis and evaluation of antitumor properties. Eur J Med Chem 2016; 112: 114-29. PMID: 26890118. DOI: 10.1016/j.ejmech.2016.01.050.

9. Щекотихин А.Е., Сенкевич Ю.Б., Деженкова Л.Г. и др. Противоопухолевый антрафурандион и фармацевтические композиции на его основе. Патент РФ № 2554939 от 03.06.15.

10. Treshalina H.M., Romanenko V.I., Kaluzhny D.N. et al. Development and pharmaceutical evaluation of the anticancer Anthrafuran - Cavitron complex, a prototypic parenteral drug formulation. Eur J Pharm Sci 2017; 109: 631-7.

11. Council of Europe. European Convention for the protection of vertebrate animals used for experimental and other scientific purposes. ETS. 1986: 123.

12. Руководство по проведению доклинических исследований лекарственных средств. Под ред. А.Н. Миронова. М.: Гриф и К., 2012. Ч. 1. С. 13-24.

13. Zee-Cheng K.Y., Cheg C.C. Antineoplastic agents. Structure-activity relationship study of bis (substituted amino-alkyl-amino) antraquinnes. J Med Chem 1978; 21: 291-4. PMID: 628005.

14. Xiao P., Dumur F., Graff B. et al. Cationic and thiol-ene photopolymerization upon red lights using anthraquinone derivatives as photoinitiators. Macromolecules 2013; 46: 6744-6750. DOI: 10.1021/ma401513b.

15. Novak R.F. Anthracycline and anthracenedione-based anticancer agents (Bioactive molecules). Elsevier Science Pub. B.V., Amsterdam, 1988. V.6. 519 p.

16. Shchekotikhin A.E., Glazunova V.A., Dezhenkova L.G. et al. Synthesis and evaluation of new antitumor 3-amino-methyl-4,11-dihydroxynaphtho[2,3-f] indole-5,10-diones. Eur J Med Chem 2014; 86: 797-805. PMID: 25244612. DOI: 10.1016/j.ejmech.2014.09.021.

17. Tikhomirov A.S., Shchekotikhin A.E., Lee Y.H et al. Synthesis and characterization of 4,11-diaminoanthra[2,3-b]fu-ran-5,10-diones: tumor cell apoptosis through tNOX-modulated NAD+/ NADH ratio and SIRT1. J Med Chem 2015; 58: 9522-34. PMID: 26633734. DOI: 10.1021/acs.jmedchem.5b00859.