Ukr.Biochem.J. 2014; Volume 86, Issue 6, Nov-Dec, pp. 84-95
doi: https://doi.org/10.15407/ubj86.06.084
Study of rat blood serum biochemical indicators of cardiotoxic action of novel antitumor 4-thiazolidinone derivatives and doxorubicin in complexes with polyethylenglycol-containing polymeric carrier in the rat blood serum
L. I. Kоbylinska1, D. Ya. Havrylyuk1, А. О. Ryabtseva2, N. E. Mitina2,
О. S. Zаichenko2, B. S. Zіmenkovsky1, R. S. Stoika3
1Danylo Halytsky Lviv National Medical University, Ukraine;
2Lviv National Polytechnic University, Ukraine;
3Іnstitute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
e-mail: stoika@cellbiol.lviv.ua
The aim of this study was to measure the activity of enzymes which reflect cardiotoxic action in rats of novel synthetic 4-thiazolidone derivatives – 3882, 3288 and 3833 that demonstrated antineoplastic effect in vitro towards 60 lines of human tumor cells tested in the framework of the program of screening new anticancer drugs at the National Cancer Institute (USA). Such action of these compounds was compared with the effect of well known anticancer agent doxorubicin and after conjugation of all above mentioned substances with new polyethylenglycol-containing polymeric comb-like carrier that was synthesized by the authors. Among the biochemical indicators of cardiotoxic action of anticancer agents, activity of the following enzymes in rat blood serum showed to be the most informative: creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase. Tenfold injection of doxorubicin in a dose of 5.5 mg/kg of weight caused rats’ death, while 3882, 3288 and 3833 preparations had not such action. Application of the doxorubicin in combination with polymeric carrier prolonged the survival time to 20 days. Thus, the injection of anticancer agents in a complex with polymeric carrier provides a significant decrease in their cardiotoxicity that was confirmed by the corresponding changes in the activity of marker enzymes: creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase in blood serum of treated rats.
Keywords: 4-thiazolidone derivatives, cardiotoxicity, doxorubicin, enzymatic activity, polyethylenglycol-containing polymeric comb-like carrier
References:
- Pat. UA u201114202, N 69857. 3-{2-[5-(3,5-diaril)-4,5-dihydropirazol-1-il]-4-oxo-4H-thiazol-5-iliden}-1,3-dyhidroindol-2-ons, that possess anticancer activity / Havrylyuk D. Ya., Zimenkovsky B. S., Lesyk R. B., Roman O. M. Pub. 10.05.2012, Bul. N 19. (In Ukrainian).
- Arzamastsev E. V., Gouscova T. A., Berezovskaya I. V. Methodological Мannual on study of general toxicity of new pharmacological remedies. Moscow, 2000. P.18-26. (In Russian).
- Lesyk RB, Zimenkovsky BS, Kaminskyy DV, Kryshchyshyn AP, Havrylyuk DYa, Atamanyuk DV, Subtel’na IYu, Khyluk DV. Thiazolidinone motif in anticancer drug discovery. experience of DH LNMU medicinal chemistry scientific group. Biopolym Cell. 2011;27(2):107-17. CrossRef
- Mohort M. A., Seredinska M. N., Kyrychok L. M. Cardiotoxic effects of doxorubicin and expedience of their pharmacological correction by the antagonists of calcium of dihydropyrydin type and activators of the АТP-sensitive potassium channels of guanidine type. Pharmacol Drug Toxicol. 2010;4(7):35-44. (In Ukrainian).
- Semenova A. I. Cardio- and neurotoxicity of anticancer preparations (pathogeny, clinics, prophylaxis, treatment). Pract Oncol. 2009;10(3):168-176. (In Russian).
- Lesyk R., Zimenkovsky B. 4-Thiazolidones: centenarian history, current status and perspectives for modern organic and medicinal chemistry. Curr Org Chem. 2004;8(16):1547-77. CrossRef
- Havrylyuk D, Zimenkovsky B, Vasylenko O, Day CW, Smee DF, Grellier P, Lesyk R. Synthesis and biological activity evaluation of 5-pyrazoline substituted 4-thiazolidinones. Eur J Med Chem. 2013 Aug;66:228-37. PubMed, CrossRef
- Havrylyuk D, Zimenkovsky B, Vasylenko O, Gzella A, Lesyk R. Synthesis of new 4-thiazolidinone-, pyrazoline-, and isatin-based conjugates with promising antitumor activity. J Med Chem. 2012 Oct 25;55(20):8630-41. PubMed, CrossRef
- Havrylyuk D, Zimenkovsky B, Vasylenko O, Lesyk R. Synthesis, anticancer and antiviral activity of new 2-pyrazoline substituted 4-thiazolidinones. J Heterocyclic Chem. 2013;50(S1):E55-E62. CrossRef
- Havrylyuk D, Zimenkovsky B, Vasylenko O, Zaprutko L, Gzella A, Lesyk R. Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. Eur J Med Chem. 2009 Apr;44(4):1396-404. Epub 2008 Oct 7. PubMed, CrossRef
- Bharali DJ, Khalil M, Gurbuz M, Simone TM, Mousa SA. Nanoparticles and cancer therapy: a concise review with emphasis on dendrimers. Int J Nanomedicine. 2009;4:1-7. Review. PubMed, PubMedCentral, CrossRef
- Caruthers SD, Wickline SA, Lanza GM. Nanotechnological applications in medicine. Curr Opin Biotechnol. 2007 Feb;18(1):26-30. Review. PubMed, CrossRef
- Senkiv Yu, Ryabtseva A, Heffeter P, Boyko N, Shlyahtina Ye, Mitina N, Berger V, Zaichenko OS, Stoika RS. Immobilization of doxorubicin on oligoelectrolyte polymeric VEP-GMA-PEG carrier enhances delivery of this anticancer agent in tumor cells and efficiency of its cytotoxic action. Studia Biologica. 2012;6(2):1-12. (In Ukrainian).
- Heffeter P, Riabtseva A, Senkiv Y, Kowol CR, Körner W, Jungwith U, Mitina N, Keppler BK, Konstantinova T, Yanchuk I, Stoika R, Zaichenko A, Berger W. Nanoformulation improves activity of the (pre)clinical anticancer ruthenium complex KP1019. J Biomed Nanotechnol. 2014 May;10(5):877-84. PubMed, CrossRef
- Senkiv Y, Riabtseva A, Heffeter P, Boiko N, Kowol CR, Jungwith U, Shlyakhtina Y, Garasevych SG, Mitina N, Berger W, Zaichenko A, Stoika R. Enhanced anticancer activity and circumvention of resistance mechanisms by novel polymeric/ phospholipidic nanocarriers of doxorubicin. J Biomed Nanotechnol. 2014 Jul;10(7):1369-81. PubMed, CrossRef
- Riabtseva A, Mitina N, Boiko N, Garasevich S, Yanchuk I, Stoika R, Slobodyanyuk O, Zaichenko A. Structural and colloidal-chemical characteristics of nanosized drug delivery systems based on pegylated comb-like carriers. Chem Chem Technol. 2012;6(3):291-295.
- Stefanov OV. Preclinical studies of medicines. Methodological Recommendations. Kyiv, 2001. 527 p. (In Ukrainian).
- On claims of order of conducting preclinical study of medications and examination of materials of preclinical study of medications: Order of Ministry of Health of Ukraine, 14.12.2009 N944. Available at http:. zakon.rada.gov.ua. cgi-bin. laws. main.cgi?nreg=z0053-10.
- Kamyshnikov V. S. Manual on clinical biochemical investigations and laboratory diagnostics. Moscow: MEDpress-inform, 2004. 911 p. (In Russian).
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