Українська Русский English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2017; 63(4): 37-47


THE HEMATOLOGICAL EFFECTS OF THE PROTEIN KINASES INHIBITOR MALEIMIDE DERIVATIVE AND 5‑FLUOROURACIL

I.V. Byelinska, T.V. Rybalchenko, S.M. Tsyvinska, V.K. Rybalchenko

    Taras Shevchenko National University of Kyiv, Ukraine
DOI: https://doi.org/10.15407/fz63.04.037

Abstract

The effect of the protein kinase inhibitor maleimide derivative (MI‑1, 1‑(4‑Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1Hpyrrole-2,5-dione) with antitumor activity (inhibits colorectal carcinogenesis) at five fold (13.5 mg/kg, ~ 5.10‑4 mol/l in the blood) and ten fold (27 mg/kg, ~ 10.10-4 mol/l in the blood) the effective dose for 14 days on blood cells of rats in comparison with cytostatic 5‑fluorouracil (5‑FU) have been studied. It is shown that MI‑1 causes activation of erythropoiesis, as evidenced by an increase in reticulocyte count and hematocrit and hemoglobin concentration in the blood without changing of morphofunctional state of erythrocytes: volume, content and concentration of hemoglobin. Comparison drug 5‑FU at the concentration ~ 10×10‑4 M in the blood (which correspod the effective dose 8.6 mg/kg) inhibits erythropoiesis, as evidenced by a decrease in the erythrocyte and reticulocytes count in the blood. MI-1 at 5 and 10 times the effective dose cause a trend to reduce the number of leukocytes and monocytes, and platelets in the blood. Count of basophilic, eosinophilic and neutrophilic granulocytes and lymphocytes in the blood do not change. 5‑FU at the appropriate concentration reduces the number of leukocytes, lymphocytes, monocytes, neutrophils and platelets in the blood. Five fold (45 mg/kg) the effective dose of 5-FU causes 100% mortality of rats after the first week of administration. In the blood of animals 5 days after the influence of 5-FU reduces the number of erythrocytes, leukocytes, lymphocytes, monocytes and platelets and tend to reduce of neutrophils number. Thus, a maleimide derivative MI-1 with antitumor activity has low, as compared to high toxic 5‑FU, haematotoxicity at the 10 fold the effective dose, that is an advantage in its use and promising for further studies

Keywords: maleimide derivative; protein kinases inhibitor; 5-fluorouracil; erythrocytes; leukocytes; platelets

References

  1. Sviezhentseva IO, Perekhrestenko TP, Bilko DI, Gordienko AI, Diachenko MV, Dyagil IS. Functional activity of CD34-positive cells in chronic myeloid leukemia patients with different response to imatinib therapy. Exp Oncol. 2015;37(1):70-2. PubMed
  2.  
  3. Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: Results from the BELA trial. J Clin Oncol. 2012;30(28):3486-92. CrossRef PubMed PubMedCentral
  4.  
  5. Morabito F, Gentile M, Seymour JF, Polliack A. Ibrutinib, idelalisib and obinutuzumab for the treatment of patients with chronic lymphocytic leukemia: three new arrows aiming at the target. Leuk Lymphoma. 2015;56(12):3250-6. CrossRef PubMed
  6.  
  7. Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Mesa R, He S, Jones MM, Garrett W, Li J, Pirron U, Habr D, Verstovsek S. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426-35. CrossRef PubMed PubMedCentral
  8.  
  9. Perekhrestenko T, Diachenko M, Sviezhentseva I, Gordienko A, Bilko D. Mechanisms of resistance in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Georgian Med News. 2015;(240):43-50. PubMed
  10.  
  11. Dmytrenko IV, Fedorenko VG, Shlyakhtychenko TY, Sholoyko VV, Lyubarets TF, Malinkina TV, Dmytrenko OO, Balan VV, Kravchenko SM, Martina ZV, Tovstogan AO, Minchenko JM, Dyagil IS. Assessment of response to imatinib therapy in patients with chronic myeloid leukemia with e13a2 and e14a2 transcripts of BCR/ABL1 gene. Problemy Radiatsiinoi Medytsyny ta Radiobiolohii. 2015;20:328-40. PubMed
  12.  
  13. Dubinina GG, Chupryna OO, Platonov MO, Borisko PO, Ostrovska GV, Tolmachov AO, Shtil AA. In Silico Design of Protein Kinase Inhibitors: Successes and Failures. Anticancer Agents Med Chem. 2007;7(2):171-88. CrossRef PubMed
  14.  
  15. Dubinina GG, Golovach SM, Kozlovsky VO, Tolmachov AO, Volovenko YuM. Antiproliferative activity of the new derivatives of 1-(4-R-benzyl)-3-R1-4-(R2- phenylamino)-1N-pyrrole-2,5-dione. J Organ ta Farm Khimii 2007;5(1):39–49. [Ukrainian].
  16.  
  17. Garmanchuk LV, Linchak OV, Niculina VV, Dzhus OI, Chranovskaya NN, Nicolaenko TV, Babuta EN, Rybalchenko VK. Potential cytostatic effect of the Maleimide derivative 1-(4-Sl-benzyl)-3-Cl-4-(CF3-phenylamino)- 1N-pyrrole-2,5-dione. Eksperim Klin Farmakol. 2013;76(8):39–42. PubMed
  18.  
  19. Lynchak OV, Prylutskyy YuI, Rybalchenko VK, Kyzyma OA, Soloviov D, Kostjukov VV, Evstigneev MP, Ritter U, Scharff P. Comparative Analysis of the Antineoplastic Activity of C60 Fullerene with 5-Fluorouracil and Pyrrole Derivative In Vivo. Nanoscale Res Lett. 2017;12:8. CrossRef PubMed PubMedCentral
  20.  
  21. Byelinska IV, Lynchak OV, Rybalchenko TV, Gurnyak OM. Hematological effects of the protein kinases inhibitor maleimide derivative of dimethylhydrazine-induced colorectal carcinogenesis of rats. Fiziol Zh. 2014;60(4):40–9. [Ukrainian]. CrossRef  
  22. Filinska OM, Yablonska SV, Mandryk SY, Kharchuk IV, Ostrovska GV, Rybalchenko VK. State of the liver antioxidant system and content of matrix metalloproteinase-2 of large intestine under the effect of maleimide derivative in experimental colon carcinogenesis in rats. Ukr Biochem J. 2010;82(4):69–77.
  23.  
  24. Byelinska IV, LynchakOV, Tsyvinska SM, RybalchenkoVK. Morphofunctional state of blood cells after chronic exposure of the protein kinase inhibitor maleimide derivative. Fiziol Zn. 2015;61(4): 71–77. [Ukrainian]. CrossRef  
  25. Kharchuk IV, Filinska OM, Yablonska SV, RybalchenkoTV. The structure functional status of rat kidney and pancreas after the long-term influence of novel targeted-action compound — maleimide derivative. Reports NASU. 2010;7:150–4.
  26.  
  27. Kent D, Copley M, Benz C, Dykstra B, Bowie M, Eaves C. Regulation of Hematopoietic Stem Cells by the Steel Factor/KIT Signaling Pathway. Clin Cancer Res. 2008;14(7):1926–30. CrossRef PubMed
  28.  
  29. Slavova-Azmanova NS, Kucera N, Satiaputra J, Stone L, Magno A, Maxwell MJ, Quilici C, Erber W, Klinken SP, Hibbs ML, Ingley E. Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling. Blood. 2013;122(2):262-271. CrossRef PubMed
  30.  
  31. Kudokotseva OV, Kovalenko IF, Lomakin II, Babijchuk GA. Correction of Anemia Resulting From 5-Fluorouracil Toxic Effect Using Cryopreserved Preparations of Cord Blood. Probl Cryobiol Cryomed. 2014;24(4):312-321. CrossRef  
  32. Kuznietsova HM, Lynchak OV, Danylov MO, Kotliar IP, Rybal'chenko VK. Effect of dihydropyrrol and maleimide derivatives on the state of the liver and colon in normal rats and those with colorectal carcinogenesis induced by dimethylhydrazine. Ukr. Biokhimicheskii Z. 2013;85(3):62-67. CrossRef  
  33. Minakova MYu, Skurikhin EG, Pershina OV. Dopaminergic regulation of erythropoiesis in modeled myelosuppressions induced by cyclophosphamide and 5-fluorouracil. Bull Experim Biol Med. 2007;143(1):68-74. CrossRef  
  34. Nakao T, Geddis AE, Fox NE, Kaushansky K. PI3K/ Akt/FOXO3a pathway contributes to thrombopoietininduced proliferation of primary megakaryocytes in vitro and in vivo via modulation of p27Kip1. Cell Cycle. 2008;7(2):257-266. CrossRef PubMed
  35.  

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2020.