ISSN 2415-3060 (print), ISSN 2522-4972 (online)
JMBS
  • 30 of 59
Up
JMBS 2016, 1(1): 139–143
https://doi.org/10.26693/jmbs01.01.139
Biology

Effect of Pyrrole Derivative on the Rat Colonic Mucosa Compared to 5-Fluorouracil

Yena M.S., Dzyubenko N.V., Rybalchenko V.K.
Abstract

In recent years there has been a fairly high level of digestive system cancer, which tends to increase. This remains a topical issue in modern medicine. Often one of the causes of cancer is impaired tyrosine kinase activation processes, which regulate the different stages of growth and proliferation of cells. Therefore, a promising trend in modern medicine is associated with targeted highly selective medicinal products, in particular membrane tyrosine kinase inhibitors characterized by high antitumor activity and lower toxicity as compared with traditional cytostatics. Medicinal products in this class include dihydropyrrole derivative (D1) іn silico synthesized at Research and Production Biochemical Center of Taras Shevchenko National University as targeted inhibitors of protein kinase, which due to the spatial structure of the molecule interacts with the ATP-binding centre of tyrosine proteinkinases and is their effective blocker. Since the cytotoxic effect of the medicinal product D1 has been demonstrated on the transformed lineand cancer cells, it is said to be a potential compound for use in clinical practice.The aim of the study was to evaluate the effect of different doses of dihydropyrrole derivative (D1) on the rectal mucosa of rats compared to the traditional chemotherapeutic agent 5-fluorouracil (5-FU). The studies were conducted on 90 white mongrel male rats with an average body weight of 90±108 g. The rats were housed understandard environmental conditions (23±1°C,55±5 % humidityand a 12-h light: 12-h dark cycle) and maintained with free accessto water and a standard laboratory diet ad libitum The study was conducted in accordance with the generally accepted bioethical standards of humane treatment of laboratory animals, in accordance with national and international regulations on carrying out experimental tests (“European Convention for the Protection of Vertebrate Animals used for experimental and other scientific purposes” (Strasbourg, 1986), “General Ethical Principles of Animal Experiments”, adopted by the First National Congress on Bioethics (Kiev, 2001). The effect of dihydropyrrole derivative (D1) at different doses, and its comparison with 5-FU effect on the morphological and functional condition of the rat colon were studied in the setting of short exposure (14 days). The test substance was administered daily on an empty stomach.D1 at the doses of 2.3 mg/kg (conventionally effective), 11.5 mg/kg (5-fold the effective dose) and 23 mg/kg (10 times the effective dose) was injected dissolved in sunflower oil containing 15% DMSO (0.1 ml in total) per os, which, under the conditions of complete absorption, creates blood concentration of 10-4M, 5x10-4M and 10x10-4M respectively. 5-FU was administered intraperitoneally at the doses of 0.86mg/kg, 4.3 mg/kg, 8.6 mg/kg (conventionally effective), which, under the conditions of complete absorption, creates blood concentration 10-4M, 5x10-4M, 10x10-4M respectively, and 45 mg/kg (-fold the effective dose). Control animals received oil containing 15% DMSO (0.1ml in total). Thus, the state of the ascending colon mucosa of rats exposed to increasing doses of the protein kinase inhibitor, pyrrole derivative 5-amino-4-(1,3-benzothiazole-2-yl)-1-(3-methoxyphenyl)-1,2-dihydro-3Н-pyrrol-3-one (D-1) compared to antineoplastic 5-fluorouracil (5-FU) has been studied. It has been found out that the dihydropyrrole derivative has no damaging effect on the colon of rats, whereas the administration of 5-fluorouracil causes marked mucosal lesion of the ascending colon.

Keywords: intestinal mucosa, dihydropyrrole derivative, 5-fluorouracil

Full text: PDF (Rus) 170K

References
  1. Babuta OM, Linchak OV, Ribalchenko VK. Gistologichna harakteristika slizovoyi obolonki slipoyi kishki schuriv pislya vplivu MI-1 ta 5-ftoruratsilu pri hemoindukovanomu kantserogenezi. Visnik problem biologiyi i meditsini. 2013; 3 (102): 31-35.
  2. Garmanchuk LV, Linchak OV, Nikulina VV, i dr. Proizvodnoe maleimida 1-(4-Sl-benzil)-3-Cl-4-(CF3-fenilamino)-1N-piroll-2,5-dion kak effektivnyiy i malotoksichnyiy tsitostatik. Eksperimentalnaya i klinicheskaya farmakologiya. 2013; 8 (76): 39-42.
  3. Garmanchuk LV, Senchilo NV, Nikulina VV, ta in. Tsitotoksichniy vpliv na puhlinni klitini in vitro agentiv z protipuhlinnim ta antimetastatichnim efektom. Fizika zhivogo. 2011; 19 (2): 51-3.
  4. Goralskiy LP, Homich VT, Kononskiy OI. Osnovi gistologichnoyi tehniki i morfo-funktsionalni metodi doslidzhen u normi ta pri patologiyi. Zhitomir: Polissya; 2005. 288 s.
  5. Dubinina GG, Golovach CM, Kozlovskiy VO, ta in. Antiproliferativna diya novih pohidnih 1-(4-R-benzil)-3-R1-4-(R2-fenilamino)-1H-pirol-2,5-dionu. Zhurnal organichnoyi ta farmatsevtichnoyi himiyi. 2007; 5 (1): 39-49.
  6. Zhukov NV, Tyulyandin SA. Tselevaya terapiya v lechenii solidnyih opuholey: praktika protivorechit teorii. Biohimiya. 2008; 73 (5): 751-68
  7. Imyanitov EN. Obschie predstavleniya o targentnoy terapii. Prakt Onkologiya. 2010; 11 (3): 123-30.
  8. Kuznetsova GM, Linchak OV, Ribalchenko VK, ta in. Vpliv pohidnih digidropirolu ta maleimidu na stan pechinki i tovstoyi kishki schuriv u normi ta v umovah indukovanogo dimetilgidrazinom kolorektalnogo raku. Ukrainskiy biohimichniy zhurnal. 2013; 85 (3): 74-84.
  9. Lilli R. Patogistologicheskaya tehnika i prakticheskaya gistohimiya. M: Mir; 1969. 648 s.
  10. Linchak OV, Ostrovska GV, Ribalchenko VK, ta in. Morfo-funktsionalniy stan organiv shlunkovo-kishkovogo traktu pislya vplivu pohidnogo maleimidu MI-1 protyagom misyatsya. Suchasni problemi toksikologiyi. 2011; 1 (2): 52-5.
  11. Parfenov AI. Enterologiya. M: «Triada-H»; 2002. 724 s.
  12. Patent na korisnu model № 22204 (UA), Ab1K31/40. Spoluka 1,4-zamIschenih 5-amшno-1,2-digшdropirol-3-oniv, scho mae protirakovu aktivnist. GG Dubinina, YuM. Volovenko; zayavnik i vlasnik GG Dubininna, YuM Volovenko. № u200601855; zayavl 21.02.2006; opubl 25.04.2007, Byull № 5.
  13. Sergienko VI, Bondareva IB. Matematicheskaya statistika v klinicheskih issledovaniyah. M: GEOTAR MEDITSINA; 2006. 304 s.
  14. Strukov AI, Serov VV. Patologicheskaya anatomiya: uchebnik. 5-e izd, ster. M: Litterra; 2010. 848 s.: il.
  15. Bozzetti F. The Site of the Tumor. Not the Type of Operation. Determines the Worse Prognosis of the Low Rectal Cancer. Ann Surg. 2006; 244 (2): 330-1. https://doi.org/10.1097/01.sla.0000230007.89561.91
  16. Garmanchuk LV, Ribalchenko VK, Ostapchenko LI, et al. MI1 – derivative of maleimide inhibits cell cycle progression in tumor cells of epithelial origin. Biopolymers and Cell. 2013; 29 (1): 70-4. https://doi.org/10.7124/bc.000808
  17. Siegel R, Ma J, Zou Z, Jemal A. Cancer Statistics, 2014. CA: A Cancer Journal for Clinicians. 2014; 64 (1): 1-74. https://doi.org/10.3322/caac.21208
  18. Singer C. F. Principles and method of action of targeted therapies. Wien Med Wochenschr. 2010; 160 (19-20): 501-5. https://doi.org/10.1007/s10354-010-0839-5
  19. Tsai C-J, Nussinov R. The molecular basis of targeting proteinkinases in cancer therapeutics. Seminars in Cancer Biologу. 2013; 23 (4): 235-42. https://doi.org/10.1016/j.semcancer.2013.04.001
  20. Yablonska S, Lynchak О, Filinska О. Manifestation of antiproliferative effects of new kinase inhibitor inrespect of normal cell. The FEBS Journal. 2009; 276 (1): 352.