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

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.