No abstract

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 LD 50 (14 × 3 mg/kg or 14 × 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 clini cal-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.

Objective. The aim of the study was to research the toxicity of L-asparaginase Was79 in rabbits. Materials and methods. Chronic toxicity of L-asparaginase Was79, obtained by modification of native enzyme Wolinella succinogenes in Research Institute of Genetics and Selection, was performed in male and female Russian chinchilla rabbits. L-asparaginase was injected intravenously at the 1 and 5 therapeutic dose (15 x 100 IU/kg or 15 x 500 IU/kg with 24-h interval). The following parameters were tested: body mass, clinical and biochemical blood tests, urinalysis, electrocardiography, pathomorphological evaluation of internal organs. Resutls. The results of the study suggest that the treatment with L-asparaginase Was79 does not influence on the function of heart and kidneys, but damages their structure. Loss in body mass, diarrhea and alteration of stomach and intestine mucosa could be interpreted as evidence of gastrointestinal toxicity. Hematological toxicity was exhibited as a decrease of total leukocyte count, lymphocyte and neutrophils count level in peripheral blood and atrophy of lymphoid tissue of the spleen, thymus and lymph nodes. Elevation of total and direct bilirubin in serum and histopathological findings in liver were found in groups treated with both high and low doses of Was79. Conclusion. Most of these abnormalities were reversible and dose-dependent.

Toxicological study of L-asparaginase Was79, obtained by modification of native enzyme Wolinella succinogenes in Research Institute of Genetics and Selection, was performed in male and female inbred rats. L-asparaginase was injected intraperitoneally at the 1 and 10 therapeutic dose (15x1200 IU/kg or 15x12000 IU/kg with 24-h interval). Dynamics of body weight, hematological parameters, blood biochemical parameters, electrocardiography and urinalysis were performed for all animals. Five animals in each group were sacrificed 1 and 15 days post treatment. At necropsy, the organs were inspected macroscopically. The mass coefficients of heart, kidneys, liver, spleen and thymus were calculated. The pathomorphological evaluation was performed for internal organs. The results of the study demonstrate that the treatment with L-asparaginase Was79 did not produce any changes in body weight, hematology, blood biochemical or urinary parameters. Hematological, renal, gastrointestinal, and pancreatic toxicity of L-asparaginase have been documented only by microscopic pathology observation. Liver toxicity, revealed in the histopathological findings, was supported by the results of clinical chemistry. Marked elevation of ALT and alkaline phosphatase in serum was found in both treated groups. Most of these abnormalities were reversible and dose-dependent.