The new antitumor agent anthrafuran has demonstrated a consistent effect in murine tumor models when administered parenterally due to the simultaneous inhibition of multiple cellular targets such as topoisomerases I/II and protein kinases. In this study, we assessed the anticancer efficiency and acute toxicity of anthrafuran administered orally. The action of anthrafuran was studied on transplanted tumor models which included P388 leukemia, Ca755 mammary adenocarcinoma, LLC lung carcinoma, and T47D human breast cancer xenografts on Balb/c nude mice. A significant antitumor efficacy of oral anthrafuran was revealed for all tested tumor models as follows: T/Cmax = 219% for P388, TGImax = 91% for Ca755, TGImax = 84% with CRmax = 54% for LLC, and T/C = 38% for T47D. The optimal treatment schedule of orally administered anthrafuran was 70–100 mg/kg given daily for five days. The LD50 value of orally administered anthrafuran (306.7 mg/kg) in mice was six times higher than that for i.p. administration (52.5 mg/kg). The rates of antitumor efficacy and acute toxicity indicate the high potential for further research on anthrafuran as a new original oral anticancer multitarget agent with an expected satisfactory tolerability and bioavailability.

Introduction.New antitumor multitarget drug LCTA-2034, obtained in Gause Institute of New Antibiotics, has demonstrated high activity against prognostically significant transplantable mice tumors by the oral application.Objective.To investigate the toxicological properties of LCTA-2034 by the oral route of administration on rats.Materials and methods.Toxicological study of LCTA-2034 was performed on 30 male Wistar rats. Drug substance dissolved in potable water. 2 % solution was administrated per os at the 1 and 5 therapeutic dose (15 × 20 mg/kg or 15 × 100 mg/kg with 24-h interval). During the study 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 30 days post treatment. The internal organs were subjected to histological evaluation.Results.The results of the study demonstrate that the treatment with low dose of LCTA-2034 does not produce any changes in majority of examined clinical-laboratory parameters with the exception of urinalysis revealed hematuria on day 1 post treatment. Microscopic pathology observation showed structure abnormalities of varying severity in liver, kidneys, heart, stomach, jejunum, ileum, spleen and thymus. Administration of high dose of LCTA-2034 caused mortality of 2 rats in group. The rest of the rats were observed a body weight lag, decrease of total leukocyte and erythrocyte count, hemoglobin and hematocrit level, relative weight of the thymus. Erythrocytes and nitrates were found in urine both on day 1 and on day 30 post treatment. In groups treated with high dose of the drug in addition to the listed above organs damage of the structure of lymph nodes, pancreas, ileum and brain was detected. Conclusion. Revealed toxic properties of LCTA-2034 depended on dose. Multiple administration of 1 therapeutic dose of the drug produces transient toxic effects completely reversible within 30 days.

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The antimicrobial activity and toxicity of three novel synthetic antibacterial agents containing tris(1H-indol-3-yl)methylium fragment were studied in vitro and in vivo. All compounds in vitro revealed high activity (minimal inhibitory concentration (MIC) 0.13–1.0 µg/mL) against bacteria that were either sensitive or resistant to antibiotics, including multidrug-resistant clinical isolates. The derivatives combining high antimicrobial activity with relatively low cytotoxicity against human donor fibroblasts HPF-hTERT were subjected to further testing on mice. In vivo they revealed fairly good tolerance and relatively low toxicity. Acute toxicity was evaluated, and the main indicators of toxicity, including LD50 and LD10, were determined. A study of compounds in vivo showed their efficiency in the model of staphylococcal sepsis in mice. The efficiency of compounds may be due to the ability of indolylmethylium salts to form pores in the cytoplasmic membrane of microbial cells and thereby facilitate the penetration of molecules into the pathogen.

A new antitumor multi-target drug anthrafuran, with cellular targets such as topoisomerase I/II and some protein kinases, was obtained in Gause Institute of New Antibiotics and was demonstrated to have a reliable specific effect on different murine and human tumor models by oral administration. In this study, we focused on the evaluation of subchronic toxicity of oral anthrafuran drug formulation (AF) on Chinchilla rabbits. The absence of any changes in the condition or behavior of animals was shown for oral anthrafuran. Changes with reversible and dose-dependent hepato- and nephrotoxicity at low doses, as well as hemato- and gastrointestinal toxicity at high doses, were confirmed pathomorphologically. The identified toxic properties are extremely valuable, since oral anthrafuran does not have the limiting cardio- and myelotoxicity. Anthrafuran with 2 mg/kg/day or 6 mg/kg/day doses was administrated orally over 15 days. Investigations include assessment of the body weight, hematological and serum biochemical parameters and urinalysis, electrocardiography and pathomorphological evaluation of the internal organs. Quantitative data were processed statistically with Student’s t-Test, p < 0.05. Revealed during the subchronic study were the favorable toxicological properties of oral anthrafuran as opposed to clinical anthracyclines, oral idarubicin, or parenteral doxorubicin, which allows it to be considered promising for further research.