A new model for the evaluation of selective toxicity of antineoplastic funds in transgenic mice with human genes Nat1hom

The toxicity of the drug Cisplatin after intragastric administration was assessed on humanized transgenic mice with human genes Nat1hom . The evaluation was conducted in comparison with mice lines C57BL6/Y ("fast" type of acetylation) and line SHK ("slow" type of acetylation). LD50 for mice Nat1hom amounted to 56,3 mg/kg, for mice of the C57BL6/Y - 35,1 mg/kg, for mice line SHK - 33,7 mg/kg. The death of animals C57BL6/Y and SHK line was observed within 1-6 hours after administration and in mice Nat1hom - a day after the introduction. There were lethargy, lack of exercise, a sharp decline in muscle tone with episodic generalized convulsive episodes, collapsing on its side in animals of all lines closely to lethal condition. The autopsy of the dead animals showed signs of congestive venous plethora of internal organs, edema of the meninges with a single bleeding under the lining of the brain. After administration of Cisplatin at a dose of 45-55 mg/kg in histological research there were detected cerebral edema with signs of acute encephalopathy and changes in the myocardium, which indicate the early development of acute heart failure. Venous plethora manifested in all internal organs and in the brain. Lower level of toxicity of Cisplatin in mice with human genes Nat1hom, authors explain the presence of the human gene with the "fast" type of acetylation. It is concluded that in the metabolism and detoxification of Cisplatin, as well as reducing its toxicity, more than 60% N-acetyltransferase processes. The creation of transgenic humanized mice can be based on the use of CRISPR/Cas9 technology. Proposed a new model of humanized transgenic mice with the gene Nat1hom for preclinical researches of anticancer drugs.

токсичность антибластомных препаратов, Цисплатин, трансгенные гуманизированные мыши с геном Nat1hom, мыши линий C57BL6/Y и SHK, гистоморфология, ПЦР в реальном времени, CRISPR/Cas9-технология, toxicity of antineoplastic drugs, Cisplatin, humanized transgenic mice with the gene Nat1hom, mouse C57BL6/Y and SHK lines, histomorphology, real-time PCR, CRISPR/Cas9 technology

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