The Acute Toxicity Study Of New Anti-tumor Drug "NUC-1031"

Objective:NUC-1031 is a nucleoside analogue obtained through the application of ProTide patent technology to modify gemcicitabine.Preclinical studies have shown that nuc-1031 overcomes the main restrictive pharmacodynamic mechanism of gemcicitabine and is a new anticancer drug with great development prospects.In this study,SD rats were selected as the research objects,and the maximum tolerance method(MTD)was used to investigate the acute toxicity of NUC-1031,observe the acute toxic manifestations of drugs,understand the time,incidence,degree and duration of toxic manifestations and the reversibility of toxic manifestations,and preliminarily judge the safe range of drugs.To find organs,tissues or systems involved in toxic reactions,and preliminarily judge the possible toxic target organs according to the pathological changes visible to the naked eye and histopathological examination results in the gross anatomy;It provides a reference for drug dosing,possible target organs,toxicity reaction and other indicators in long-term toxicity tests,provides a basis for the selection of starting dose in clinical trials,and provides some information related to acute poisoning caused by drug overdose in humans.Methods:100 SD rats(SPF grade)were selected and divided into 9 groups according to gender and body weight by simple randomization.G1 sodium chloride injection(Omg/kg),G2 excipient(Omg/kg),G3 NUC-1031(150mg/kg),G4 NUC-1031(200mg/kg),G5 gemcitabine hydrochloride injection(91mg/kg),G6 sodium chloride injection(Omg/kg),G7 excipient(Omg/kg),G8 NUC-1031(400mg/kg),G9 gemcitabine hydrochloride(182mg/kg),5 animals of each sex in each group.The administration method was tail vein injection.The g1-g5 group was given once on the first day(D1),and the g6-g9 group was given twice on D1,with an interval of 2 hours.The toxic reaction and death of rats were observed,and the toxic target organs were searched by combining the results of body weight,food intake,clinical pathology and gross anatomy.Results:The acute toxicity test showed that the maximum tolerance dose of NUC-1031 given intravenously in SD rats was 200 mg/kg.In rats after intravenous NUC-1031,its toxic effects compared with the same dose of gemcitabine hydrochloride did not see obvious difference,low dose group,all male and female animals have no obvious abnormal,and high dose group of male and female animals see more red eye,nose weeks wet/dry sex secretion,nasal/facial swelling,watery stools,angular,salivate,female animals also see more,visible animal body weight,food intake significantly decreased at the same time,and can cause animals die,the death of animals for females,watch animal body weight and food intake were late pick up.Hematology test found that obvious RBC(red blood cell count),HGB(hemoglobin),LYMPH(lymphocyte count)to reduce the phenomenon,at the same time visible RET(absolute reticulocyte red blood cell count)and the percentage,the MCV(average red blood cell volume),MCH(average red blood cell hemoglobin content)and PLT platelet count increased significantly,the above phenomena were statistically significant,and there is dose dependent,RET count and percentage rise phenomenon is obvious.Gross anatomy of the dead animal revealed no obvious organ damage.ConclusionsThere was a gender difference in the acute toxicity of NUC-1031 injection in SD rats intravenous injection,and the toxicity injury was reversible.Hematological examination showed that it may have certain damage to the immune system and hematopoietic function of bone marrow,and has certain immunotoxicity and bone marrow toxicity,but has not yet caused pathological changes in tissue.