General Toxicity Study In Rodent Of CPS013

Background: CPS013 is a new type of bithiazole broad-spectrum histones deacetylase inhibitor(HDACi)developed independently in China.It can maintain the wquilibrium state of histone acetylation and deacetylation and is closely related to many processes such as cancer-related gene transcriptional expression,cell proliferation and differentiation and apoptosis.Previous studies have determined that CPS013 has strong antitumor activity.It can induce apoptosis of T celllymphoma cell lines Jurkat and Hut78.Different concentrations of CPS013 can inhibit the proliferation of OVCAR-3 cells in a dose-and time-dependent manner.Previous studies have also found that CPS013 has a certain effect on the proliferation,cell cycle and apoptosis of breast cancer cell lines T47 D and MDA-MB-231.In the tumor-braring nude mice,CPS013 has a good therapeutic effect on tumors such as glioma,lung cancer and breast cancer.In summary,CPS013 has a very good development prospect in anti-tumor effect.The effectiveness,safety and quanlity controllability need to be considered during drug development process.To investigate the safety of CPS013,we conducted a series of general studies in rodents o elucidate its target organs,dose-dependent,relationship to exposure and potential reversibility(when appropriate).This information is used to estimate a safe initial stsrting dose and dose range for the human trials and to parameters selection for clinical monitoring of potential adverse effects.In this study,two species of rodent animal(SD rats and ICR mice)were used for general toxicology studies.For single dose toxicity study in rats,SD rats were administrated with 0,500,1000 and 2000 mg/kg CPS013 by gavage.Death was found at dose of 2000 mg/kg.The main toxicity reaction was gastrointestinal reaction and the maximal tolerance dose(MTD)was 1000 mg/kg.For repeat dose 30-day toxicity study in rats,SD rats were administrated with 0,10,30 and 90 mg/kg CPS013 by gavage daily for 30 days.When the dosage was ?30 mg/kg,the granulocyte maturation was reversibly inhibited.At dose of 90 mg/kg,reversibly changes were found such as weight loss,thymiac(decreased thickness of cortical medulla and cell number),medullary cavity(decreased hematopoietic cell count and increased fat)and possible pancreatic(slight fibrosis around a single islet and visible phagocytosis around).No Observed Adverse Effect Level(NOAEL)was 10 mg/kg.For single dose toxicity study in mice,ICR mice were administrated with 0,500,1000 and 2000 mg/kg CPS013 by gavage.Delayed death was found at dose of 2000 mg/kg.The main toxicity reaction was piloerection,dull hair,moult,filth crissum and weight loss,etc.MTD was 1000 mg/kg.For repeat dose 30-day toxicity study in mice,ICR mice were administrated with 0,50,100 and 250 mg/kg CPS013 by gavage daily for 30 days.When the dosage was ?50 mg/kg,changes can be found such as vertical hair,decreased food consumption,granulocyte cell inhibition,prolonged clotting time,compensatory extranmedullary hematopoiesis(liver,spleen and lymph node),atrophy uterine,etc.;When the dosage was ?100 mg/kg,changes can be found decreased weight gain,urinary occult blood,atrophy thymus and ovarian,etc.;at dose of 250 mg/kg,animal were found died,testicular atrophy and no mature sperm in epididymis.NOAEL was < 50 mg/kg and no serious toxicity effect level was 50 mg/kg.According to result of general toxicology studies,after a single dose of CPS013 in rodents,animals can see weight loss,gastrointestinal reactions(diarrhea)and death at high doses.ICR mice also can be observed vertical hair,dull hair,hair loss,etc.When rodents were administrated with CPS013 for 30 days,the animals showed weight loss,thymus atrophy,and bone marrow changes.SD rats can be found chang on pancreas,when ICR mice also can be obseverd vertical hair,reduced food consumption,immunosuppression(liver,spleen,granulocytes,etc.)and reproductive system(testis,The epididymis,ovaries and uterus)were atrophied.The severity or incidence of toxic reactions increased with increasing dose and can be recovered in whole or in part after withdrawal.