硅钨钛杂多化合物用作抗肿瘤新药的研究

α-K8H6[Si2W18Ti6O77](α-Si2W18Ti6 or α-SiW9Ti3) is a novel complex prepared by our group at frist. α-Si2W18Ti6 has clear antitumor activity,its activity is higher than that of cyclophosphamide used in clinical,such as its inhibitor rates on H22 ascites cancer was 46%,surviral rates was 36% and the cyclophosphamide was 25.5% only.The median lethal(LD50) of α-Ti6, P.O. in mice was 2055.3mg/kg, and the ranges of 95% confidence limit was 1862.1 to 2267.8 mg/kg,showing thatα-Ti6 is a low toxic material. Long -term toxicity test: Wistar rates were treated P.O. with doses of 205.5、41.1、20.6 mg/kg of α-Ti6 over 13 weeks.The results showed that:(1)There were no marned changes in organ coefficient of heart、lungs 、liver、spleen、kindeys、testes、ovary and brain of rats over 13w treated with different doses ofα-Ti6 compared with the control group。(2)serum AST、ALTand LDH values in all three dose groups over 13w treated withα-Ti6 increased .There were no significant changes of ALP values in all dose groups compared with the control group.After 4w off treatment,all but ALT in the group of 205.5 mg/kg decreased,suggesting a mild hepatotoxicity of α-Ti6 on rats.(3)Levels of serum BUN and CR of female rats in all three dose groups decreased after 13w treatment. There were no difference in CR in all three dose groups,but a decrease of BUN in the group of 205.5 mg/kg after 4w off treatment compared with the control group.(4)Compared with the control group,there was only a Marked decrease of surum TCH in the group of 205.5 mg/kg in male rats (P<0.05),but no changes were observed on the other items,such as surum TP、ALB、TBIL and GLU in all three dose groups after 13w treatment .ther were no mark differences of TP、ALB、TBIL and GLU in all three dose groups after 4w off treatment compared with the control group.Distribution in mice: After taxe orally α-Ti6,the content of stomach and bowl is the highest at 8w in female,that of spleen、encephalon、liver、heart、kidney is secondary,muscles is the least.The content of kidney is the highest at 24h in female,that of stomach、liver、encephalon is secondary.The case of male is similar with that of female.Pharmacokinetic:Model of injection of vein α-Ti6 in rabbits is two rooms modle. Distribution half life is 0.1055h and eliminate half is 402857h.Model of P.O. α-Ti6 in mice is two rooms model.Absorption half life is 0.2731h;distribution half life is 0.3794h;eliminate half life is 36.8617h.

九钨三钛硅酸盐是我们首次合成的新化合物，此化合物具有体内抗癌活性，其药效高于临床应用的环磷酰胺，基一般生殖毒性、致畸和围产期毒性试验均呈阴性，并且能促进机体免疫功能增强。本项目拟按国家新药规定，完成大动物的药效学、药代动力学、长期毒性等临床前研究，为临床研究奠定基础。