模拟静脉输注与肿瘤靶向给药

,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,浅谈,模拟静脉输注与肿瘤靶向给药,5FU,可能的替代者,5-FU,是经典的化疗药物，是胃癌治疗的,“,基石,”,，其联合方案是胃癌化疗的标准治疗,代替,5-FU,可能的候选者,替加氟,UFT,，,S1,卡培他滨,5-FU,的药物作用特点：形成血浆组织,5-Fu,池发挥抗肿瘤作用,5,FU,血浆,组织,5-Fu,池,F-,-Ala,FdUMP,降解,磷酸化,FdUMP,FdUMP,肿瘤,抗肿瘤活性,骨髓等其他,胃肠道,胃肠道毒性,毒性,DPD,静脉注射,FT207,替加氟,UFT,和,S1,的基本成分,1966,年合成,5-FU,的前体，口服后主要在肝脏内由,P450,活化产生,5-FU,，后分布到全身,替加氟,血浆,组织,5-Fu,池,F-,-Ala,FdUMP,降解,磷酸化,FdUMP,FdUMP,肿瘤,抗肿瘤活性,骨髓等其他,胃肠道,胃肠道毒性,毒性,DPD,肝脏,P450,酶,5-FU,肝脏毒性,UFT,利用尿嘧啶抑制,DPD,酶维持全身,5-FU,浓度，模拟静脉输注,替加氟,血浆,组织,5-Fu,池,浓度,提高,F-,-Ala,FdUMP,降解,磷酸化,FdUMP,FdUMP,尿嘧啶,肿瘤,抗肿瘤活性,骨髓等其他,胃肠道,胃肠道毒性,毒性,DPD,肝脏,P450,酶,DPD,：,二氢嘧啶脱氢酶,毒性上升成为限制剂量（疗效）提高的主因素,？,5-FU,肝脏毒性,UFT,两项,UFT,单一治疗胃癌的,II,期研究显示，其中位生存期并不令人鼓舞，分别只有,5.8,个月和,6.9,个月,一项,III,期试验在,280,名晚期胃癌患者中，对,UFT,联合丝裂霉素,C,与单药,5-FU,，以及,FP,进行了比较，未能证实联合疗法的总生存期比单药,5-FU,更具优势，,UFT,治疗组只有,16%,的患者生存达,1,年,未能在日本、中国以外获得适应症,Kim,Y.H.,Cheong,S.K.,Lee,J.D.,Park,J.S.,Shin,S.W.,Kim,J.S.Phase II trial of oral UFT and leucovorin in advanced gastric carcinoma.Am J Clin Oncol 1996,19(2):212-6.,Kim,Y.H.,Shin,S.W.,Kim,B.S.,Park,Y.T.,Kim,J.G.,Kim,J.S.A phase II trial.Oral UFT and leucovorin in patients with advanced gastric carcinoma.Oncology 1997,11(9,Suppl.10):119-23.,Ohtsu,A.,Shimada,Y.,Shirao,K.et al.Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable,advanced gastric cancer:The Japan Clinical Oncology Group Study(JCOG9205).J Clin Oncol 2003,21(1):54-9.,替吉奥通过抑制,DPD,酶维持全身,5-FU,浓度，模拟静脉输注,替加氟,血浆,组织,5-Fu,池,浓度,提高,F-,-Ala,FdUMP,降解,磷酸化,FdUMP,FdUMP,吉莫斯特,氧嗪酸钾,肿瘤,抗肿瘤活性,骨髓等其他,胃肠道,胃肠道毒性,毒性,OXO,抑制,OPRT,酶，抵消提高的胃肠道毒性,DPD,神经毒性,OPRT,：,乳清酸磷酸核糖转移酶；,DPD,：,二氢嘧啶脱氢酶,OPRT,，,TP,OPRT,肝脏,P450,酶,5-FU,肝脏毒性,？,比尿嘧啶更强的,DPD,抑制剂，使肝脏内,5FU,易积聚,OPRT,也是,5FU,发挥抗肿瘤疗效的关键酶，,OXO,同样降低了抗肿瘤疗效,成为限制剂量（疗效）提高的主因素,以上的药物都形成了全身的,浓度均一的,5-FU,池，成为发挥疗效和产生毒性的基础,TP,酶在肿瘤内特异性增高是靶向激活希罗达的基础条件,-,在肿瘤内经,TP,酶活化形成,5-FU,A.Kono,H.Ishitsuka et al.,Chem.Pharm.Bull,.,31,175(1983),TP,酶人类肿瘤及临近组织分布,：,Cervix,Breast,Kidney,Liver,*,Stomach,Uterine,Colorectal,Bladder,Ovary,Thyroid,8,13,309,309,24,37,16,20,291,351,17,18,115,115,13,11,14,23,36,35,*,Colorectal cancers,metastasized to the liver,g 5,-,FU/mg protein/h),0,100,200,300,400,(,n=),*,*,*,*,*,*,*,*,*,*,*,p0.05 vs.Normal,Normal,Tumor,N,H,N,F,O,O,H,O,H,O,O,N,H,N,H,F,O,O,O,P,O,3,H,3,O,O,H,O,H,Pi,+,5,-,DFUR,5,-,FU,：,Cervix,Breast,Kidney,Liver,*,Stomach,Uterine,Colorectal,Bladder,Ovary,Thyroid,8,13,309,309,24,37,16,20,291,351,17,18,115,115,13,11,14,23,36,35,*,Colorectal cancers,metastasized to the liver,TP,酶活力,(,g 5,-,FU/mg protein/h),0,100,200,300,400,(,n=),*,*,*,*,*,*,*,*,*,*,*,p0.05 vs.Normal,正常组织,肿瘤组织,小肠,肝脏,卡培他滨,5-DFCR,5-DFUR,CyD,5-DFCR,5-DFUR,5-FU,肿瘤,卡培他滨,肿瘤血管生成因子,（胸苷磷酸化酶，,TP),CyD,5-DFCR=5,脱氧氟胞苷,;5-DFUR=5,脱氧氟脲苷,;,CyD=,胞苷脱氨酶,;CE=,羧酸酯酶,CE,卡培他滨作用机制,真正实现肿瘤靶向,羧酸酯酶消化道中低表达,降低肠道不良反应,降低骨髓不良反应,增加肿瘤特异性,血浆的,5FU,池被毒性更低的卡培他滨取代,卡培他滨的肿瘤靶向,血药浓度不再模拟静脉给药,抗肿瘤活性,毒性低,卡培他滨,卡培他滨,卡培他滨直接提高肿瘤细胞内浓度,Reigner B,et al.Clin pharmacokinet 2001;40:85,口服,卡培他滨,动力学也不再遵循传统静脉给药的模式,Ishikawa T et al.,Biochem Pharmacol,55:1091-1097(1998),Hours after drug administration,0,2,4,6,8,16,14,12,10,8,6,4,2,0,Tumor,Muscle,Plasma,5,-,FU level(,g/ml or g),Xeloda,p.o.,(1,348mg/m,2,),5-FU,19.5 mg/kg(MTD),0,1,2,3,2,1,0,Muscle,16,14,12,10,8,6,4,2,0,0,2,4,6,8,0,1,2,3,2,1,0,Plasma,Tumor,16,14,12,10,8,6,4,2,0,0,2,4,6,0,2,4,6,8,16,14,12,10,8,6,4,2,0,Tumor,Muscle,Plasma,5,-,FU level(,g/ml or g),0,2,4,6,16,14,12,10,8,6,4,2,0,Tumor,Muscle,Plasma,1)Reigner B et al.,Clin Pharmacokinet 2001;40:85-101,不同的药代动力学使希罗达的肿瘤选择性大大增强,2)Kobach JS et al.,Invest New Drugs 1989;7:13-25,肿瘤组织,5-FU,5-FU,5-FU,5-FU,5-FU,5-FU,5-FU,5-FU,5-FU,5-FU,5-FU,5-FU,5-FU,正常组织,3.2,21.4,血浆,5-FU,与其他口服氟尿嘧啶相比，,只有卡培他滨获得优于,5-FU,的研究结果,卡培他滨,base VS 5-FU base,meta,分析,1,0,1,2,3,4,5,6,5-FU,Xeloda,Survival(%),总体死亡风险下降,13,优效,HR of 0.87,P=0.027,%Survival,100,90,80,70,60,50,40,30,20,10,0,月,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,CS,CF,HR:0.92,P=0.1983,100,90,80,70,60,50,40,30,20,10,0,年,S-1 base VS 5-FU base,FLAGS,试验,2,优效失败,Okines,et al.,Annals of Oncology 2009 doi:10.1093/annonc/mdp047,Ajani,et al.ASCO GI 2009,希罗达初步实现高效低毒,卡培他滨与,S-1,用于胃癌一线治疗的,III,期临床安全性组间比较,希罗达初步实现高效低毒,同一中心所进行两个研究间的比较,5-FU,作用机制,通过,TP,酶等代谢生成,FdUMP,和,FdUTP,抑制,DNA,合成,通过,OPRT,酶等代谢生成,FUTP,抑制,RNA,合成,TP,，,OPRT,、,TS,是,5FU,发挥疗效的关键酶,奥沙利铂诱导,TP,酶增强卡培他滨的抗肿瘤活性,Human colon cancer CXF280 model,Control,Oxaliplatin,5,mg/kg,Oxaliplatin,10,mg/kg,Oxaliplatin,15,mg/kg,Control,Oxaliplatin,5,mg/kg,Oxaliplatin,10,mg/kg,Oxaliplatin,15,mg/kg,0,2,4,6,8,dThdPase(unit/mg protein),*,*,*,Growth,Inhibition,(%),45,42,73,-,10,12,*,*,*,*,*,*,Growth,Inhibition,(%),45,42,73,-,肿瘤内,TP,酶活性,奥沙利铂,10 mg/kg,(2/3MTD),卡培他滨,359 mg/kg,(2/3 MTD),联合治疗,(,奥沙利铂,2/3MTD,+,卡培他滨,2/3 MTD),0.1,1,10,5,0.5,1,11,21,31,41,51,对照组,肿瘤体积的大小,(cm,3,),药物治疗后时间（天）,Xeloda+Oxaliplatin:applied to“,XELOX,”trial,XELOX,是晚期胃癌的主要方案之一,II(T1N2,T2N1,T3N0),IIIa(T2N2,T3N1,T4N0),和,IIIb(T3N2,),期胃腺癌,n=1024 planned,XELOX,希罗达,:1000mg/m2 bid,d115 q3w,奥沙利铂,:130mg/m2 d1 q3w,8,周期,Observation alone,XELOX,也会成为胃癌辅助化疗的重要基石,RANDO MIS,ATION,主要终点,“Xelox”,方案,3,年无病生存优于单纯手术,次要终点,比较总