,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,高分飞,抗恶性肿瘤药,Antineoplastic Agents,概述,恶性肿瘤,(malignant tumor,malignant neoplasm),，又称癌症,(cancer),。,全世界每年死于恶性肿瘤的患者达数百万之多，约占总死亡人数的,1/4,。,目前人类第二大死因。,Worldwide overall annual cancer incidence,Death rates for heart disease and cancer among people younger and older than age 85.,癌症特点,不受机体约束的增殖,与细胞增殖有关的基因被开启或激活；,与细胞分化有关的基因被关闭或抑制；,局部侵袭,(local invasiveness),转移,(metastasis),低分化,(less differentiated),保留原组织一些特征,The,Aim,of Cancer Treatments,Palliation,缓解症状，姑息治疗,Alleviation of symptoms,Increased survival and improved quality of life,Remission,临床治愈,all macroscopic and microscopic features of the cancer disappear,though disease is known to persist,Cure,治愈,all the cells of the clone must be destroyed,目前主要治疗手段,Six Established Therapeutic Modalities,Surgery(,外科手术,),：实体瘤,Rediotherapy,(,放射治疗,),：鼻咽癌、早期声带癌,Cytotoxic,chemotherapy,(,化学治疗,化疗,),Endocrine therapy(,内分泌治疗,),Immunotherapy(,免疫治疗,),Biological/targeted therapy,(,生物治疗,),CTM treatment(,中医治疗,),Multi-modality treatment,肿瘤化疗的障碍,毒性反应,选择性差,“杀敌一千，自损五百”,耐药性,不敏感,从单一治疗向综合治疗,从单一药物到联合用药,从姑息治疗向根治治疗,从细胞毒性药物向针对机制多环节新型药物,抗恶性肿瘤药的三大趋势,Biologic basis of chemotherapy,Cell Cycle and Cancer,细胞周期的调控,1,3,2,2001,年生理学或医学奖,Leland H.Hartwell(1939-,USA),控制点,(check point),R Timothy Hunt(1943-,UK),周期蛋白依赖性激酶,(,cyclin,dependent,kinase,Cdk,),Paul M.Nurse(1949-,UK),细胞周期蛋白,(,cyclin,),Cell Cycle,MITOSIS ENTRY(G2/M),Replication Complete,Growth/Protein Synthesis adequate,No DNA Damage,S-PHASE ENTRY(G1/S),Mitosis Complete?,signal-,cyclin,degradation,Growth/Protein Synthesis(G1 CYCLINS),No DNA Damage,OTHERS,MITOSIS EXIT:?coupling to S-phase,S PHASE:coupling to mitosis,also in response to DNA damage,G1 sequence of events,signaling from cell surface,生长比率,(,Growth fraction,GF),GF,大：早期。急性白血病、何杰金病、绒癌，对药物敏感；,GF,小：晚期。慢性白血病、多数实体瘤，对药物敏感,GF=,肿瘤增殖期细胞数,总肿瘤细胞数,静止细胞群,非增殖细胞群,（,G,0,期）,对药物不太敏感，是复发根源。,The growth fraction of a tumor declines exponentially over time.The growth rate of a tumor peaks before it is clinically detectable.,Tumor size increases slowly,goes through an exponential phase,and slows again as the tumor reaches the size at which limitation of nutrients or auto-or host regulatory influences can occur.,The maximum growth rate occurs at 1/e,the point at which the tumor is about 37%of its maximum size.,Tumor becomes detectable at a burden of about 10,9,(1 cm,3,)cells and kills the patient at a tumor cell burden of about 10,12,(1 kg).,Efforts to treat the tumor and reduce its size can result in an increase in the growth fraction and an increase in growth rate.,Gompertzian,tumor growth,Gompertzian,tumor growth,The log-kill hypothesis:,Chemotherapeutic agents kill a constant fraction of cells(,first order kinetics,)rather than a specific number of cells,after each dose,Dashed line:no treatment,Top:infrequent treatment,Middle:combination chemotherapy treatment,Bottom:early surgery and intensive adjuvant chemotherapy,Log kill hypothesis:,Pharmacological basis of chemotherapy,抗肿瘤药的发展,1946,年，化学战中的细胞毒,氮芥及其衍生物有抑瘤作用，但选择性差，故称细胞毒剂,(,cytotoxic,agents),。,50,年代中期之后的十余年，寻找毒性较低的抑制免疫功能的抗肿瘤药物，如抗嘌呤类,(6-MP),、阿霉素等抗生素。,70,年代中期，由抗细胞繁殖药物转向多因素的免疫调节药。,今近年，肿瘤的生物治疗受到重视。,The Goal of chemotherapy,Cure,Total,radication,of cancer cells,Curable cancers include testicular tumors,Wills tumor,Palliation,Alleviation of symptoms,Avoidance of life-threatening toxicity,Increased survival and improved quality of life,Adjuvant therapy,Attempt to eradicate microscopic cancer after surgery,e.g.breast cancer&colorectal cancer,抗恶性肿瘤药的分类,按作用方式分：,细胞毒类（传统化疗药物）,非细胞毒类,生物反应调节药,(biological response modifiers,BRMs,),单克隆抗体,细胞分化诱导剂,细胞凋亡诱导剂,抗肿瘤侵袭及转移药,新生血管生成抑制剂,体内激素平衡药,肿瘤耐药性逆转药,肿瘤基因治疗药物,细胞毒类抗肿瘤药,根据药物化学结构和来源,烷化剂：氮芥类、亚硝脲类等。,抗代谢物：叶酸、嘧啶、嘌呤类似物等。,抗肿瘤抗生素：丝裂霉素、博来霉素等。,抗肿瘤植物药：长春碱类、喜树碱类、紫杉醇类等。,杂类：铂类配合物和酶等。,细胞毒类抗肿瘤药,根据抗肿瘤作用的生化机制,干扰核酸生物合成的药物（抗代谢药）,二氢叶酸还原酶抑制剂：甲氨蝶呤,胸苷酸合成酶抑制剂：,5-FU,嘌呤核苷酸互变抑制剂：,6-MP(,巯嘌呤,),核苷酸还原酶抑制剂：,HU(,羟基脲,),DNA,多聚酶抑制剂：,Ara,-C(,阿糖胞苷,),直接影响,DNA,结构与功能的药物,烷化剂：氮芥、噻替派、白消安,破坏,DNA,的铂类配合物：顺铂、卡铂,破坏,DNA,的抗生素类：丝裂霉素、博来霉素,拓扑异构酶抑制剂：喜树碱类,干扰转录过程和阻止,RNA,合成的药物,：,放线菌素、阿霉素,干扰蛋白质合成与功能的药物,微管蛋白活性抑制剂：长春碱类、紫杉醇类,干扰核蛋白体功能的药物：三尖杉生物碱类,影响氨基酸供应的药物：,L-,门冬酰胺酶,细胞毒类抗肿瘤药,根据药物作用的周期或时相特异性,细胞周期非特异性药物,(cell cycle nonspecific agents,，,CCNSA),：,能杀灭增殖周期各时相的细胞，甚至包括,G,0,期细胞的药物，如烷化剂和抗癌抗生素等。,杀伤作用强，呈剂量依赖性，临床以静推为宜。,细胞周期特异性药物,(cell cycle specific agents,，,CCSA),：,仅对增殖周期某些时相敏感的药物，抗代谢药物甲氨蝶呤、巯嘌呤、阿糖胞苷等主要作用于,S,期；长春碱类主要作用于,M,期。,杀伤作用弱，呈时间依赖性，临床以缓慢滴注、肌注或口服为宜。,细胞增殖周期和药物作用示意图,细胞周期,(,时相,),特异性药物,细胞周期非特异性药物,烷化剂,抗肿瘤抗生素,铂类配合物,抗代谢药物,长春碱类药物,细胞毒类抗肿瘤药,一、影响核酸生物合成的药物,抗代谢药,原理：化学结构与核酸代谢的必需物质如叶酸、嘌呤、嘧啶、核苷酸等相似，特异性干扰核酸的代谢，阻止细胞的分裂和增殖。,竞争与酶结合,以伪代谢物参与代谢,主要作用于,S,期细胞，属细胞周期特异性药物。,特点：,起效慢,多数对白血病有效,(5-FU,除外,),长期应用可产生耐药性,选择性不高、不良反应常见，对快速分裂的正常细胞毒性大：骨髓和肠上皮,分类,二氢叶酸还原酶抑制剂：,MTX(,甲氨蝶呤,),胸苷酸合成酶抑制剂：,5-FU(5-,氟尿嘧啶,),嘌呤核苷酸互变抑制剂：,6-MP(,巯嘌呤,),核苷酸还原酶抑制剂：,HU(,羟基脲,),DNA,多聚酶抑制剂：,Ara,-C(,阿糖胞苷,),I.,甲氨蝶呤,(,Methotrexate,MTX),机理：,竞争性抑制二氢叶酸还原酶，,dTMP,合成受阻，,DNA,合成障碍,也可阻止嘌呤核苷酸合成，干扰蛋白质合成,适应症：,儿童急性白血病、绒癌,Severe disabling psoriasis(,牛皮癣,),Refractory rheumatoid arthritis(,类风湿性关节炎,),不良反应：,消化道反应：口腔、胃肠道粘膜损害,骨髓抑制（用后肌注亚叶酸钙作救援剂，保护骨髓正常细胞）,肝肾损害,致畸、死胎、流产,Ant