AdvancesinAnticancerDrugs.ppt

1,“CANCER” Refers to a Malignant Neoplasm (New growth) Cancer cells can manifest: Uncontrolled proliferation. 无限增殖 Dedifferentiation. 去分化 Invasiveness. 浸润性 The ability to metastasize. 转移性,2,Leading causes of death Epidemiology,Heart Diseases Cancer Cerebrovascular Diseases Chronic Obstructive Lung Diseases Accidents Pneumonia & Influenza Diabetes Mellitus Suicide Homicide HIV Infection,Percentage of Total Deaths, US,3,Morbidity and Mortality of Main Cancers,4,Phases of Oncogenesis,5,Molecular Mechanism of Oncogenesis,DNA损伤： 化学物 电离辐射 病毒,正常细胞,DNA损伤,体细胞基因突变,活化调节凋亡的基因,活化促进生 长的癌基因,灭活肿瘤 抑制基因,表达异常的癌蛋白失去抑 制生长产物凋亡失去控制,恶性肿瘤形成,遗传性DNA突变见于： DNA修复有关基因 细胞生长或凋亡基因,6,Neoplastic Cell Cycle Time,Differentiation,Resting,G2,S,G1,M,无增殖能力 细胞,Death,G0,7,Remedy for Cancer,Surgery Chemotherapy Radiotherapy Chinese medicine Immunotherapy Genetherapy Combined therapy Palliative therapy Others,8,Antineoplastic Agents and Biologic Response modifiers,9,History,1865年，Lissauer 亚砷酸盐白血病 1941年，耶鲁大学Goodman & Gilman 氮芥淋巴瘤 1941年，Huggins 雌激素前列腺癌 1943年，Rhoads 烷化剂恶性淋巴瘤 1948年，Farber 氨甲碟呤小儿急性淋巴细胞性白血病 1961年，李明秋 联合化疗治疗睾丸肿瘤 1966年，Skipper 用L1210模型确立化疗药动学 1966年，Bruce 抗癌药物药理学研究 1966年，DjeRassi 大剂量化疗 1968年，Karnofsky 提出肿瘤内科学 1985年，Rosenberg 倡导过继性免疫疗法 1991年，首例肿瘤（黑色素瘤）基因治疗,10,Classes of drugs,11,CELL CYCLE - NONSPECIFIC (CCNS) -cytotoxic in any phase of cell cycle -effective against slowly growing tumors CELL CYCLE - SPECIFIC (CCS) -cytotoxic is S phase -cytotoxic in M phase -effective against rapidly growing tumors,2 Main groups of agents:,12,13,14,PENTOSTATIN,Inhibits adenosine Deaminase,PALA,Inhibits Pyrimidine Biosynthesis,Purine synthesis,Pyrimidine synthesis,Ribonucleotides,Deoxyribonucleotides,DNA,HYDROXYUREA,Inhibit Ribonucleotide Reductase,6-MERCAPTOPURINE 6-THIOGAUNINE,Inhibit Puring ring biosynthesis,Inhibit Neocleotide interconversions,5-FLOUROURACIL,Inhibit TMP Synthesis,METHOTREXATE,Inhibit dihydrofolate reduction, blocks TMP and Purine synthesis,15,DNA,RNA,(Transfer, messenger, ribosomal),CYTARABINE FLUDARABINE 2-CHLORODEOXY ADENOSINE,Inhibit DNA Synthesis,ALKYLATING AGENTS MITOMYCETIN CISPLATIN PROCARBAZINE DACARBAZINE,Form adducts DNA,BLEOMYCIN ETOPOSIDE TENIPOSIDE,Damage DNA and Prevent repair,DACTINOMYCINE DAUNORUBICIN DOXORUBICIN MITOXANTRONE,Intercalate with DNA Inhibit RNA synthesis,PROTEINS,Enzymes,Microtubules,A-PARAGINASE,Deaminate asparagine,Inhibits protein synthesis,PACLITAXEL VINCA ALKALOIDS COLCHICINE,Inhibit function of Microtubules,16,ALKYLATING AGENTS 烷化剂,NITROGEN MUSTARDS first developed in 1940s CCNS killing ability USES: Hodgkins disease & lymphomas, leukemias, lung, breast, ovary, testes, brain, bladder Most widely used agent, often in combination with other agents.,17,Types of alkylating agents,Nitrogen mustards Ethylenimine derivatives Alkyl sulfonates Triazines Nitrosoureas Metal salts,18,CH2-CH2-Cl H3C-N CH2-CH2-Cl,CH2-CH2-Cl CH2-CH2-Cl,N,O=P-N,环磷酰胺,氮芥,N-CH2-CH2-Cl,O=P-N-CH2-CH2-Cl,异环磷酰胺,O,19,CH3-S-O-CH2CH2 CH2CH2-O-S-CH3,=O,=O,=O,=O,Cl-CH2 -CH2-N-C -NH-CH2 -CH2- Cl NO,=O,Cl-CH2 -CH2-N-C -NH- -CH3 NO,=O,马利兰,卡氮芥,甲环亚硝脲,20,ANTIMETABOLITES 抗代谢类,ACTIONS: -Antagonism of folate -purines, and pyrimidines needed for synthesis of nucleic acids -stops cell replication USES: -Solid tumors (breast, lung, liver, brain, colon,stomach) -Lymphomas, leukemias -Some agents also immunosuppressive -Useful in treating immune-mediated diseases,21,Types of antimetabolites,Folic acid analogs Pyrimidine analogs Purine analogs,22,antimetabolites,MTX (甲氨蝶呤） 5-FU（氟尿嘧啶） 5-DFUR (脱氧氟尿苷） Xeloda (希罗达，卡培他宾） Gemzar (健择，吉西他宾）,23,NATURAL PRODUCTS,ACTIONS: -Plant alkaloids (periwinkle, yew tree, mandrake plant, etc.) -Bind to and disrupt mitotic spindles USES: -Lymphomas (Hodgkins and non- Hodgkins) -Neuroblastoma -Kaposis sarcoma -Solid tumors (breast, testicular, etc.),24,Types of natural products,Mitotic inhibitors Podophyllum derivatives Camptothecins Antibiotics： Enzymes,25,NATURAL PRODUCTS,N环类：阿霉素，表阿霉素 生物碱（抑制微丝，微管形成）：长春碱，长春新碱，长春瑞宾（诺维本） 紫杉醇类：紫杉醇（泰素），泰索帝 羟基喜树碱：CPT，CPT-11(伊立替康），TPT（拓扑替康） 酯质体：5-FU，紫杉醇，阿霉素,26,PLATINUM(铂类),DDP（顺铂） CBP（卡铂） SHP（环硫铂) L-OHP（草酸铂，奥沙利铂） NDP（奈达铂）,27,HORMONES AND ANTAGONISTS,Adrenocortical Suppressant: Adrenal Cortex Adrenocortical Steroids: Lukemias, Lymphomas, Breast Progestins: Breast Estrogens: Breast, Prostate Antiestrogens: Breast Androgens: Breast Antiandrogens: Prostate Gonadotropin Releasing Hormone Analog: Prostate,28,MOLECULAR TARGETED AGENTS 分子靶向药物,ACTIONS: -potent therapeutics for some tumors -specifically targeting the molecular overexpressing on tumor cells -reducing the side-effects USES:,29,Molecular mechanisms,30,31,Types of molecular targeted agents,Tyrosine kinase inhibitors Monoclonal antibodies Other agents,32,单克隆抗体,抗Her-2/neu单抗：Herceptin(赫赛汀） 乳腺癌 抗CD20单抗：Rituxan（美罗华） NHL 抗EGFR单抗：IMC-C225 各种实体瘤 抗VEGF单抗：Avastin 肾细胞瘤 抗17-1A单抗：Panorex 直肠癌,33,酪氨酸激酶抑制剂,Iressa EFGR酪氨酸激酶抑制剂 Taceva EFGR酪氨酸激酶抑制剂 Gleevec bcr/abl酪氨酸激酶抑制剂,34,DNA,Mode of action of EGFR inhibitors,Membrane,Extracellular,Intracellular,R,K,R,K,EGFR-TKI,EGFR-TKI,Signalling,Proliferation,Cell survival (anti-apoptosis),Growth factors,Chemotherapy/ radiotherapy sensitivity,Angiogenesis,Metastasis,R, epidermal growth factor receptor,EGF/TGF,Antibody,35,36,DNA Delivery to Cells in Patients Tissue,基因治疗进展,37,38,1. Replacement and Knockout Gene Therapy The induction of cell death or apoptosis. The production of changes in cell growth, behavio