肿瘤治疗的药理学基础与原则

Transcription

1 Zhuling 四川大学华西医学中心基础药理教研室

2

3 肿瘤发生 正常组织 l 失衡腺瘤肿瘤浸润性癌 1 非正常细胞 可检测肿瘤 : 10 9 细胞 t = 0 t > 10 年 细胞增殖数 = 死亡细胞数 细胞增殖 细胞增殖数 >> 调亡细胞 增殖 调亡

4 Case Patient 54, male, colorectal cancer metastasized to liver, 5 months of chemotherapy followed by 1 week of targeted therapy. Routine checkup in Sept.2010 discovered tumor in the left liver. No symptoms of fever, shivering, jaundice, bloated, fatigue, lack of appetite, no stomach ache, diarrhea, no shortness of breath, vomiting of blood, headache and body pain, untreated. March 2011 PET-CT scan revealed left liver low density image, unclear borders, increased metabolism. Schedule for surgery, 4cm*4cm tumor was removed from left liver and 3cm*3cm tumor was removed from colon.

5 After sugery: Colonic ulcerative adenocarcinoma II degree, invaded to the entire tissue wall and fibers, metastasized to liver, 3/12 lymph node metastasis, the ends of colons has no cancer tissue, tumor was cut at 0.1cm in the liver. After surgery analysis: EGFR mutation, K-ras wild type. It began in April 2011 to 6 cycles of systemic chemotherapy ( docetaxel 多西紫杉醇 60 mg Day 1, 40 mg Day 5, 200 mg oxaliplatin 奥沙利铂 on day 1, leucovorin 亚叶酸钙 400 mg the 1 st -5 days, tegafur 替加氟 800 mg, 1-5 days) and combined with 8 times cetuximab 西妥昔单抗 treatment ( first dose 600 mg maintenance dose 400 mg, once a week ), the end of the review of the treatment of PET / CT and no significant findings, in July 2011 continued nimotuzumab 尼妥珠单抗 ( 400 mg ) weekly maintenance therapy.

6 ? Question: 1. What is the principle of treatment of colon cancer? 2. What type of antitumor drug is oxaliplatin? What is its mechanism of action? 3 What kind of chemotherapy drugs does tegafur belong to? What is its mechanism of action? 4 What are the characteristics of " molecularly targeted ' anticancer drugs compared to traditional cytotoxic anticancer drugs

7 免疫功能缺失 细胞凋亡失衡 细胞增值失控 : 自分泌 膜外信息丢失或感觉迟钝

8 Treatment Modalities in Cancer Pharmacological basis Herb?

9 I. History and the Present cancer chemotherapy II. III. Pharmacological Basis of anticancer drugs Application of the fundamental principles of anticancer drugs

10 History of cancer chemotherapy Position and status of cancer chemotherapy

11 4 Stages 现在 Clinical Tumor model Evidencebased medicine Comprehensive evaluation of : evaluation of treatment : multidrug combination the efficacy antitumor instead of of anticancer activity of the empiric chemotherapy, drugs, compound therapy, novel mechanism toxicity: the molecular of drugs into first use of clinical targeted drugs mustard into clinical Mustard CTX 5-FU Cytotoxic chemotherapy ADM Cisplatin Immunotherapy Gleevec Sorafenib Targeted therapy

12 " Palliative care " to " cure " the transition Antineoplastic research ideas into molecular targeted drugs --- "Discrimination targets differentiation " --- diagnostic molecular pathology

13 Classification of anticancer drugs Pharmacodynamic characteristics of anticancer drugs Anticancer drugs pharmacokinetic characteristics of anticancer drugs Side effects of anticancer drugs and prevention principles Resistance and overcoming resistance to anticancer drugs Countermeasures Features common anticancer drugs

14 Mitosis Interference Spindle damage, stagnation mitosis Phase of cell Impede DNA synthesis - Vincristine cycle -specific antimetabolites: Methotrexate, 5- anticancer fluorouracil drugs Damage DNA structure and function - Mechlorethamine, platinum Inhibit the synthesis of topoisomerase inhibitors- Protein kinase inhibitors Camptothecin, podophyllotoxin Interfere with transcription, Cell cycle, apoptosis regulators Farnesyl transferase inhibitor RNA synthesis- Doxorubicin, daunorubicin Cell cycle phase nonspecific Molecular targeted antineoplastic drugs Interfering nucleic acid

15

16 Effect of cell cycle characteristics of the drug Cell Cycle Effect Time Dose-response curve Cell cycle non-specific drugs Cell cycle specific drugs Strong Fast Linear Weak Slow Asymptote G0 G0

17 Alkylating and related agents: Cyclophosphamide, nitrogen mustards, ethylene imines, nitrosourea, methane sulfonic acid esters Cytotoxic chemotherapy Antimetabolites: folic acid, pyrimidine, purine analogs, etc. Cytotoxic antibiotics : anthracyclines, mitomycin, bleomycin Classification by class, actinomycin etc. chemical structure Anti-tumor herbal and plant derivatives: vinca alkaloids, source and camptothecin, paclitaxel, three sharp cedar alkaloids, mechanism podophyllotoxin derivatives Hormones: adrenocorticotropic hormone, estrogen, androgen and other hormones and their antagonists Protein kinase inhibitors: imatinib, gefitinib Non-Cytotoxic chemotherapy Monoclonal antibodies: trastuzumab, cetuximab,vectibix Other: platinum complexes and enzymes

18 Classification: According to the biochemical mechanism of action Interfering nucleic acid biosynthesis drugs Directly affect the structure and function of DNA drugs Interfere with the transcription process and prevents RNA synthesis drugs Interfere with protein synthesis and function of the drug Drugs affect hormone balance Inhibition of dihydrofolate reductase : methotrexate Inhibition of thymidylate synthase : fluorouracil Inhibition of purine nucleotide interconversions : mercaptopurine Ribonucleotide reductase inhibition : hydroxyurea Inhibition of DNA polymerase : Ara DNA cross-linking agents ( alkylating agents ) : mustard, cyclophosphamide, thiotepa, carmustine, busulfan DNA-damaging platinum complexes : cisplatin, carboplatin DNA-damaging antibiotics : mitomycin, bleomycin Inhibition of topoisomerase : camptothecin, podophyllotoxin derivatives DNA intercalating agents : dactinomycin, doxorubicin, daunorubicin Inhibiting tubulin activity : vinca alkaloids, taxol Interfere with ribosome function : Cephalotaxaceae alkaloids Effect of Amino Acid Supply : L- asparaginase Hormone drugs : estrogens, androgens, medroxyprogesterone acetate Anti-estrogen drugs: tamoxifen Adrenal corticosteroids : glucocorticoids

19 抗肿瘤药物的作用 细胞增殖周期动力学肿瘤细胞的共同特点与细胞增殖有 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

20 细胞增殖周期动力学肿瘤细胞群包括增殖细胞群 静止细胞群 无增殖能力细胞群增殖比率 growth fraction GF 增殖细胞群占全 部肿瘤细胞群的 比值

21 Anti-cancer drugs to cancer cells follow the first order kinetics ---- antifixed proportion of cells/unit dose Common anti-cancer drug dose - survival curve type

22 Cell proliferation rate, phase specific Drugs on the fast proliferating cells was stronger than slow cell proliferation --- The rate of cellular proliferation tissue--- selectivity differences

23 According to the role of the cycle or phase specific classification Cell cycle non-specific drugs : alkylating agents, antitumor antibiotics and platinum complexes, etc. Cell cycle specific drugs : anti-metabolic drugs, vinca alkaloids and other drugs

24 Pharmacodynamic characteristics of anticancer drugs Cell proliferation rate, phase specific Drugs on the fast proliferating cells was stronger than slow cell proliferation --- The rate of cellular proliferation tissue--- selectivity differences Different cell cycle phases of cell sensitivity to different drugs Cycle specific killing effect synchronization?

25 Anticancer drugs blocking effect on cell cycle progression Delay or arrest in cell cycle progression Cytotoxic anticancer drugs on the strength and performance Half inhibitory rate (IC50) The lower the IC50, the cytotoxic effect of the drug stronger Drug : efficacy \ potency\toxity high efficacy: 间歇给药 low efficacy: 一定时间内持续给药

26 Effects of various treatments on the cancer cell burden in a hypothetical patient

27 The basic process of anti-cancer drugs to cure cancer 1. 诱导缓解化疗 保护 增强患者免疫功能 2. 巩固 强化治疗

28 Absorption: Most drugs oral easily absorbed Administration by injection Cytarabine ( and L- asparaginase (L - )easy to damage the digestive tract, oral invalid 5-FU first pass elimination Doxorubicin(ADM ) and other anticancer antibiotics: digestive instability Vincristine: malabsorption

29 The pharmacokinetics of anticancer drugs Distribution: Poor selectivity & specificity Special route : Artery intubation, injecting the drug directly into the tumor site Dosage form: Targeting agents : passive targeting, active targeting, physical and chemical targets, multiple targeting

30 The pharmacokinetics of anticancer drugs Metabolism, excretion : Most chemotherapy drug, iv. eliminate fast, a few minutes to half an hour or so Most of metabolism by the liver Drug metabolizing enzyme gene polymorphism ---- drug efficacy and safety related Excretion: kidney and biliary

31 TPMT ( 硫嘌呤甲基转移酶 ) 8 变异等位基因, 3 (*2, *3A, *3C) 引起酶活性显著下降, 故任何两者组合, 即突变纯合子, 则无酶活性 ; 与 wt 组成杂合子, 酶活性居中 因此呈三态分布 Percentage of subjects per 0.5 units of activity 298 成人 TPMT L TPMT L 0.3% 人 RBC TPMT TPMTL TPMTH 10% TPMT H TPMT H TPMT 活性, 单位 /ml RBC 90%

32 巯嘌呤 (6-MP,), 用于小儿白血病, 终末代谢产物为硫鸟嘌呤核苷酸 (TGNs), 可插入 DNA 和 RNA 而有细胞毒性 TPMT 可将 6-MP 甲基化而不产生 TGNs TPMT TPMT DNA, RNA 6-MP 代谢产物代谢产物 TGNs N SH N N N H 6-mercaptopurine 无毒性代谢产物 Ado-Met Ado-luy N CH 3 S N N N H 6-methylmercaptopurine 细胞毒性代谢产物

33 累计发生率 (%) 低 / 无活性 TPMT 引起 TGs 蓄积, 引起严重的造血系统毒性, 导致继发性白血病和放射性肿瘤 p= 放射治疗后时间 ( 年 ) 接受脑部放射治疗小儿患者继发性放射性恶性脑肿瘤的累计发生率 在事先基因型检测选择合适药物和剂量的病人, 在低 / 无活性的病 儿未出现继发性脑恶性肿瘤 突变型 TPMT (N=7, 小儿 ) 野生型 TPMT (N=45, 小儿 ) McLeod et al., 2000

34 Immediate response : local irritation, nausea, vomiting, fever, allergy Recent reactions: myelosuppression, alopecia, stomatitis, diarrhea, organ damage Long-term response : tumor -induced immune suppression infertility,

35 Toxicity Toxicity Short Term Long Term Shared Toxicity Unique Toxicity Second primary malignancies Infertility and teratogenicity Bone marrow suppression Gastrointestinal reactions Hair Loss Cardiotoxicity Respiratory toxicity Hepatotoxicity Kidney and bladder toxicity Neurotoxicity allergy

36 Bone marrow suppression Most chemotherapy drugs that inhibit bone marrow, lymphocyte division On the more immature hematopoietic stem cells stronger, but later mature peripheral cells also have an impact, but can be restored through a feedback mechanism Granulocytes platelets erythrocyte The main consequence of increased risk of serious infections Antibiotics, GM-CSF, D-CSF

37 etc Gastrointestinal reactions 5-HT 3 antagonist Ondansetron, granisetron. Symptomatic treatment : local anesthesia and pain relief, anti- local infection nystatin, diarrhea relief, Nausea, vomiting, the most common early toxicity Mechanism: Directlystimulate Stimulate the intestinal wall cells release 5-HT vomiting chemosensory area stimulate the vomiting center Gastrointestinal mucosal injury: inflammation, edema, diarrhea, etc MTX antibiotics Act-D) 5-FU Vincristine

38 Hair Loss Drugs on the hair follicle cell proliferation due to toxicity Resume after the withdrawal

39 抗肿瘤药的毒性反应 1. 共有反应骨髓抑制 : 除外激素类, 博来霉素, 门冬酰胺酶 ; 消化道反应 : 恶心 呕吐 脱发 一 毒性反应

40 Pulmonary toxicity The most serious side effects of bleomycin busulfan carmostine mitomycin Clinical manifestations: dry cough, shortness of breath ; X film showed diffuse interstitial lung disease and pulmonary infiltration sheet Late evolution between non -specific pulmonary fibrosis and lung fibrosis Drug withdrawal, corticosteroid therapy

41 Cardiotoxicity Congestive heart failure, cardiomyopathy, ECG changes, arrhythmias, myocardial ischemia and myocardial infarction Anthracyclines ( doxorubicin ) cardiotoxicity --- most likely to cause dose-limiting toxicity Dose control,monitoring, Digitalis and diuretics

42 Hepatotoxicity withdrawal resume ; those with poor liver function, caution (hepatic protector) chemotherapy or prohibit Acute process, caused by the drug or its metabolites Clinical manifestations: elevated serum transaminases, fat infiltration, cholestasis L- asparaginase (L - 天冬酰胺酶 ), High dose: carmostine,vp16, 6MP, MTX,VCR..

43 Renal toxicity and cystitis Prevention, with the infusion, increased urine output, reducing kidney drug concentration Urinary tract irritation and renal parenchymal damage MTX DDP CTX nitrosourea MMC..

44 Reproductive inhibition Temporary or permanent infertility Cumulative dose, treatment duration is too long, a greater impact Combinations drugs of

45 抗肿瘤药的毒性反应 (2) 特有反应 心脏毒性 : 柔红霉素 多柔比星 三尖杉酯碱 呼吸系统毒性 : 博来霉素 白消安 CTX 肝脏毒性 :MTX 羟基脲 CTX 鬼臼毒素类 肾和膀胱毒性 :CTX 顺铂 神经毒性 : 长春新碱 紫杉醇 门冬酰胺酶 过敏反应 : 博来霉素 门冬酰胺酶 紫杉醇

46 The primary 天然耐药性 reason for (natural the failure resistance):g of chemotherapy 0 期 Inherent or acquired resistance The existence of cross-resistance of tumor cells to the same class of chemotherapy drugs Multidrug resistance (MDR), P -gp Resistance mechanisms : pharmacodynamics ( drug targets change ) Pharmacokinetics ( cells can not achieve an effective concentration ) Tumor stem cells : drug resistance, resistance to radiation

47 Low tumor burden, using a variety of effective anti-cancer drug as soon as possible Merge all means ( surgery, radiotherapy and chemotherapy ) Rational design of chemotherapy, multiple targets attack (drug combinations) Development of tumor cell resistance reversal agents A new target for the development of anticancer drugs

48 瓶颈 机遇? 挑战? Halsted Fish ( imatinib mesylate, STI-571 ) FDA Bcr-Abl (CML) (GIST)

49 肿瘤靶向治疗

50 靶向治疗 选择性 靶点 抑制肿瘤生长 肿瘤治疗 阻断剂 ( 肿瘤表达 进展 转移 新途径 信号通路 )

51 肿瘤靶向治疗的三个层次 器官靶向 : 某种药物或方法只对某个器官的肿瘤有效, 如肿瘤 的介入治疗 射频热疗等 细胞靶向 : 只针对某种类别的肿瘤细胞, 药物或制剂进入体内后可选择性地与这类细胞特异性地结合, 从而消灭肿瘤细胞, 如 I 131 希罗达 脂质体阿霉素等 分子靶向 : 针对肿瘤细胞特有的受体, 关键基因和调控分子为 靶点的治疗 ( 阻断癌细胞信号传导通路中某一个分 子靶点 ), 抑制肿瘤细胞生长的方法

52 肿瘤化疗是不是分子靶向治疗?

53 Non-selective

54

55 肿瘤化疗是不是分子靶向治疗? 攻击靶点的目标不同 细胞毒药物 : 抑制增值迅速的肿瘤细胞的 DNA 合成 ( 杀灭作用 ) 分子靶向药物 : 细胞癌变过程中的受体或转导过程中关键性酶 ( 改错作用 ) 药物开发程序不同 细胞毒药物 : 分子靶向药物 : 筛选 - 疗效 - 靶点 靶点 - 设计 - 疗效

56 肿瘤药物治疗的靶点 传统靶点新靶点 DNA:5FU, MTX,GEM CTX, MMC RNA:ADM,MIT,ACD, EPI 蛋白质 :L-ASP 微管蛋白 :VCR,NVB PTX,DTX 拓扑异构酶 :CPT-11 TPT,VP16 内分泌 :TAM,Anatrozole Letrozole 1 EGFR 赫赛汀 (Trastuzumab) 乳腺癌 (Her-2 高表达 ) 爱必妥 (Cetuximab) 泰欣生 (Nimotuzumab) 2 EGFR TK 格列卫 (Imatinib) 特罗凯 ( Erlotinib ) 易瑞沙 ( Gefitinib ) Lapatinib Vandetanib 3 VEGF 贝伐 (Bevacizumab) 血管内皮抑素 (YH16) 4 血管内皮细胞 5 多靶点多吉美 (Surafinib) 舒尼替尼 (Sunitinib) 大肠癌 头颈癌 NSCLC 头颈癌 CML,GIST NSCLC NSCLC 乳腺癌 甲状腺癌大肠癌 NSCLC 肾癌 乳腺癌 NSCLC 肾癌 肝癌 GIST, 肾癌

57 New!!! Immunotherapy 作

58 Immunotherapy

59 Immunotherapy 已经上市的 PD-1 抗体抑制剂主要有两种 :Opdivo 和 Keytruda 美国 FDA 已经批准其分别用于黑色素瘤的一二线治疗, 转移性非小细胞肺癌的二线治疗, 以及其他一些癌症

60 Define the basic goals of chemotherapy Selection sensitive anticancer drugs, using a tolerable sufficient dose Learn the basic principles for the combined application of antitumor drugs Reduce the toxicity and resistance of anticancer drugs

61 There may cure the cancer patients to take an active treatment as soon as possible Effective and a sufficient amount of chemotherapy, radical chemotherapy We can not cure patients, palliative therapy to relieve symptoms and prolong survival for the therapeutic purposes

62 How to perform clinical screening of sensitive drugs for cancer patients? Molecular targeted drugs before determining treatment regimens, patients detect cancer-related targets Chemotherapy dose intensity associated with treatment

63 Constitute the drug combination chemotherapy programs, when used alone, the drug should be valid Try to choose several different mechanisms of action of cell cycle phase selectivity of different pharmaceutical composition combined with chemotherapy Choose different types of toxic drugs in combination Through rigorous clinical trials to prove its clinical value

64 Combination therapy principle From the viewpoint of cell proliferation kinetics From the mechanism of drug action From drug toxicity From the spectrum of anti-tumor drugs Recruitment effect Synchronized action Complementary blocking Sequential block Reduce overlapping toxicity Reduce the toxicity of the drug Different tumor sensitivity to different drugs

65 抗恶性肿瘤药的用药原则 1. 细胞增殖动力学机制 : (1) 序贯抑制 : 使用周期特异和非特异性药物 ; (2) 同步化抑制 : 序贯使用周期特异性药物 2. 生化机制 ( 互补抑制 ): 核酸合成 (Doxorubicin) + 细胞毒 (cyclophosphamide) DNA 修复 3. 毒性反应 : 合用激素, 长春新碱, 博来霉素 骨髓抑制 4. 抗癌谱 : 消化道腺癌 5-FU; 鳞癌 MTX: 骨肉瘤 Doxo

66 Chemotherapy Success: effect relationship, between Toxicity Tolerable toxicity and should be limited to the range of recoverable During chemotherapy close observation, monitoring

67 肌苷酸 脱氧鸟苷酸 腺苷酸 脱氧腺苷酸 脱氧尿苷酸 脱氧胸苷酸 DNA Synthesis 尿苷酸 胞苷酸 脱氧胞苷酸 核苷酸还原酶抑制剂 ( 羟基脲 ) 干扰核酸生物合成的药物 DNA 多聚酶抑制剂 ( 阿糖胞苷 )

68 Methotrexate (Methotrexate, MTX) Pharmacological effects of methotrexate to dihydrofolate reductase has a strong and long-lasting inhibition of 5,10 leucovorin produce enough deoxythymidine acid (dtmp) blocked the synthesis, DNA synthesis disorders, cells were blocked off in s phase

69 Clinical application: Treatment of children with acute leukemia Choriocarcinoma Osteosarcoma Intrathecal injection can be used for central nervous system tumors Adverse reactions The most prominent bone marrow suppression Oral and gastrointestinal mucosal damage, such as stomatitis, gastritis, diarrhea Pregnant women may be teratogenic, stillbirth Large doses of long-term medication can cause liver and kidney damage

70 氟尿嘧啶 (Fluorouracil, 5-FU ) 5 of uracil is hydrogen is replaced by fluorine derivatives, pyrimidine anti drugs. Mechanism of action: change in the cells of 5-fluorouracil deoxynucleotides (5F-dUMP) inhibit deoxy thymidylate synthase, prevent deoxyuridine acid (dump) methyl thymidine into acid (dtmp), thereby interfere with the synthesis of DNA

71 Clinical Use Digestive System Cancer Breast Cancer Ovarian Cancer Cervical Cancer Choriocarcinoma Bladder Cancer Head and neck cancer Bone marrow suppression Gastrointestinal toxicity, appeared bloody diarrhea should be immediately discontinued It can cause hair loss, skin pigmentation, and occasionally liver and kidney dysfunction Adverse Effect

72 阿糖胞苷 (Cytarabine, AraC) ACTION: cytarabine in vivo by deoxycytidine kinase catalytic into two or cytidine triphosphate (Ara-CDP or Ara-CTP), thereby inhibiting DNA polymerase activity on DNA synthesis, can also be incorporated into the DNA of interference its replication, the cells die. S phase cells of the most sensitive, is a cycle specific drugs Clinical applications: the treatment of adult patients with acute myeloid or monocytic leukemia Adverse reactions : There are severe bone marrow suppression and gastrointestinal reactions, intravenous injection can cause phlebitis, have some impact function on liver

73 常用的抗恶性肿瘤药物 干扰核酸生物合成 ( 抗代谢药 ) 1. 二氢叶酸还原酶抑制剂 绒癌 恶性葡萄胎 卵巢癌 消化道癌 头颈部肿瘤 ; 同种骨髓移植 器官移植 类风湿关节炎等 2. 胸苷酸合成酶抑制剂氟尿嘧啶 (5-FU):S- 期 ; 消化道癌, 乳腺癌, 3. 嘌呤核苷酸合成抑制剂巯嘌呤 (6-MP): S- 期 ; 4. 核苷酸还原酶抑制剂羟基脲 (hydroxycarbamide,hu): S- 期 ; 慢粒 ; 黑色素瘤 5. DNA 多聚酶抑制剂 甲氨蝶呤 (MTX): 儿童急性白血病 ; 宫颈癌, 卵巢癌, 绒癌, 膀胱癌, 鼻咽癌, 前列腺癌 卡培他滨 (capecitabine) 儿童急淋 ( 维持治疗 ), 绒癌 硫鸟嘌呤 阿糖胞苷 (Ara-C): S- 期 ; 急非淋 ( 急粒 单核细胞白血病 )

74 . 环磷酰胺 (Cyclophosphamide, CTX ) Pharmacological effects: in vitro inactive into the body by the liver cytochrome P450 oxidation, split ring generates intermediate aldophosphamide, in tumor cells break down the phosphoramide mustard to DNA alkylation, formation of cross-linking, inhibition tumor cell growth and reproduction Clinical application: CTX is a broad spectrum anti-tumor, malignant lymphoma significant effect. Multiple myeloma, acute lymphoblastic leukemia, lung cancer, ovarian cancer, breast cancer, neuroblastoma and testicular cancer have a certain effect Adverse reactions : bone marrow suppression, nausea, vomiting, hair loss, toxicity is specific to hemorrhagic cystitis

75 Alkylating agent 白消安 (Busulfan ) 又名马利兰 (myleran ) Action: small doses can inhibit neutrophil production, may be related to the drug granule membrane permeability. Clinical Applications: Chronic myeloid leukemia significant, chronic myeloid leukemia acute lesions invalid Adverse reactions : gastrointestinal reactions and bone marrow suppression, long used can cause amenorrhea or testicular atrophy

76 Alkylating agent 卡莫司汀 (Carmustine, 氯乙亚硝脲, 卡氮芥,BCNU ) 为亚硝脲类烷化剂 ACTION: In addition to alkylated DNA, the protein and RNA also alkylation. Clinical applications: highly fat-soluble, can through the blood-brain barrier. Mainly used for primary brain tumors or brain metastasis, malignant lymphoma, myeloma, etc. have a certain effect. Adverse reactions : myelosuppression, gastrointestinal reactions and pulmonary toxicity

77 Cisplatin (Cisplatin, cisplatin, DDP) is a divalent platinum with two chlorine atoms and two amino combine to form metal complexes ACTION: After entering the body, the first chlorine dissociation and the formation of cross- links and bases on the DNA strand, thereby undermining the structure and function of DNA. Genus cell cycle non-specific drugs

78 DNA-damaging platinum complexes Clinical application : a broad-spectrum anti-tumor, hypoxic tumor cells and effective features. Non- seminoma testicular tumors most effective head and neck squamous cell carcinoma, ovarian cancer, bladder cancer, prostate cancer, lymphatic sarcoma and lung cancer has a good effect Adverse reactions : gastrointestinal reactions, bone marrow suppression, peripheral neuritis, ototoxicity and other high-dose or continuous medication can cause serious and lasting kidney toxicity.

79 DNA-damaging platinum complexes Carboplatin (Carboplatin, carboplatin, CBP) The second -generation platinum anticancer drugs Pharmacological effects Mechanism of action is similar to cisplatin, but nephrotoxicity, ototoxicity, neurotoxicity and gastrointestinal reactions are low compared with cisplatin. Clinical application For the treatment of small cell lung cancer, head and neck squamous cell carcinoma, ovarian cancer and testicular tumors. Adverse reactions myelosuppression

80 Oxaliplatin (oxaliplatin, oxaliplatin, CBP) The third -generation platinum anticancer drugs Pharmacological effects but also inhibit its replication and transcription anti-tumor effect cross-linking DNA by platinum atoms. Clinical application of colorectal and ovarian cancer has a good effect on the gastric cancer, non-hodgkin's lymphoma, non-small cell lung cancer and head and neck cancer are also effective. Neurotoxicity and adverse gastrointestinal reactions.

81 Mitomycin (Mitomycin C, self-adriamycin, MMC 丝裂霉素 ) Has the chemical structure and ethyleneimine carbamoyl ester group, alkylation with Pharmacological effects: can cross- link double-stranded DNA. Inhibits DNA replication, but also make part of the DNA break. It is a periodic non-specific drugs Clinical application : a broad spectrum of tumors, for stomach cancer, lung cancer, breast cancer, chronic myelogenous leukemia, malignant lymphoma Adverse effects: were significant and long-lasting bone marrow suppression, gastrointestinal reactions followed, sometimes the heart, liver, kidney toxicity and interstitial pneumonia. Injection site irritation

82 Actinomycin D (Dactinomycin, dactinomycin, DACT 放线菌素 ) A peptide antitumor antibiotics Between pharmacological effects can be embedded into the DNA double helix adjacent guanine and cytosine (G-C) base, and DNA binding RNA polymerase impede the function prevents RNA synthesis in particular mrna. Genus cycle nonspecific drugs, but the effect of a strong G1 phase, and may prevent the transition G1 to S phase

83 Clinical application Malignant mole, choriocarcinoma, Hodgkin's disease and lymphoma, Wilms tumor, skeletal muscle sarcoma and neuroblastoma effective In combination with radiation therapy can increase tumor sensitivity to radiation Adverse reactions common gastrointestinal reactions bone marrow suppression was the first thrombocytopenia, pancytopenia appears after a few patients there may alopecia, dermatitis, and birth defects and other.

84 Doxorubicin (Doxorubicin, doxorubicin, adriamycin, ADM 阿霉素 ) lossḣxzl Pharmacological effects: can be embedded between the base pairs of DNA, and closely bound to the DNA, RNA transcription process to prevent, inhibit RNA synthesis, but also to prevent DNA replication. Genus cycle non-specific drugs, but the S -phase cells more sensitive to them. Clinical application: anti- tumor brond spectrum, high efficacy, mainly used for commonly used anti-cancer drug resistance in acute lymphoblastic leukemia or myelogenous leukemia, malignant lymphosarcoma, breast cancer, ovarian cancer, small cell lung cancer, stomach cancer, liver cancer and bladder cancer. Adverse reactions most serious toxic reactions to cardiac toxicity and bone marrow suppression, in addition, adverse gastrointestinal reactions, skin pigmentation and hair

85 Camptothecin (Camptothecin, CPT) It is a cytotoxic quinoline alkaloid Specifically inhibit pharmacological effects TOPO-I activity, thereby disrupting the DNA structure and function. Belonging to the cell cycle non-specific drugs, but the effect is stronger than the S phase G1 and G2 phases. The clinical application of gastric cancer, choriocarcinoma, malignant mole, acute and chronic myelogenous leukemia have a certain effect. on bladder cancer, colorectal cancer have a certain effect, and liver cancer. Adverse reactions are largely urinary tract irritation, gastrointestinal reactions, myelosuppression and alopecia. Relatively small hydroxy camptothecin derivative hydroxycamptothecin (hydroxycamptothecin, HCPT) toxicity

86 常用的抗恶性肿瘤药物 2. 影响 DNA 结构与功能的药物 1) 烷化剂 特点 : 化学性质高度活泼, 具有一或两个烷基 作用机制 : 与 DNA 或蛋白质分子中亲核基团 ( 氨基 羧基 羟基 磷酸基 ) 起烷化反应 交叉联结或脱嘌呤 DNA 链断裂或复制时碱基配对错码 DNA 结构和功能 损害 / 细胞死亡

87 烷化剂分类及代表药 2. 影响 DNA 结构与功能的药物 环磷酰胺 (cyclophosphamide, CTX): 高效, 速效, 广谱 CYPP450 醛磷酰胺 磷酰胺氮芥 DNA 烷化 ; 恶性淋巴瘤 急淋 肺癌 乳腺癌 卵巢癌 多发骨髓瘤 骨髓抑制, 消化道, 脱发 ; 代谢物丙烯醛 化学性膀胱炎 塞替哌 (Thiotepa, TSPA): 乙撑亚胺类, 乳腺癌, 卵巢癌, 肝癌 ; 可注射和腔内给药 骨髓抑制

88 2. 影响 DNA 结构与功能的药物烷化剂分类及代表药白消安 (busulfan; 马利兰, myleran): 慢粒, 原发性血小板增多症, 真性红细胞增多症 ; 久用 肺纤维化 ( 马利兰肺 ), 闭经, 睾丸萎缩 亚硝脲类卡莫司汀 (carmustine), 洛莫司汀 (lomustine), 司莫司汀 (semustine); 脂溶性高 易透过 BBB; 脑瘤 黑色素瘤 胃肠道肿瘤 骨髓抑制, 肝毒性

89 2. 影响 DNA 结构与功能的药物 2) 破坏 DNA 的抗生素类 博来霉素 (bleomycin): DNA 结合 DNA 链断裂 复制受阻 ; G 2 和 M 期 ; 鳞状上皮癌, 淋巴瘤, 睾丸癌, 卵巢癌 ; 间质性肺炎 纤维化 丝裂霉素 (mitomycin): 生物还原烷化作用 ( 与 DNA 双链交叉 联结, 抑制其复制 ; 使 DNA 断裂 ); 周期非特异性 ; 广谱 ; 消化系癌 肺癌 子宫颈癌 慢性白血病 毒性大.

90 2. 影响 DNA 结构与功能的药物 3) 破坏 DNA 的铂类 顺铂 (cisplatin, DDP):Pt 2+ 与碱基 (G A C) 交叉联结 ; 周期非特异性, 广谱 ; 口服无效, 静注 ; 睾丸 卵巢 膀胱癌 ; 子宫内膜 头颈部癌 ; 肾和耳毒性 卡铂 (carboplatin) 4) 拓朴异构酶 (I 或 II) 抑制药 喜树碱 (camptothecine) 和羟喜树碱 : I; S 期,G 2 M ; 胃肠癌 绒癌 急慢粒 依托泊苷 ( (etoposide) 和替尼泊苷 (teniposide) II; S 和 G 1 期 ;( 鬼臼毒素半合成衍生物 ) 睾丸癌 肺癌 儿童白血病 ( 婴儿单核白 )

91 3. 干扰转录过程和阻止 RNA 合成的药物 共性 : 抗癌抗生素 嵌入 DNA 碱基对, 干扰转录过程, 阻止 RNA 合成 ; 放线菌素 D (dactinomycin):g 1 期 ; G 1 C ; 拓扑酶 II ; 肾母细胞瘤 绒癌 恶性葡萄胎 放射召回. 柔红霉素 (daunorubicin) 和多柔比星 (doxorubicin): S 和 M 期 ; 急淋 急粒 恶性淋巴瘤 实体瘤 ; 心脏毒性 普卡霉素 (plicamycin): 降低血钙 ; 睾丸胚胎瘤 低钙血症, 肝毒性. 周期非特异性

92 Effect of DNA structure and function of other drugs

93 分裂中期分裂后期 Vinca alkaloids, taxol mechanism diagram 长春碱类 Inhibition of microtubule polymerization and spindle fibers are formed, mitosis stopped in mid 有丝分裂 微管聚合 微管解聚 紫杉醇类 Promote microtubule polymerization, inhibiting microtubule depolymerization, loss of normal function of spindle cell mitotic arrest

94 长春碱 (Vinblastin, 长春花碱,VLB ) 及长春新碱 (vincristin, VCR ) Chief of oleander flowers (Vinca Rosea L.) plant alkaloids contained. Vindesine (VDS) and vinorelbine (NVB) are semi-synthetic derivative of vinblastine. Pharmacological effects: binding to tubulin, inhibit microtubule polymerization, and thus can not form a spindle cell mitosis stopped in the medium term. Inhibition of mitosis, VLB stronger than the VCR. Genus cell cycle specific drugs, a major role in M phase cells.

95 长春碱 (Vinblastin, 长春花碱,VLB ) 及长春新碱 (vincristin, VCR ) Clinical application: VLB is mainly used for the treatment of acute leukemia, malignant lymphoma, and choriocarcinoma. VCR for childhood acute lymphoblastic leukemia good efficacy, rapid onset, often combined with prednisone drug used to induce remission. Adverse reactions: myelosuppression, neurotoxicity gastrointestinal reactions hair loss local irritation VCR peripheral nerve toxicity

96 紫杉醇 (Paclitaxel,taxol) It is the active ingredient of yew or Taxus brevifolia bark extract. Paclitaxel Patel ( docetaxel, docetaxel) is extracted from the plant Taxus Baccata needles Baccatin (baccatin) and by semi-synthetic transformation from its basic structure is similar to paclitaxel, but easier to source, high water solubility. Pharmacological effects : Taxol can promote microtubule polymerization while inhibiting microtubule polymerization solution loss of normal function of spindle cell mitotic arrest.

97 Clinical application: ovarian and breast cancer lung cancer esophageal cancer colorectal cancer melanoma head and neck cancer lymphoma brain tumors. Adverse reactions bone marrow suppression Allergies Neurotoxicity Cardiotoxicity

98 门冬酰胺合成酶 天冬氨酸 天冬氨酸 门冬酰胺 蛋白合成 正常细胞 谷氨酰胺 谷氨酸 Normal cells from aspartic acid by asparagine synthetase enzymatic synthesis of asparagine L- 门冬酰胺酶 门冬酰胺 门冬酰胺合成酶 天冬氨酸 天冬氨酸 门冬酰胺 蛋白合成 肿瘤细胞 谷氨酰胺 谷氨酸 Tumor cells lack the enzyme asparagine synthetase, asparagine must direct use, exogenous L- asparaginase so asparagine hydrolysis, tumor cells lack asparagine supply, growth was inhibited

99 4. 干扰蛋白质合成与功能的药物 1) 微管蛋白活性抑制药 微管装配和纺锤丝形成 有丝分裂停止 (M 期 ) 长春碱 (vinblatine) 长春新碱 (vincristine) 急性白血病, 恶性淋巴瘤, 绒癌 ; 外周神经炎. 紫杉醇 (paclitaxel): 紫杉烷二萜 ; 转移性卵巢癌 乳腺癌 ; 周围神经病变 过敏反应

100 4. 干扰蛋白质合成与功能的药物 2) 干扰核蛋白体功能的药物 三尖杉酯碱 (harringtonine) : 抑制蛋白质合成起始阶段 核蛋白体分解 释出新生肽链 有丝分裂 ; 急粒, 急单 ( 急非淋 ), 淋巴肉瘤, 肺癌 ; 心肌损害 3) 影响氨基酸供应的药物 门冬酰胺酶 (asparaginase): 急淋 ; 过敏反应 精神症状

101 抑制蛋白质合成与功能药物的分类

102 5. 调节体内激素平衡的药物 补充或拮抗 调节平衡 糖皮质激素 : 急淋 恶性淋巴瘤 慢淋 雌激素 : 前列腺癌 绝经期乳腺癌 雄激素 : 晚期乳腺癌 选择性雌激素受体调节药 : 他莫昔芬 (tamoxifen) 乳腺癌

103 垂体 雄激素 促卵泡激素 芳香酶 氨鲁米特 雌素酮 卵巢 雌激素 他莫昔芬 雌激素受体 雌激素依赖乳腺癌细胞

104 Regulate hormone balance drug mechanism of action, clinical application

105 Cell differentiation -inducing agent Retinoic acid (Retinoic acid, tretinoin, vitamin A acid ) includes all-trans retinoic acid (ATRA), 13- cis- retinoic acid and 9-cis -retinoic acid, etc. Pharmacological effects: of a variety of chemical carcinogens and inhibit virus induced cancer effect and induce differentiation and maturation of leukemia, inhibits their proliferation and promote apoptosis. Acute promyelocytic leukemia remission rate Clinical application : is mainly used for the prevention and precancerous lesions and acute promyelocytic leukemia treatment of malignant tumors.

106 Cell differentiation -inducing agent Arsenate (Arsenious acid, arsenic trioxide, ) Pharmacological effects: mainly through degradation overexpression promyelocytic leukemia gene - retinoic acid receptor fusion protein Bcl-2 and down-regulated genes and induce apoptosis of leukemia Clinical application for the treatment of acute promyelocytic leukemia.

107 抗肿瘤药物靶点 递质 靶点 药物 NF-AT 钙调神经磷酸酶 环孢素 A/ 他克莫司 二氢叶酸二氢叶酸还原酶甲氨蝶呤 核苷 胸苷酸合成酶 氟尿嘧啶 核苷酸 DNA 聚合酶 阿糖胞苷 α- 微管蛋白 β- 微管蛋白 紫杉醇 DNA DNA 拓扑异构酶 І/П 拓扑替康 / 依托泊苷 DNA DNA 依赖的 RNA 多聚酶放线菌素 D 鸟苷 / 脱氧鸟苷肌苷一磷酸脱氢酶霉酚酸酯 细胞因子酪氨酸激酶伊马替尼

108 Molecular targeting of anticancer drugs selectively kills tumor cells but has no effect on normal cells, it has become the most important research ( A ) tumor vaccine Tumor vaccine (tumor vaccine) for the specific immune Cancer vaccine into cell vaccine, virus vaccine, DNA vaccine, peptide vaccine, vaccines and unique carbohydrate vaccine Mainly used for patients already suffering from cancer, the patient to stimulate the body's specific immune response to the tumor in order to achieve repulsion an effective

109 Vaccine Cancer Cervarix cervical cancer sipuleucel T prostate cancer Melacine and M-Vax melanoma DC-Vax brain tumor, Onco-Vax colon cancer HSPPC-96, renal cell carcinoma Cima Vax EGF, non-small cell lung cancer Gardasil prevent cervical cancer and precancerous genital lesions

110 Gene therapy (gene therapeutic agents) by means of a certain vector normal human gene or have a therapeutic effect of introducing DNA into human cells Replace defective genes or closed abnormal gene, so as to achieve the therapeutic effect of the drug.

111 Recombinant adenovirus p53 (recombinant human Adp53) 2003, China's former State Food and Drug Administration (SFDA) approved the listing of the world's first gene therapy drugs in the world market The drug is a type 5 adenovirus vector and p53 gene recombinant human tumor gene therapy drugs The gene in tumor cells can guide the synthesis of p53 protein plays role in regulation of cell proliferation, inhibiting cell division, but no damage to normal cells P53 tumor suppressor gene also has raised a variety of anti-cancer activity of multiple oncogenes and genes down-regulated, and effectively inhibit the VEGF gene and multidrug resistance gene (MDR) Gene Expression

112 Nanoparticles as gene carriers (rexin-g) Philippine Bureau of Food and Drug (BFAD) approved in 2007, listed on the cell cycle regulatory genes anticancer injection After intravenous infusion can do kind of nausea tumor targeted therapy, primarily for pancreatic cancer, breast cancer, liver cancer and colorectal cancer, efficacy, and safety.

113 Monoclonal Antibody Monoclonal antibodies (monoclonal antibody) refers only to a single molecular target in tumor immune antibody antagonism

114 Monoclonal antibody treatment of various tumors 单抗名称英文名称分子靶点适应症

115 Monoclonal antibody treatment of various tumors Chinese name English name target application

116 target mechanism example ( 四 )Cell cycle regulatory molecules that. Histone deacetylase inhibitors By inhibiting histone N- target antiproliferative drugs mtor inhibitor terminal amino acid residues of deacetylation, increase the expression levels of p21 and other gene, inhibition of tumor cell proliferation, induction of cell differentiation or apoptosis Is PI3k / AKT pathway downstream effectors, the signal path is a critical pathway regulating cell growth and proliferation Romidepsin ) Vorinostat( ) vorinostat) Sirolimus ( ) Everolimus ( )

117 Cell cycle regulatory molecules that target antiproliferative drugs 作用靶点作用机制代表药物

118 Important Intracellular Signal Transduction Molecules as a Target for Pro- Apoptosis Drug

119 drugs Target clininc use Bcr-abl( 氨酸激酶抑制剂 )

120 Angiogenesis inhibitor ( molecular targeted drugs) 癌

121 Case Patient 54, male, colorectal cancer metastasized to liver, 5 months of chemotherapy followed by 1 week of targeted therapy. Routine checkup in Sept.2010 discovered tumor in the left liver. No symptoms of fever, shivering, jaundice, bloated, fatigue, lack of appetite, no stomach ache, diarrhea, no shortness of breath, vomiting of blood, headache and body pain, left untreated. March 2011 PET-CT scan revealed left liver low density image, unclear borders, increased metabolism. Schedule for surgery, 4cm*4cm tumor was removed from left live and 3cm*3cm tumor was removed from colon.

122 After sugery: 2 nd degree peptic ulcer, invaded to the entire tissue wall and fibers, metastasized to liver, 3/12 lymph node metastasis, the ends of colons has no cancer tissue, tumor was cut at 0.1cm in the liver. After surgery analysis: EGFR mutation, K-ras wild type. It began in April 2011 to 6 cycles of systemic chemotherapy ( docetaxel 多西紫杉醇 60 mg Day 1, 40 mg Day 5, 200 mg oxaliplatin 奥沙利铂 on day 1, leucovorin 亚叶酸 400 mg the 1st - 5 days, tegafur 替加氟 800 mg, 1-5 days ) and combined with 8 times cetuximab 西妥昔单抗 treatment ( first dose 600 mg maintenance dose 400 mg, once a week ), the end of the review of the treatment of PET / CT and no significant findings, in July 2011 continued nimotuzumab 尼妥珠单抗 ( 400 mg ) weekly maintenance therapy.

123 ? Problems and Thoughts : cytotoxic anticancer drugs 1. What is the principle of treatment of colon cancer? 2. What type of antitumor drug is oxaliplatin? What is its mechanism of action? 3 What kind of chemotherapy drugs does tegafur belong to? What is its mechanism of action? 4 What are the characteristics of " molecularly targeted ' anticancer drugs compared to traditional

124 Docetaxel Applicable to the use of advanced or metastatic cancer, treatment with cisplatin-based chemotherapy failed. It belongs to the taxane antitumor compounds. Mechanism of action Docetaxel is to strengthen the role of tubulin polymerization and inhibition of microtubule depolymerization, leading to the formation of a stable non-functional microtubule bundles and thus destroy tumor cells in mitosis. The product concentration in the cells than Taxol three times higher, and long residence time in the cell, which is the product in vitro anti-tumor activity than paclitaxel big important reason When used in combination with cisplatin, are advised to use after docetaxel with cisplatin, so as not to reduce docetaxel elimination rate

125 Tegafur In the body gradually becomes fluorouracil and work. Fluorouracil its role and the same in the body can interfere with antagonistic synthetic DNA, RNA and proteins No in vitro Animal experiments showed that the toxicity of fluorouracil only 1/ 4 to 1 /7 ; index of fluorouracil chemotherapy 2 times Chronic toxicity test not seen severe bone marrow suppression, the impact on the less serious immune.

126 Leucovorin With fluorouracil and used to improve the efficacy of fluorouracil. Deoxy- uridine monophosphate (dump) required to undergo THF catalyzed bear guanylate synthase (TMPS) in DNA synthesis in turn to the formation of methyl deoxythymidine acid (dtmp). In this case, the need to make dihydrofolate dihydrofolate reductase into THF The main mechanism of action of fluorouracil after entering the body into a first - fluorouracil deoxynucleotides inhibiting thymidylate synthase (TMPS). During the reaction TMPS with THF, it dumps three form a transition complex. After completion of the reaction is generally complexes decompose, releasing dihydrofolate, TMPS enzymes and dtmp. But after giving the triple composite formation can not be decomposed fluorouracil, enzyme function is inhibited, can not be produced dtmp. The binding of the enzyme and deoxynucleotide fluorouracil proportional to the concentration of THF, THF improve the supply of Fluorouracil can inhibit the action of the enzyme TMPS enhanced.

127 Cetuximab Can be used with a variety of expression in normal cells and cancer cell surface binding of EGF receptor-specific, and competitive blocking EGF and other ligands, such as transforming growth factor- α (TGF-α) binding. This product is directed to the EGF receptor IgG1 monoclonal antibody specifically binding the latter two, and by binding to the EGF receptor tyrosine kinase (TK) inhibition, block intracellular signal transduction, thereby inhibiting cancer cell proliferation and induce apoptosis in cancer cells, reducing matrix metalloproteinase and vascular endothelial growth factor production.

128 Nimotuzumab In 2008, China's first for the treatment of malignant tumors of functional monoclonal antibody drugs Taixinsheng ( nimotuzumab ) approved for marketing EGFR is overexpressed in a variety of solid tumors, such as head and neck cancer, lung cancer, colorectal cancer, the presence of both EGFR overexpression phenomenon. High invasiveness EGFR overexpression with tumor, highly metastatic and highly correlated with poor prognosis. Taixinsheng ( nimotuzumab, Nimotuzumab), is the world's first to the epidermal growth factor receptor (EGFR) monoclonal antibody drugs targeting China's first treatment of malignant tumors of the humanized monoclonal antibody Taixinsheng able to compete for binding to EGFR, blocking the EGFR and its downstream mediated signal transduction pathway, thereby inhibiting tumor cell proliferation, induction of differentiation and promote apoptosis and inhibit tumor angiogenesis, and enhance the efficacy of radiotherapy and chemotherapy.

129 1. 阻碍细胞有丝分裂的抗癌药是 A. 阿霉素 B. 氟尿嘧啶 C. 长春新碱 D. 甲氨蝶呤 E. 以上都不是 A 型题 2. 烷化剂中易发生出血性膀胱炎的抗癌药是 A. 氮芥 B. 环磷酰胺 C. 马利兰 D. 长春新碱 答案 E. 卡氮芥 答案

130 3. 有细胞周期特异性的抗肿瘤药物是 A.5- 氟尿嘧啶 B. 环磷酰胺 C. 阿霉素 D. 氮芥 E. 塞替派 4. 抑制二氢叶酸还原酶的抗肿瘤药是 A. 顺铂 B. 阿霉素 C. 环磷酰胺 D.5- 氟尿嘧啶 答案 E. 甲氨蝶呤 答案

131 5. 烷化剂中易诱发出血性膀胱炎的药物是 A. 甲酰溶肉瘤素 B. 卡氮芥 C. 环磷酰胺 D. 苯丁酸氮芥 E. 氮芥 6. 治疗绒毛膜上皮细胞癌和恶性葡萄胎疗效最差的是 A.6- 巯基嘌呤 B. 喜树碱 C. 甲氨蝶呤 答案 D. 放线菌素 D E. 博莱霉素 答案

132 7. 对儿童急性淋巴细胞性白血病疗效好 见效快的是 A. 长春新碱 B. 阿糖胞苷 C. 巯嘌呤 D. 丝裂霉素 E. 环磷酰胺 8. 不抑制骨髓造血功能的抗肿瘤药物是 A. 烷化剂 B. 抗代谢类 C. 抗生素类 D. 植物碱类 答案 E. 激素类 答案

133 9. 应用环磷酰胺疗效显著的是 A. 多发性骨髓瘤 B. 急性淋巴细胞性白血病 C. 卵巢癌 D. 乳腺癌 E. 恶性淋巴瘤 10. 长春新碱使肿瘤细胞较多的处于增殖周期的 A.S 期 B.G 0 期 C.G 1 期 答案 D.G 2 期 E.M 期 答案

134 11. 以下属于 M 期特异性抗肿瘤药物是 A. 长春新碱 B. 环磷酰胺 C. 鬼臼毒素 D. 左旋门冬酰胺酶 E. 甲氨蝶呤 12. 以下属于 S 期特异性的抗肿瘤药物是 A. 喜树碱 B. 博莱霉素 C. 甲氨蝶呤 D. 左旋门冬酰胺酶 答案 E. 鬼臼毒素 答案

135 13. 作为基本用药 5- 氟尿嘧啶治疗 A. 绒毛膜上皮癌 B. 急性淋巴细胞白血病 C. 慢性粒细胞性白血病 D. 消化道肿瘤 E. 恶性黑色素瘤 14. 预防环磷酰胺引起出血性膀胱炎的是 A. 维生素 B 12 B. 叶酸 C. 碳酸氢纳 D. 甲酰四氢叶酸钙 答案 E. 巯乙磺酸钠 答案

136 15. 顺铂首选用于治疗 A. 慢性淋巴细胞性白血病 B. 非精原细胞性睾丸瘤 C. 多发性骨髓瘤 D. 恶性淋巴瘤 E. 绒毛膜上皮细胞癌 答案

137 A. 博莱霉素 B. 马利兰 C. 放线菌素 D D. 环磷酰胺 E. 雌激素 B 型题 ( 配伍选择题 ) 16. 慢性粒细胞白血病 17. 急性淋巴细胞白血病 18. 绒毛膜上皮癌 19. 前列腺癌 20. 鳞状上皮癌 答案

138 A. 己烯雌酚 B. 丙酸睾丸酮 C. 甲氨蝶呤 D. 白消安 E. 放射性碘 131 I 21. 治疗激素依赖性播散性乳腺癌的药物是 22. 治疗播散性前列腺癌的药物是 23. 治疗绒毛膜上皮细胞癌的药物是 24. 治疗高度分化性甲状腺癌的药物是 25. 治疗慢性粒细胞白血病的药物是 答案

139 X 型题 ( 多项选择题 ) 26. 下列周期特异性抗肿瘤药物是 A. 甲氨蝶呤 B. 顺铂 C. 羟基喜树碱 D. 长春新碱 E. 氟尿嘧啶 27. 阿霉素的特点是 A. 骨髓抑制 B. 肾毒性 C. 心脏毒性 D. 抑制 DNA 及 RNA 的合成 答案 E. 属于细胞周期特异性药物 答案

140 28. 长春新碱的特点是 A. 作用于肿瘤细胞增殖的 G 1 期 B. 作用于 M 期 C. 作用于 S 期 D. 属于细胞周期非特异性药物 E. 对儿童急性淋巴细胞白血病疗效较好 29. 下列主要作用于 M 期的药物是 A. 秋水仙碱 B. 丝裂霉素 C.5- 氟尿嘧啶 D. 阿霉素 答案 E. 长春新碱 答案

141 30. 阻止微管解聚的抗癌药物有 A. 紫杉醇 B. 紫杉特尔 C. 喜树碱 D. 长春碱 E.L- 门冬酰胺酶 31. 抑制微管聚合的抗癌药物是 A. 鬼臼毒素 B. 阿糖胞苷 C. 长春新碱 D. 紫杉醇 答案 E. 巯嘌呤 答案

142 32. 通过嵌入 DNA 中干扰转录过程阻止 RNA 合成的抗肿瘤药物是 A. 放线菌素 D B. 多柔米星 C. 羟基脲 D. 柔红霉素 E. 紫杉醇 33. 直接影响 DNA 结构与功能的抗肿瘤药物是 A. 博莱霉素 B. 阿糖胞苷 C. 丝裂霉素 D. 紫杉醇 答案 E. 顺铂 答案

143 34. 抗恶性肿瘤药物共有的毒性有 A. 消化道黏膜损害 B. 肝 肾功能损害 C. 脱发 D. 骨髓抑制 E. 抑制免疫功能 35. 下列属于周期非特异性抗肿瘤药物是 A. 环磷酰胺 B.5- 氟尿嘧啶 C. 泼尼松 D. 柔红霉素 答案 E. 丝裂霉素 答案

144 简答题 1. 简述抗肿瘤药的分类方法 2. 简述抗肿瘤药的生化机制 3. 简述抗肿瘤药的主要不良反应 4. 简述环磷酰胺的临床应用 5. 简述氟尿嘧啶的临床应用

145 简答题参考答案 (1) 根据抗肿瘤药的结构和来源分类 (2) 根据抗肿瘤药的生化机制分类 (3) 根据抗肿瘤药的抗瘤机制分类

146 根据抗肿瘤药的生化机制可将其分为以下几类 1. 干扰核酸合成药物 2. 直接影响 DNA 结构和功能的药物 3. 干扰转录 阻止 RNA 合成药 4. 干扰蛋白质合成与功能的药物 5. 影响激素平衡药物

147 (1) 近期毒性 : 骨髓抑制 消化道反应 脱发以及不同药物有其各自的其他系统毒性反应 (2) 远期毒性 : 第二原发肿瘤 不育和畸形

148 (1) 环磷酰胺主要用于治疗恶性淋巴瘤 ( 显效 ) 急性淋巴细胞白血病 儿童神经母细胞瘤 ; (2) 对其他多种肿瘤如 : 肺癌 乳腺癌 卵巢癌 多发性骨髓癌 睾丸肿瘤等有一定疗效 ; (3) 作为免疫抑制剂用于自身免疫性疾病及器官移植排斥反应等

149 (1) 对消化系统癌 ( 食管癌 胃癌 肠癌 胰腺癌 肝癌 ) 和乳腺癌疗效好 ; (2) 对女性生殖系统癌 ( 宫颈癌 绒毛膜上皮癌 卵巢癌 ) 头颈部肿瘤及膀胱癌也有效

150