教学课题 - 哈尔滨医科大学精品课程建设工程

教学课题 - 哈尔滨医科大学精品课程建设工程 第四十七章 抗肿瘤药 教学课题 抗肿瘤药 课型:理论课 1.掌握 抗肿瘤药物的分类，代药的作用机制及临床应用原则 教学目的 2熟悉 药物的药代动力学 3.了解 细胞周期，药物的药代动力学 1. 细胞周期特异性药物和非特异性药物的代表药及抗瘤机制 教学重点 2. 抗肿瘤药的耐药机制及预防策略 教学难点 1. 抗肿瘤药的耐药机制及预防策略 教学方法 讲授式，启发式，讨论式 教学步骤、内容 一、细胞周期及其抗肿瘤药物的治疗原则 课时安排 二、抗代谢药:作用部位，临床应用，药代学，不良反应 45分钟 三、抗生素:作用部位，临床应用，药代学，不良反应 四、烷化剂:作用部位，临床应用，药代学，不良反应 40分钟 五、微管抑制剂:作用部位，临床应用，药代学，不良反应 六、激素类:作用部位，临床应用，药代学，不良反应 小结( 5分钟) 1.以提问方式，了解学生的情况以及指明重点所在 1.试列举抗肿瘤药按化学性质的分类及各类代表药。 2.试列举抗肿瘤药按作用机制的分类及各类代表药 3.常用抗肿瘤药有哪些主要的不良反应, 4.新型抗癌药有哪些类型, 5.试述抗癌药物联合应用的原则。 思 考 题 抗肿瘤药Cancer chemotherapy Overview G1: Pre-synthetic phase (Gap 1 phase) S: DNA synthesis phase G2: DNA post synthetic phase (Gap 2 phase) M: Mitosis phase 多媒体演示 Principle of cancer chemotherapy A. Treatment strategies 1. Goal of treatment Cure: means long-term disease-free survival Palliation: that is alleviation of symptom and avoidance of life-threatening toxicity Reduced the neoplastic cell burden, by surgery/radiation/ chemotherapy 2. cell-cycle specificity of drugs Chemotherapeutic agent that are effective only in replicating cells, that is those cells that are cycling, are said to be cell-cycle specific drug 5. cell-cycle nonspecificity of drugs 3. Mode of action 多媒体演示 1(Inhibition of DNA and RNA synthesis 2(Inhibition of cell division 3. Damage to the mitotic spindle B. Treatment of regimens and scheduling 1. Log kill 2. Pharmacologic sanctuaries 3. Treatment protocols POMP: for treatment of acute lymphocytic leukemia 多媒体演示 P: prednisone O: oncovin M: methotrexate P: purinethol C. Problem associated with chemotherapy 1. Resistance 2. Multidrug resistance P-glycoprotein pumping of drug out of the cell 3. Toxicity Common adverse effect Duration of adverse effect Minimizing adverse effects Treatment-induced rumors ?Antimetabolites(抗代谢药) Methotrexate (甲氨喋呤) 1. Site of action Inhibition of dihydrofolate reductase Consequences of decreased FH4 Plyglutamated MTX 2. Resistance 1.Nonproliferating cells 2. Due to amplification of the gene that codes for dihydrofolate reductase. 3. Reduced influx of MTX 3. Therapeutic applications a. Combination with other drugs acute lymphocytic leukemia, chroiocarcinoma, Burkitt’s lymphoma in children, breast cancer, head and neck carcinomas b. high-dose MTX+ leucovorin osteogenic sarcoma, choriocarcinoma c. low-dose MTX inflammatory diseases, such as severe psoriasis and rheumatoid arthritis 4. Pharmacokinetics : Administration and distribution Oral, IM, IV and intrathecal routes Found in the GI, liver and kidney, ascites 5. Adverse effect a. Commomly observed toxicities b. Renal damage c. Hepatic function: fibrosis d. Pulmonary toxicity cough, dyspnea, fever, cyanosis e. Neurologic toxicities subacute meningeal irritation, stiff neck,headache, fever, long-lasting effects could induce learning disabilities f. contraindication: avoided in pregnancy B. 6-Mercaptopurine(6-MP) (甲氨喋呤) 1.Site of action a.Formation of nicleotide 6-Thioinosinic acid, or thio-IMP b.Inhibition of purine synthesis 多媒体演示 c.Incorporation into nucleic acids 2. resistance (1)An inability to biotransform 6-MP to the corresponding nucleotide (2) An increased dephosphorylation (3) Increased metaboism of the drug to thiouric acid 3.Pharmacokinetics Administration and metabolism Absorption: oral Liver:6-methylmercaptopurine (S-CH3) derivation or thiouric Excrete: urine 4. Adverse effects Nausea,vomiting, diarrhea, bone marrow depression and hepatotoxicity 5. Therapeutic applications Principally in the maintenance of remission in acut lymphoblastic leukemia(ALL) C.6-thioguanine (6-TG)(6-硫代鸟嘌呤) Treatment: acute nonlimphocytic leukemia in combination with daunorubicin and cytarabine D. 5-Fluorouracil (5-FU) (5-氟尿嘧) 1.Site of action. 5-FU per se is devoid of antineoplastic activity and must be conberted to the corresponding deoxynucleotide monophosphate 2. Resistance (1) Lost the ability to convert 5-FU into its active form (2) Increased rate of 5-FU catabilism 3.Therapeutic application: (1) Altered or increased thymidylate (2)Slowly growing, solid tumor: colorectal, breast, ovarian, pancreatic, and gastric carcinomas (3) Adjuvant therapy with levamisole improves the survival of patients with colonic cancer 4.Phamacokinetics IV treatment and applied topically 5.Toxicities: 多媒体演示 Nausea,vomiting, diarrhea, alopecia, severe ulceration, bone marrow depression, anorexia, hand-foot syndrome E. Cytarabine (ara-C) (阿糖胞苷) 1. Site of action: Ara-C-----Cytosine arabinoside triphosphate (ara-CTP) 2. Resistance (1) Defect in the transport process (2) A change in phosphorylating enzymes (3) In creased pool of the natural dCTP nucleotide 3.Therapeutic indications: Acute nonlymphocytic leukemia in combination with 6-TG and daunorubicin 多媒体演示 4.Pharmacokinetics 5.Adverse effect (1)Reduction of blood cells (2) Stomach upset (3) Hair loss ?Antibiotics (抗生素) A. Dactinomycin Hinders DNA synthesis 1. Site if action Cause strand breaks 2. Resistance: 3.Therapeutic applications: In combination with surgery and vincristine: for wilm’s tumor In combination with methotrexate: for gestational choricocarcinoma 5.Adverse effect 1.Increased risk of bleeding for 3 weeks after therapy 2.Nausea,vomiting, or loss of appetitke for 4-20 hours after therapy 3.Sores in mouth, throat, or on lips 4.Darkening or redness of skin, usually where radiation was given 5.Reversible hair loss B. Doxorubicin and daunorubicin (阿霉素和柔红霉素) 1.Site of action a.Interaction in the DNA b. Binding to cell membranes c. Generation of oxygen radicals through lipid peroxidation 2. Resistance: a.Increased efflux via the amplified transport P-glycoprotein b.Decreased cytochrome P-450 reductase, topoisomerase ? and DNA repair 多媒体演示 3. Therapeutic applications a.Breast and lung b.Acute lymphocytic leukemia Lymphomas c.Acute lymphocytic and myelocytic leukemias 4.Pharmacokinetics 5.Adverse effects a.dose-dependent cardiotoxicity b.Bone marrow suppression c.Stomatitis d.GI tract disturbances C. Bleomycin(博来霉素) 1.Site of action Bleomucin is cell–cycle specific and cause cells to accumulate in the G2 phase 2.Resistance The mechanisms have not been elucidated 3.Therapeutic applications: a.In combination with vinblastine or etoposide: testicular tumors b.For squamous cell carcinomas and lymphomas 4.Pharmacokinetics: Administration: subcutaneous, intramuscular, intravenous and intracavitary Excrete: urine 5.Adverse effect Pulmonary toxicity, mucocutaneous reaction, alopecia, hypertrophic skin, hyperpigmentation of the hand ? Alkylating agents(烷化剂) A. Mechlorethamine (氮芥) 1.Mechanism of action Alkylation can occur in both cycling and resting cells, but proliferation cells are more sensitive to the drug, especially those in G1 and S phase 2. Resistance: 多媒体演示 a. Decreased permeability of the drug b. Increased conjugation with thiols c. Increased DNA repair 3. Therapeutic applications a.Hodgkin’s disease b.Solid tumar 4.Pharmacokinetics : IV only 5.Adverse effects a.Commonly observed toxicities (1)an allergic reaction ( shortness of breath); (2)closing of your throat; difficulty breathing; (3)swelling of your lips, face, or tongue; or hives; (4)blood in the urine; (5)black or tarry stools; (6)signs of infection such as fever;chills, or sore throat; (7)joint pain and stiffness similar to gout (high levels of uric acid in the blood); (8)jaundice (yellowing of the skin or eyes); or unusual bleeding or bruising. B.Cyclophosphamide and ifosfamide (环磷酰胺) 1.Mechanism of action 2.Resistance a.Increased DNA repair b.Reaction of the drug with thiols 3.Therapeutic applications: These agents have a broad clinical spectrum, being used either single or as part of a regiment in treatment of a wide variety of neoplastic diseases. 4.Pharmacokinetics: 5.Adverse effects Common side effects:Fatigue, Nausea and vomiting, Loss of appetite, bone marrow, Infections Occasional side effects:Diarrhoea, Skin may darken, Mouth ulcers ? Microtubule inhibition (微管抑制剂) A.Vincristine and vinblastine(长春新碱) 多媒体演示 1. Mechanism Both of them are cycle-specific and phase-specific 2.Resistance: a.Incrased efflux via the amplified transport P-glycoprotein 多媒体演示 3.Therapeutic applications: a.Vincristine Acute lymphoblastic leukemia in children, wilm’s tumar, Ewing’s soft-tissue sarcoma, hodgkin’s and non-Hodgkin’s lymphomas b.Vinblastine In combine with bleomysin and cisplatin for the treatment of metastatic testicular carcinoma and systemic hodgkin’s and non-Hodgkin’s lymphomas. 4.Pharmacokinetics: 5.Adverse effects a.Shared toxicities: b.Unique toxicities B.Paclitaxel 1. 1. Mechanism 2.Resistance: a.Increased efflux via the amplified transport P-glycoprotein b. Mutation in tubulin structure P-glycoprotein 3.Therapeutic applications: a.Advanced ovarian cancer b.Metastatic breast cancer c.Small-cell lung cancer d.Squeamous-cell carcinoma of the head and neck 5.Adverse effects a.Hypersensitivity: b.Neutropenis: c. Other toxicities Peripheral neuropathy Transient asymptomatic bradycardia alopecia ? Steroid hormones and their antagonists(类固醇激素及其拮抗剂) 1.Hormone-responsive, where the tumor regresses following treatment with a specific hormone 2.Hormone-dependent, where removal of a hormonal stimulus causes tumor regression 3.Both A.Prednisone Acute lymphocytic, hodgkin’s and non-Hodgkin’s lymphomas. B.Tamoxifen Esrogen-dependent breast cancers C.Estrogens Prostatic cancer D.Aminoglutethimide Metastatic breast cancer ? Other chemotherapeutic agents A.Crisplatin and carboplatin 1.mechanism of action 2.Resistance: a.Elevated glutathione b.Increased DNA repair c.Induced metallothionein 3.Therapeutic application in combine with vinblastine and bleomycin: metastatic in combine with cyclophosphamide:bladder 4.Pharmacokinetics: Administration: IV, and intraperitoneally for ovarian cancer Distrubution: serum protein, liver, kidney, intestinal, testicular and ovarian Excrete: urine 5.Adverse effects: Severe, persistent vomiting Hypomagnesemia Hypocalcemia Ototoxicity Hearing loss and tinnitus Mild bone marrow suppression