抗癌藥教學(xué)課件

1、抗癌藥抗癌藥（Antineoplastic agents） Overview IntroductionnMalignant disease accounts for a high proportion of deaths in industrialised countries.nThe treatment of anticancer drug is to give palliation, induce remission and, if possible, cure.OverviewIntroductionw Cancer occurs after normal cells have been

2、 transformed into neoplastic cells through alteration of their genetic material and the abnormal expression of certain genes. Neoplastic cells usually exhibit chromosomal abnormalities and the loss of their differentiated properties. These changes lead to uncontrolled cell division and many result i

3、n the invasion of previously unaffected organs, a process called metastasis.Advances in Cancer Chemotherapy Treatment options of cancer:w Surgery: before 1955w Radiotherapy: 19551965w Chemotherapy: after 1965w Immunotherapy and Gene therapyAdvances in Cancer ChemotherapyThe treatment of a patient wi

4、th cancer may aim to:w give palliation, for example prompt relief of unpleasant symptoms such as superior vena cava obstruction from a mediastinal tumorw induce remission so that all macroscopic and microscopic features of the cancer disappear, though disease is known to persistw cure, for which all

5、 the cells of the clone must be destroyed.Cancer Chemotherapy Disease Name 5 Years Survival Ratew Childhood Acute Lymphoblastic Leukemia 5080%w Adult Acute Lymphoblastic Leukemia 2060%w Childhood Acute Myeloblastic Leukemia 2060%w Adult Acute Myeloblastic Leukemia 1020%w Breast Cancer（Premenopausal）

6、 1020%w Breast Cancer（Postmenopausal） 015%w Hodgkin s lymphoma * 4080%Cancer ChemotherapyDisease Name 5 Years Survival Ratew Small Cell Lung Cancer （Limited Stage） 1020%w （Extensive Stage） 05%w Non-Hodgkin s lymphoma * 4065%w Ovarian Cancer 4060%w Children Solid Tumor (Nephroblastoma, Rhabdomyosarco

7、ma, Lymphoma，Osteosarcoma）* 6090%w Trophoblastoma （Chorion Epithelioma）* 8090%w Seminoma of Testis* 6090%w Embryonic Carcinoma of Testis 6080%Note：* Combination with other therapeutics *Chemotherapy Level of our country is highThe Classification of Anticancer Drugsresource of the drugbiochemistry me

8、chanisms of anticancer actionnAccording to the cycle or phase specificity of the drugThe Classification of Anticancer Drugsresource of the drugAlkylating AgentsAntimetaboliteHormonesThe Classification of Anticancer Drugsbiochemistry mechanisms of anticancer action:nucleic acid biosynthesis Direct in

9、fluence Interfere transcription and block RNA synthesis Interfere protein synthesis and function Influence hormone homeostasis Others2021/7/911w9、 人的價值，在招收誘惑的一瞬間被決定。2022-2-102022-2-10Thursday, February 10, 2022w10、低頭要有勇氣，抬頭要有低氣。2022-2-102022-2-102022-2-102/10/2022 9:49:28 PMw11、人總是珍惜為得到。2022-2-10202

10、2-2-102022-2-10Feb-2210-Feb-22w12、人亂于心，不寬余請。2022-2-102022-2-102022-2-10Thursday, February 10, 2022w13、生氣是拿別人做錯的事來懲罰自己。2022-2-102022-2-102022-2-102022-2-102/10/2022w14、抱最大的希望，作最大的努力。2022年2月10日星期四2022-2-102022-2-102022-2-10w15、一個人炫耀什么，說明他內(nèi)心缺少什么。2022年2月2022-2-102022-2-102022-2-102/10/2022w16、業(yè)余生活要有意義，不

11、要越軌。2022-2-102022-2-10February 10, 2022w17、一個人即使已登上頂峰，也仍要自強不息。2022-2-102022-2-102022-2-102022-2-10The Classification of Anticancer DrugsnAccording to the cycle or phase specificity of the drug: Cell cycle nonspecific agents (CCNSA) Cell cycle specific agents (CCSA)The Basic Concept of Cell Generatio

12、n Cyclew The cycle of cell replication includes: M（Mitosis）phase G1（Gap1, period before S）phase S（DNA synthesis）phase G2（Gap2,period after S）phaseu Growth Fraction (GF）Growth Fraction (GF)GFCCSA and CCNSAuCell Cycle Nonspecific Agents (CCNSA) p Alkylating Agentsp Platinum Compounds uCell Cycle Speci

13、fic Agents (CCSA) S Phase Specific Drug: Aantimetabolites, Topoisomerase Inhabitors M Phase Specific Drug: Vinca Alkaloids, Taxanes G2 Phase Specific Drug: BbleomycinCCSA and CCNSAMechanism of Anticancer Drugsw Block nucleic acid (DNA, RNA) biosynthesisw Directly destroy DNA and inhibit DNA reproduc

14、tionw Interfere transcription and block RNA synthesisw Interfere protein synthesis and functionw Influence hormone homeostasisBlock Nucleic Acid (DNA, RNA) BiosynthesisAntimetabolites:w Folic Acid Antagonist: inhibit dihydrofolate reductase (methotrexate)w Pyrimidine Antagonist: inhibit thymidylate

15、synthetase (fluorouracil) ; inhibit DNA polymerase (cytarabine)w Purine Antagonist: inhibit interconversion of purine nucleotide (mercaptopurine)w Ribonucleoside Diphosphate Reductase Antagonist: (hydroxyurea) Interfere Protein Synthesis w Antitubulin: vinca alkaloids and taxanes;w Interfere the fun

16、ction of ribosome: harringtonines；w Influence amino acid supply: L-asparaginase Bind tubulin, destroy spindle to produce mitotic arrest.Interfere Transcription and Block RNA Synthesisw Bind with DNA to block RNA production. doxorubicinInfluence the Structure and Function of DNAw Alkylating Agent: me

17、chlorethamine, cyclophosphamide and thiotepaw Platinum: cis-platiniumw Antibiotic: bleomycin and mitomycin Cw Topoismerase inhibitor: camptothecine and podophyllotoxin Influence Hormone Homeostasis These drugs bind to hormone receptors to block the actions of the sex hormones which results in inhibi

18、tion of tumor growth.w Estrogens and estrogen antagonistic drugw Androgens and androgen antagonistic drugw Progestogen drugw Glucocorticoid drugw gonadotropin-releasing hormone inhibitor: leuprolide, goserelinw aromatase inhibitor: aminoglutethimide, anastrazoleThe Long Road of a New MedicineThe Mai

19、n Step of Anticancer Drug Research wNon-clinical Research：1.Anticancer Drug Screen: in vitro：tumor cell culture, tumor inhibitor/kill test in vivo：2. Pharmacodynamics, pharmacokinetics and toxicology testThe Main Step of Anticancer Drug Researchw Clinical Research: Phase 1 clinical trial Phase 2 cli

20、nical trial Phase 3 clinical trial Phase 4 clinical trialThe Main Step of Anticancer Drug ResearchPhase 1 clinical trial In Phase 1 clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, a

21、nd identify side effects. TOLERANCE PHARMACOKINETICSThe Main Step of Anticancer Drug ResearchPhase 2 clinical trialIn Phase 2 clinical trials, the study drug or treatment is given to a larger group of people (40-100) to see if it is effective and to further evaluate its safety.The Main Step of Antic

22、ancer Drug ResearchPhase 3 clinical trialIn Phase 3 studies, the study drug or treatment is given to large groups of people (more than 200) to further determine its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatm

23、ent to be used safely.The Main Step of Anticancer Drug ResearchPhase 4 clinical trial Phase 4 studies are done after the drug or treatment has been marketed. These studies continue testing the study drug or treatment to collect information about their effect in various populations and any side effec

24、ts associated with long-term use. Anticancer Drugsw Alkylating Agentw Antimetabolitew Antibioticsw Alkaloid w Hormonesw Others（cis-platinum，carboplatin，lobaplatin）Alkylating Agentsw One of the frightening developments of World War I was the introduction of chemical warfare. These compounds were know

25、n as the nitrogen mustard gases. The nitrogen mustards were observed to inhibit cell growth, especially of bone marrow. Shortly after the war, these compounds were investigated and shown to inhibit the growth of cancer cells.Alkylating AgentsMechanism of Actionw Nitrogen mustards inhibit cell reprod

26、uction by binding irreversibly with the nucleic acids (DNA). The specific type of chemical bonding involved is alkylation. After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and other essential cell metabolites. Consequently, cell reproduction is inhibited a

27、nd the cell eventually dies from the inability to maintain its metabolic functions.Classification of Alkylating AgentsuBis Chloroethyl Amines： Cyclophosphamide, Chlormethine, Chlorambucil, SarcolysineuNithrosoureas： Carmustine，LomustineuEthyeneammonium or Aziridines： Thiotepa，triethylene melamine uA

28、lkysulfonates：BusulfanResistance of Alkylating Agents Resistance to alkylating agents has several causes: uMembrane transport may be decreased.uThe drug may be bound by glutathione (GSH) via GSH-S-transferase or metallothioneins in the cytoplasm and inactivated.uThe drug may be metabolized to inacti

29、ve species.Adverse Effects of Alkylating Agentsw Myelosuppression is the dose-limiting adverse effect for alkylating agents.w Nausea and vomiting are common as are teratogenesis and gonadal atrophy, although in the latter cases these are variable, according to the drug, its schedule, and route of ad

30、ministration.w Treatment also carries a major risk of leukemogenesis and carcinogenesis.Alkylating AgentsMustinew Mustine must be injected intravenously because it is highly reactive. It disappears very rapidly from the blood, the activity of Mustine lasts only a few minutes.w The main indication fo

31、r Mustine is in treatment of Hodgkins disease and lymphomas, but it may also be useful in other malignancies.Alkylating Agents CyclophosphamideCyclophosphamide can also be given orally.Indications：uIt is used in the treatment of chronic lymphocyctic leukemia, non-Hodgkins lymphomas, breast and ovari

32、an cancer, and a variety of other cancers.uIt is also a potent immunosuppressant, it is used in the management of rheumatoid disorders and autoimmune nephritis.Adverse Effects:uAlopecia, nausea, vomiting, myelosuppression, and hemorrhagic cystitis.Alkylating AgentsNitrosoureasCarmustine, Lomustine,

33、SemustinePharmacokinetics:w Nitrosoureas are highly lipophilic and reach cerebrospinal fluid concentrations that are about 30% of plasma concentrations.Indications:w Because of their excellent CNS penetration, carmustine and lomustine have been used to treat brain tumors.Alkylating Agents Phenylalan

34、ine Nitrogen Mustardw Melphalan is a nitrogen mustard that is primarily used to treat multiple myeloma (plasma cell myeloma), breast cancer, and ovarian cancer.Alkylating Agents AlkysulfonatesBusulfan MyleranIndications:w Busulfan is administered orally to treat chroic granulocytic leukemia and othe

35、r myeloproliferative disorders.Adverse Effects:w Busulfan produces advers effects related to myelosuppression. It only occasionally produces nausea and vomitting. In high doses, it produces a rare but sometimes fatal pulmonary fibrosis, ”busulfan lung”.Alkylating AgentsThiotepa Thiotepa is converted

36、 rapidly by liver mixed-function oxidases to its active metabolite triethylenephosphoramide (TEPA); it is active in bladder cancer.AntimetabolitesGeneral Characteristics：Antimetabolites are S phase-specific drugs that are structural analogues of essential metabolites and that interfere with DNA synt

37、hesis.Myelosuppression is the dose-limiting toxicity for all drugs in this class.Classification of Antimetabolitesu Folic acid Antagonists: MTXu Purine Antagonists: 6MP 6TGu Pyrimidine Antagonists：5FU araC HUAntimetabolitesFolic Acid AntagonistMethotrexate （MTX）Mechanism of Action： The structures of

38、 MTX and folic acid are similar. MTX is actively transported into mammalian cells and inhibits dihydrofolate reductase, the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis.AntimetabolitesFolic Acid AntagonistMethotrexate （MTX）Indi

39、cations：w The use of MTX in the treatment of choriocarinoma, a trophoblastic tumor, was the first demonstration of curative chemotherapy.w It is especially effective for treating acute lymphocytic leukemia and for treating the meningeal metastases of a wide range of tumors.AntimetabolitesFolic Acid

40、Antagonist Methotrexate （MTX）Adverse Effects：uMTX is myelosuppressive, producing severe leukopenia, bone marrow aplasia, and thrombocytopenia.uThis agent may produce severe gastrointestinal disturbances.uRenal toxicity may occur because of precipitation (crystalluria) of the 7-OH metabolite of MTX.

41、AntimetabolitesPurine Antagonists6-Mercapapurine（6-MP） The drugs are believed to act similarly to inhibit purine base synthesis, although their exact mechanisms of action are still uncertain.Indications:w Mercaptopurine is used primarily for the maintenance of remission in patients with acute lympho

42、cytic leukemia and is given in combination with MTX for this purpose.Adverse Effects:w Well tolerate.w Myelosuppression is generally mild with thioguanine.Long-term mercaptopurine use may cause hepatotoxicity. AntimetabolitesPyrimidine Antagonists5-Fluorouracil (5-FU)Mechanism of Action：w Fluorourac

43、il is an analogue of thymine in which the methyl group is replaced by a fluorine atom. It has two active metabolites: 5-FdUMP and 5-FdUTP. 5-FdUMP inhibits thymidylate synthetases and prevents the synthesis of thymidine, a major building block of DNA. 5-FdUTP is incorporated into RNA by RNA polymera

44、se and interferes with RNA function.AntimetabolitesPyrimidine Antagonists5-Fluorouracil (5-FU)Indications：w Fluorouracil is exclusively used to treat solid tumors, especially breast, colorectal, and gastric tumors and squamous cell tumors of the head and neck.AntimetabolitesPyrimidine Antagonists5-F

45、luorouracil (5-FU)Adverse Effects：w Fluorouracil may cause nausea and vomiting, myelosuppression, and oral and gastrointestinal ulceration. Nausea and vomitting are usually mild.w With fluorouracil, myelosuppression is more problematic after bolus injections, whereas mucosal damage is dose-limiting

46、with continuous infusions.AntimetabolitesPyrimidine AntagonistsCytarabineIndications：w Cytarabine has a narrow clinical spectrum and is primarily used in combination with daunorubicin or thioguanine for the treatment of acute nonlymphocytic leukemia.Adverse Effects:w High doses of cytarabine can dam

47、age the liver, heart, and other organs. Classification of Antibiotics:w Adriamycin (Anthracyaline Antibiotics) w Mitomycin C w Bleomycinw Actinomycin DAdriamycin and Daunorubicin：Properties:w Adriamycin and Daunorubicin are tetracycline rings with the sugar daunosamine. They are DNA intercalating ag

48、ents that block the synthesis of DNA and RNA.w These agents are primarily toxic during the S phase of cell cycle.w These agents imparts a red tinge to the urine.w Adramycin is used to treat acute leukemias, lymphoma, and a number of solid tumors. Mitomycin C:Mechanism:w Mitomycin C is an antineoplas

49、tic antibiotic that alkylates DNA and thereby causes strand breakage and inhibition of DNA synthesis.Indications:w It is primarily used in combination with vinvristine as salvage therapy for breast cancer.Adverse Effects:w Mitomycin produces delays and prolonged myelosuppression that preferentially

50、affects platelets and leukocytes.Actinomycin D:w Actinomycin D intercalates DNA and thereby prevents DNA transcription and messenger RNA synthesis.w The drug is given intravenously, and its clinical use is limited to the treatment of trophoblastic (gestational) tumors and the treatment of pediatric

51、tumors, such as Wilms tumor and Ewings sarcoma.Bleomycin:Mechanism:w The drug has its greatest effect on neoplastic cell in the G2 phase of the cell replication cycle.Although bleomycin intercalates DNA, the major cytotoxicity is believed to result from ironcatalyzed free radical formation and DNA s

52、trand breakage.Indications:w It is useful in Hodgkins and non-Hodgkins lymphomas, testicular cancer, and several other solid tumors.Adverse Effects:w Bleomycin produces very little myelosuppression. The most serious toxicities of Bleomycin are pulmonary and mucocutaneous reactions.Anti-Cancer Plant

53、Allaloidsw Tubulin-Binding Agents Vinca Alkaloids: The cellular mechanism of action of vinca alkaloids is the prevention of microtubule assembly, causing cells to arrest in the late G2 phase by preventing formation of mitotic filaments for nuclear and cell division.Anti-Cancer Plant Allaloidsw Tubul

54、in-Binding Agentsw Vinca alkaloids: Vinblastine,vincristin, vindesine and vinorelbine are all alkaloids derived from the periwinkle plant (Vinca rosea).Indications:w Vinblastine is used in combination with Bleomycin and Cisplatin for metastatic testicular tumors.w Vincristine is used in combination

55、with prednisone to induce remission in childhood leukemia.w Vinorelbine is used to treat non-small-cell lung cancer and breast cancer.Anti-Cancer Plant Allaloidsw Tubulin-Binding Agentsw Paclitaxel: Taxanes enhance all aspects of tubulin polymerization, an action that is the opposite to that of vinc

56、a alkaloids, but they are also cytotoxic, emphasizing the dynamic importance of tubulin polymerization as a target for cytotoxic drugs. Paclitaxel, Taxoterew Interfere the Function of Ribosome:w Cephalotaxus Alkaloids : Harringtonine HomoharringtonineAnti-Cancer Plant AllaloidsPlatinum CompoundCispl

57、atin:Mechanism of Action:w Cisplatin binds to guanine in DNA and RNA, and the interaction is stabilized by hydrogen bonding. The molecular mechanism of action is unwinding and shortening of the DNA helix.Platinum CompoundCisplatin:Indications:w Cisplatin has efficacy against a wide range of neoplasm

58、s. It is given intravenously as a first-line drug for testicular, ovarian, and bladder cancer, and it is also useful in the treatment of melanoma and a number of other soild tumors.Adverse Effect:w Cisplatin produces relatively little myelosuppression but can cause severe nausea, vomiting, and nephr

59、otoxicity.Platinum CompoundCarboplatin:Indication:w Carboplatin has a similar spectrum of activity, but it is approved only as a second-line drug for ovarian cancer.Hormonesw Several types of hormone-dependent cancer (especially breast, prostate, and endometrial cancer) respond to treatment with the

60、ir corresponding hormone antagonists.w Estrogen antagonists are primarily used in the treatment of breast cancer, whereas androgen antagonists are used in the treatment of prostate cancer. Corticosteroids are particularly useful in treating lymphocytic leukemias and lymphomas.HormonesEstrogens:w Est