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1、抗癌药抗癌药（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.OverviewIntroductionwCancer occurs after normal cells have been tran
2、sformed 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 in the i
3、nvasion of previously unaffected organs,a process called metastasis.Advances in Cancer Chemotherapy Treatment options of cancer:wSurgery:before 1955wRadiotherapy:19551965wChemotherapy:after 1965wImmunotherapy and Gene therapyAdvances in Cancer ChemotherapyThe treatment of a patient with cancer may a
4、im to:wgive palliation,for example prompt relief of unpleasant symptoms such as superior vena cava obstruction from a mediastinal tumorwinduce remission so that all macroscopic and microscopic features of the cancer disappear,though disease is known to persistwcure,for which all the cells of the clo
5、ne must be destroyed.Cancer Chemotherapy Disease Name 5 Years Survival RatewChildhood Acute Lymphoblastic Leukemia 5080%wAdult Acute Lymphoblastic Leukemia 2060%wChildhood Acute Myeloblastic Leukemia 2060%wAdult Acute Myeloblastic Leukemia 1020%wBreast Cancer（Premenopausal）1020%wBreast Cancer（Postme
6、nopausal）015%wHodgkin s lymphoma*4080%Cancer ChemotherapyDisease Name 5 Years Survival RatewSmall Cell Lung Cancer（Limited Stage）1020%w （Extensive Stage）05%wNon-Hodgkin s lymphoma*4065%wOvarian Cancer 4060%wChildren Solid Tumor(Nephroblastoma,Rhabdomyosarcoma,Lymphoma，Osteosarcoma）*6090%wTrophoblast
7、oma（Chorion Epithelioma）*8090%wSeminoma of Testis*6090%wEmbryonic Carcinoma of Testis 6080%Note：*Combination with other therapeutics *Chemotherapy Level of our country is highThe Classification of Anticancer Drugsn nAccording to chemical structure and According to chemical structure and resource of
8、the drug;n nAccording to According to biochemistry mechanisms of anticancer action;nAccording to the cycle or phase specificity of the drug The Classification of Anticancer Drugsn nAccording to chemical structure and According to chemical structure and resource of the drug:Alkylating Agents,Antimeta
9、bolite,Antibiotics,Plant ExtractsAntibiotics,Plant Extracts，Hormones，Others.Others.The Classification of Anticancer DrugsAccording to According to biochemistry mechanisms of anticancer action:Block Block nucleic acid biosynthesisDirect influence the structure and function of the structure and functi
10、on of DNADNAInterfere transcription and block RNA synthesis Interfere protein synthesis and functionInfluence hormone homeostasisOthersThe Classification of Anticancer DrugsnAccording to the cycle or phase specificity of the drug:Cell cycle nonspecific agents(CCNSA)Cell cycle specific agents(CCSA)Th
11、e Basic Concept of Cell Generation CyclewThe 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)GFProliferating cell groupProliferating cell groupTotal tumor cell groupTotal tumor
12、cell groupCCNSACCNSA：drugs that are active drugs that are active throughout the cell cycle.throughout the cell cycle.CCSA:CCSA:drugs that act during a specific drugs that act during a specific phase of the cell cycle.phase of the cell cycle.CCSA and CCNSAuCell Cycle Nonspecific Agents(CCNSA)drugs th
13、at are active throughout the cell drugs that are active throughout the cell cyclecycle p Alkylating Agentsp Platinum Compoundspp Antibiotics Antibiotics uCell Cycle Specific Agents(CCSA)drugs drugs that that act act during during a a specific specific phase phase of of the cell cyclethe cell cycle S
14、 Phase Specific Drug:Aantimetabolites,Topoisomerase Inhabitors M Phase Specific Drug:Vinca Alkaloids,Taxanes G2 Phase Specific Drug:BbleomycinCCSA and CCNSAMechanism of Anticancer DrugswBlock nucleic acid(DNA,RNA)biosynthesiswDirectly destroy DNA and inhibit DNA reproductionwInterfere transcription
15、and block RNA synthesiswInterfere protein synthesis and functionwInfluence hormone homeostasisBlock Nucleic Acid(DNA,RNA)BiosynthesisAntimetabolites:wFolic Acid Antagonist:inhibit dihydrofolate reductase(methotrexate)wPyrimidine Antagonist:inhibit thymidylate synthetase(fluorouracil);inhibit DNA pol
16、ymerase(cytarabine)wPurine Antagonist:inhibit interconversion of purine nucleotide(mercaptopurine)wRibonucleoside Diphosphate Reductase Antagonist:(hydroxyurea)Interfere Protein Synthesis wAntitubulin:vinca alkaloids and taxanes;wInterfere the function of ribosome:harringtonines；wInfluence amino aci
17、d supply:L-asparaginase Bind tubulin,destroy spindle to produce mitotic arrest.Interfere Transcription and Block RNA SynthesiswBind with DNA to block RNA production.doxorubicinInfluence the Structure and Function of DNAwAlkylating Agent:mechlorethamine,cyclophosphamide and thiotepawPlatinum:cis-plat
18、iniumwAntibiotic:bleomycin and mitomycin CwTopoismerase inhibitor:camptothecine and podophyllotoxin Influence Hormone Homeostasis These drugs bind to hormone receptors to block the actions of the sex hormones which results in inhibition of tumor growth.wEstrogens and estrogen antagonistic drugwAndro
19、gens and androgen antagonistic drugwProgestogen drugwGlucocorticoid drugwgonadotropin-releasing hormone inhibitor:leuprolide,goserelinwaromatase inhibitor:aminoglutethimide,anastrazoleThe Long Road of a New MedicineThe Main Step of Anticancer Drug Research wNon-clinical Research：1.Anticancer Drug Sc
20、reen:in vitro：tumor cell culture,tumor inhibitor/kill test in vivo：animal xenograft model e.g.Ehrlich ascites tumor,S180 lymphosarcoma2.Pharmacodynamics,pharmacokinetics and toxicology testThe Main Step of Anticancer Drug ResearchwClinical Research:Phase 1 clinical trial Phase 2 clinical trial Phase
21、 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,and identify side effec
22、ts.TOLERANCEPHARMACOKINETICSThe 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 Anticancer Drug ResearchPhase 3
23、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 treatment to be used safely.The Main St
24、ep 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 effects associated with long-term use.A
25、nticancer DrugswAlkylating AgentwAntimetabolitewAntibioticswAlkaloid wHormoneswOthers（cis-platinum，carboplatin，lobaplatin）Alkylating AgentswOne of the frightening developments of World War I was the introduction of chemical warfare.These compounds were known as the nitrogen mustard gases.The nitroge
26、n 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 ActionwNitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic
27、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 and the cell eventually dies from the inability to main
28、tain its metabolic functions.Classification of Alkylating AgentsuBis Chloroethyl Amines：Cyclophosphamide,Chlormethine,Chlorambucil,SarcolysineuNithrosoureas：Carmustine，LomustineuEthyeneammonium or Aziridines：Thiotepa，triethylene melamine uAlkysulfonates：BusulfanResistance of Alkylating Agents Resist
29、ance 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 inactive species.Adverse Effects of Alkylating AgentswMyelosuppressio
30、n is the dose-limiting adverse effect for alkylating agents.wNausea 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 administration.wTreatment also carries a major risk of leukemogenesis a
31、nd carcinogenesis.Alkylating AgentsMustinewMustine 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.wThe main indication for Mustine is in treatment of Hodgkins disease and lymphomas,but it may als
32、o 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 ovarian cancer,and a variety of other cancers.uIt is also a potent immunosuppressa
33、nt,it is used in the management of rheumatoid disorders and autoimmune nephritis.Adverse Effects:uAlopecia,nausea,vomiting,myelosuppression,and hemorrhagic cystitis.Alkylating AgentsNitrosoureasCarmustine,Lomustine,SemustinePharmacokinetics:wNitrosoureas are highly lipophilic and reach cerebrospinal
34、 fluid concentrations that are about 30%of plasma concentrations.Indications:wBecause of their excellent CNS penetration,carmustine and lomustine have been used to treat brain tumors.Alkylating Agents Phenylalanine Nitrogen MustardwMelphalan is a nitrogen mustard that is primarily used to treat mult
35、iple myeloma(plasma cell myeloma),breast cancer,and ovarian cancer.Alkylating Agents AlkysulfonatesBusulfan MyleranIndications:wBusulfan is administered orally to treat chroic granulocytic leukemia and other myeloproliferative disorders.Adverse Effects:wBusulfan produces advers effects related to my
36、elosuppression.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 rapidly by liver mixed-function oxidases to its active metabolite triethylenephosphoramide(TEPA);i
37、t 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 synthesis.Myelosuppression is the dose-limiting toxicity for all drugs in this class.Classification of An
38、timetabolitesu Folic acid Antagonists:MTXu Purine Antagonists:6MP 6TGu Pyrimidine Antagonists：5FU araC HUAntimetabolitesFolic Acid AntagonistMethotrexate（MTX）Mechanism of Action：The structures of MTX and folic acid are similar.MTX is actively transported into mammalian cells and inhibits dihydrofola
39、te reductase,the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis.AntimetabolitesFolic Acid AntagonistMethotrexate（MTX）Indications：wThe use of MTX in the treatment of choriocarinoma,a trophoblastic tumor,was the first demonstration
40、 of curative chemotherapy.wIt is especially effective for treating acute lymphocytic leukemia and for treating the meningeal metastases of a wide range of tumors.AntimetabolitesFolic Acid Antagonist Methotrexate（MTX）Adverse Effects：uMTX is myelosuppressive,producing severe leukopenia,bone marrow apl
41、asia,and thrombocytopenia.uThis agent may produce severe gastrointestinal disturbances.uRenal toxicity may occur because of precipitation(crystalluria)of the 7-OH metabolite of MTX.AntimetabolitesPurine Antagonists6-Mercapapurine（6-MP）The drugs are believed to act similarly to inhibit purine base sy
42、nthesis,although their exact mechanisms of action are still uncertain.Indications:wMercaptopurine is used primarily for the maintenance of remission in patients with acute lymphocytic leukemia and is given in combination with MTX for this purpose.Adverse Effects:wWell tolerate.wMyelosuppression is g
43、enerally mild with thioguanine.Long-term mercaptopurine use may cause hepatotoxicity.AntimetabolitesPyrimidine Antagonists5-Fluorouracil(5-FU)Mechanism of Action：wFluorouracil is an analogue of thymine in which the methyl group is replaced by a fluorine atom.It has two active metabolites:5-FdUMP and
44、 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 polymerase and interferes with RNA function.AntimetabolitesPyrimidine Antagonists5-Fluorouracil(5-FU)Indications：wFluorouracil is exclusivel
45、y used to treat solid tumors,especially breast,colorectal,and gastric tumors and squamous cell tumors of the head and neck.AntimetabolitesPyrimidine Antagonists5-Fluorouracil(5-FU)Adverse Effects：wFluorouracil may cause nausea and vomiting,myelosuppression,and oral and gastrointestinal ulceration.Na
46、usea and vomitting are usually mild.wWith fluorouracil,myelosuppression is more problematic after bolus injections,whereas mucosal damage is dose-limiting with continuous infusions.AntimetabolitesPyrimidine AntagonistsCytarabineIndications：wCytarabine has a narrow clinical spectrum and is primarily
47、used in combination with daunorubicin or thioguanine for the treatment of acute nonlymphocytic leukemia.Adverse Effects:wHigh doses of cytarabine can damage the liver,heart,and other organs.AntibioticsClassification of Antibiotics:wAdriamycin(Anthracyaline Antibiotics)wMitomycin C wBleomycinwActinom
48、ycin DAntibioticsAdriamycin and Daunorubicin：Properties:wAdriamycin and Daunorubicin are tetracycline rings with the sugar daunosamine.They are DNA intercalating agents that block the synthesis of DNA and RNA.wThese agents are primarily toxic during the S phase of cell cycle.wThese agents imparts a
49、red tinge to the urine.wAdramycin is used to treat acute leukemias,lymphoma,and a number of solid tumors.AntibioticsMitomycin C:Mechanism:wMitomycin C is an antineoplastic antibiotic that alkylates DNA and thereby causes strand breakage and inhibition of DNA synthesis.Indications:wIt is primarily us
50、ed in combination with vinvristine as salvage therapy for breast cancer.Adverse Effects:wMitomycin produces delays and prolonged myelosuppression that preferentially affects platelets and leukocytes.AntibioticsActinomycin D:wActinomycin D intercalates DNA and thereby prevents DNA transcription and m