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.OverviewIntroductionw Cancer occurs after normal cells have been tra
2、nsformed 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
3、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 with cancer
4、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 the cells of
5、 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）1020%w Breast
6、 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,Rhabdomyosarcoma,Lymphoma，Osteosarcoma
7、）*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 mechanisms of anticancer actionn
8、According 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 influence Interfere transcriptio
9、n and block RNA synthesis Interfere protein synthesis and function Influence hormone homeostasis OthersThe 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 Generati
10、on 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 Specific A
11、gents(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 reproductionw Interfere
12、 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 synthetase(fluorourac
13、il);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 function of ribosome:harringtonin
14、es；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:mechlorethamine,cyclophosphamide and
15、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 inhibition of tumor growth.w Estrogens and es
16、trogen 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 Main Step of Anticancer Drug Research wNon-cli
17、nical Research：1.Anticancer Drug Screen: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 Researchw Clinical Research:Phase 1 clinica
18、l trial Phase 2 clinical 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
19、dosage range,and 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 Ste
20、p of Anticancer 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 tr
21、eatment 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 ef
22、fects 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 kno
23、wn 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 reproduct
24、ion 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 and the ce
25、ll 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 uAlkysulfonates：B
26、usulfanResistance 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 inactive species.Adverse
27、 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 administration.w Treatme
28、nt 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 for Mustine is in treatmen
29、t 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 ovarian cancer,and a variety of
30、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,SemustinePharmacokinetics:w Nitroso
31、ureas 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 Phenylalanine Nitrogen Mustardw Melphalan is a
32、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 other myeloproliferative disorders.Adverse E
33、ffects: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 rapidly by liver mixed-function oxidases to
34、 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 synthesis.Myelosuppression is the dose-limiting to
35、xicity 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 MTX and folic acid are similar.MTX is actively tr
36、ansported 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）Indications：w The use of MTX in the treatment of chorioca
37、rinoma,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 Antagonist Methotrexate（MTX）Adverse Effects：uMTX is mye
38、losuppressive,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.AntimetabolitesPurine Antagonists6-Mercapapurine（6-MP）The drug
39、s 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 lymphocytic leukemia and is given in combination with MTX for this pur
40、pose.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 Fluorouracil is an analogue of thymine in which the methyl group is replaced
41、 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 polymerase and interferes with RNA function.AntimetabolitesPyrimidine Antagonis
42、ts5-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-Fluorouracil(5-FU)Adverse Effects：w Fluorouracil may cause nausea and vomiti
43、ng,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 with continuous infusions.AntimetabolitesPyrimidine AntagonistsCytarabineIndicati
44、ons：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 damage the liver,heart,and other organs.Classification of Antibiotics:w Adriamycin(A
45、nthracyaline 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 agents that block the synthesis of DNA and RNA.w These agents are primarily toxic during
46、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 antineoplastic antibiotic that alkylates DNA and thereby causes strand breakage and inhibition of DNA
47、 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 affects platelets and leukocytes.Actinomycin D:w Actinomycin D intercalates DNA and thereb
48、y 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 tumors,such as Wilms tumor and Ewings sarcoma.Bleomycin:Mechanism:w The drug has its greatest
49、 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 strand breakage.Indications:w It is useful in Hodgkins and non-Hodgkins lymphomas,testicular can
50、cer,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 Allaloidsw Tubulin-Binding Agents Vinca Alkaloids:The cellular mechanism of action of vinca alkalo
